IJCNMH ARCpublishing
ADVANCED SEARCH


Thumb_issue_cover._2016.3.sp1.cony.border.1280

Issue 3 (2016) – Supplement 1


Special Issue on Controversies in Neurology

This supplemental issue comprises the abstracts and proceedings from the 10th World Congress on Controversies in Neurology (CONy), Lisbon, Portugal. 17–20 March 2016.

Guest editors:
Amos D. Korczyn, Tel Aviv, Israel
Elsa Azevedo, Porto, Portugal

Issue Nr:

3

|    Issue date: 2016-03-16

Lecture


Egas Moniz: the man and his work - read full article

By: Victor Oliveira

Egas Moniz was a Portuguese neurologist (1874-1955) with a multivariate scope of interests and remarkable interventions in Portuguese society: formerly as politician and later as physician, investigator and writer. Internationally he is recognized after his contributions to the advance of medicine. He was the founder of Portuguese Neurology and gained international recognition because of the development of cerebral angiography and later, because the surgical attempt to treat some psychiatric diseases: the so called Leucotomy. He was awarded with Noble Prize in 1949 shared with the Swiss psychologist Walter Hess. Egas Moniz was graduated at the University of Coimbra 1899 and begun his carrier in 1900 joining an academic position at that University of Coimbra with a place at the Portuguese monarch parliament. Soon after (1902) he directed his curiosity to Neurology and during his summer holidays he was able to spare a couple of weeks to visit La Salpétrière were some members of the golden era of the French and world neurology worked, such as Babinski who became close friend of him. After quitting a delusive political career where he was minister of foreign affairs and president of the Portuguese delegation to the peace conference at Versailles “with more sorrows than good remembrances” as he used to say, he dedicated his whole energies to medicine and the scientific talent of Egas Moniz was revealed. Angiography. The knowledge of brain circulation and though this, the brain pathology, namely tumors and other intracranial abnormalities along with cerebrovascular pathology became possible after his discovery in 1927 which is still performed everyday in large hospitals worldwide. Vascular structures like carotid siphon owe its name after him. Leucotomy. In an era of no effective treatment for psychiatric diseases forcing many patients to remain institutionalized for live, the idea of a surgical procedure to calm agitated patients allowing them to return to community was attractive. His experimental attempts by causing small lesions in both frontal lobes showed promising results. Driving these experimental ideas into an unwise massive practice as Walter Freeman in USA, did, (the so called lobotomy) launched much controversy and discredit. Egas Moniz never performed any of these procedures (either angiography or leucotomy): he was a man of ideas and as he used to say: he was the brain and his surgical colleagues, their hands. After retirement in 1945 he dedicated to writing and his private practice at downtown Lisbon. He received many international awards in recognition of his role in the development of Medicine, including the Noble prize in 1949. He died in Lisbon in December 1955 at 81 years of age.

Special Issue on Controversies in Neurology. From the 10th World Congress on Controversies in Neurology (CONy), Lisbon, Portugal. 17–20 March 2016.

International Journal of Clinical Neurosciences and Mental Health 2016; 3(Suppl. 1):L1

Icon_pdf Download PDF

Lecture


Trinucleotide repeats - read full article

By: Sandra Macedo-Ribeiro

Trinucleotide repeat (TNR) expansions are present in a wide range of genes involved in several neurological disorders, being directly involved in the molecular mechanisms underlying pathogenesis. The molecular mechanisms that correlate TNR expansions with disease are multifactorial and divergent depending on the affected gene. In fact variations in TNR can alter either gene expression and/or the function of the RNA or protein it encodes. This talk will present an overview of TNRs, with a particular emphasis on CAG repeat expansions that are translated into polyQ repeats in the affected proteins. Detail will be given to the interplay between polyQ repeat expansions and flanking regions in modulating the protein dynamics, self-assembly and aggregation of the carrier protein, which culminates in neuronal toxicity and cell death.

Special Issue on Controversies in Neurology. From the 10th World Congress on Controversies in Neurology (CONy), Lisbon, Portugal. 17–20 March 2016.

International Journal of Clinical Neurosciences and Mental Health 2016; 3(Suppl. 1):L2

Icon_pdf Download PDF

Lecture


Hysteria, simulation and functional disorders: from Charcot to Charcot - read full article

By: Julien Bogousslavsky

Jean-Martin Charcot (1825-1893) is at the origin of the modern “rebirth” of concepts on hysteria and related functional disorders. While Charcot never was interested in mental disease and what was called “alienism” at the time, his career at La Salpêtrière over 30 years was marked by the development of huge group of pupils which gathered around the study and management of hysteria. When Charcot took office at the beginning of 1862, hysteria was a no-man’s-.land, since neither the alienists, nor the internists beared a significant interest on it. At La Salpêtrière, these patients were largely left to themselves, before one of the first Charcot’s interns, Désiré Bourneville, stimulated and convinced his chief to care for them. Charles Richet’s 1875 article on somnambulism subsequently was the trigger for Charcot to introduce hypnotism in the management of hysterics. Later on, the studies of Charcot with Richer, Babinski, Gilles de la Tourette, Sollier, Janet and many others allowed to address the condition in detail. During his short stay with Charcot in 1885-6 Sigmund Freud, a young neuropathologist at the time, became fascinated by hysteria, an interest which was the main start point of his interest in psychology, and probably the origin of psychoanalysis a few years later. Charcot indeed emphasized mental – including “sexual - factors in hysteria long before Freud, along with the concept of a “dynamic” lesion, which accounted for the lack of neuropathological findings in all studies. While Charcot’s concepts on hysteria and hypnotism were criticized after his death even by former pupils, such as Babinski, recent findings from functional MRI studies show how accurate and often visionary Charcot’s thinking was in this field. In 1908, a “quarrel of hysteria” opposed several Charcot’s pupils, where Babinski was considered victorious against Charcot’s successor Raymond, despite the weaknesses of his theory on “pithiatism” (i.e.“curable by persuasion”), which erased the border between hysteria and simulation. During World War I, there was a new surge of interest in hysteria associated with war psycho-neuroses, and several students of Charcot became involved in medical-military care (Sollier, Babinski, Ballet, Souques). Babinski’s pupil Clovis Vincent developed a treatment called torpillage (torpedoing) against war hysteria, associating painful galvanic current discharges with “persuasion”, but which was dismissed after the rebellion of soldiers, who considered it as torture. After World War I, the neurological and psychiatric interest in hysteria again faded away, and this condition largely went back to the neither neurological nor psychiatric no-man’s land, where it had been before Charcot. Today, the boomerang thrown by Charcot is rightfully coming back, since current studies support most of his observations and theories, with reference to differences and similarities between hysteria, hypnotism, simulation, and organic dysfunction.

Special Issue on Controversies in Neurology. From the 10th World Congress on Controversies in Neurology (CONy), Lisbon, Portugal. 17–20 March 2016.

International Journal of Clinical Neurosciences and Mental Health 2016; 3(Suppl. 1):L3

Icon_pdf Download PDF

Lecture


Exosomes/miRNA as nano-neurological therapy mediate recovery after stroke and neural injury - read full article

By: Michael Chopp

The ability to regulate and modulate intercellular communication may provide the basis for the treatment of neurological injury, neurodegenerative diseases and stroke. Exosomes are small (30-100 nm) endosomal generated particles consisting of a complex lipid membrane and contain proteins, RNAs,mRNAs and microRNAs (miRNAs). Nearly all cells generate exosomes, and these small lipid containers are ubiquitous in biological systems and provide an intercellular communications network which regulate cellular function. Exosomes mediate intercellular communication by transferring proteins, lipids, and genomic materials including mRNAs and miRNAs between source and target cells. In this presentation, I will describe our work on the treatment of stroke, traumatic brain injury and diabetic peripheral neuropathy with exosomes, with a focus on the transfer of microRNA (miRNA) content within the exosomes to recipient cells. miRNAs are 20-25 nucleotide non coding RNA which regulate gene translation . They act as major molecular switches and are post transcriptional regulators of protein production, and they can simultaneously impact multiple molecular pathways and signaling within cells. We have found that cell-based therapies promote neurological recovery and promote neurovascular remodeling by transferring exosomes to recipient cells. Thus, we have harvested exosomes by means of ultracentrifugation or using biochemical methods from a variety of cells, and directly employed these exosomes by intravenous administration for stroke and TBI to promote neurological recovery . By labeling the exosomes with fluorescent markers we have shown that intravascular administration of these exosomes pass the blood brain barrier and enter into parenchyma cells. The content of these exosomes , as noted , consists of proteins, miRs and mRNAs. Downstream molecular targets of specific miRs known to be transferred into parenchyma cells have been shown to affect their molecular targets, thus demonstrating that the harvested exosomes transfer miRs to parenchyma cells and thereby affect the molecular downstream targets. In vitro studies using microfluidic chambers can be employed to give insight into how exosomes promote neurological recovery. Microfluidic chambers are compartmental structures where neuronal soma and axons are located in separate compartments. The microfluidic device permits distal axons to grow into the axonal compartment after passing 450?m long microgrooves that connect the cell body and axonal compartments. We demonstrate that exosomes placed either on the somal or the axonal compartment significantly promote axonal outgrowth. This exosome enhanced outgrowth can also be inhibited by using siRNA to block Argonaut proteins, such as Ago2. Ago2 protein is a component of the RNA induced silencing complex (RISC), and is the key regulator of miRNA function by mediating the activity of miRNA-guided mRNA cleavage or translational inhibition. The majority of miRNAs in exosomes are bound to Ago2. Reduction of Ago2 in exosomes abolishes axonal outgrowth. Very importantly, the content of exosomes can be tailored to contain specific miRNAs. By transfecting exosomes source cells with specific genes or using siRNA on exosomal parental source cells, we can respectively, upregulate or reduce miRNA content within exosomes derived from parental cells. Using microfluidic chambers and vascular angiogenic experiments we demonstrated that targeting specific miRs will impact specific physiological events. For example, when parental mesenchymal stromal cells (MSCs) were transfected with a miR-17-92 cluster plasmid, exosomes harvested from the MSCs exhibited enriched levels of the miR-17-92 cluster. Applying these exosomes to either the somal or axonal compartments of the microfluidic chamber significantly increased neurite outgrowth. Thus, tailored exosomes can deliver their selective cargo miRNAs into and activate their target signals in recipient neurons. We have performed extensive preclinical studies on the therapeutic use of exosomes for stroke, traumatic brain injury, diabetic peripheral neuropathy, multiple sclerosis and dementia. For example , our data demonstrate that treatment of embolic stroke with exosomes derived from MSCs or other progenitor cells one or more days after stroke onset significantly promotes neurological recovery compared to control populations. Treatment with exosomes also concomitantly enhanced neurovascular plasticity, promoted neurogenesis, angiogenesis, and oligodendrogenesis. Similarly, treatments of experimental traumatic brain injury, peripheral neuropathy, and neurodegenerative models using exosomes harvested from a variety of cells, as well as harvested exosomes tailored to contain specific miRs, were shown to enhance neurological recovery along with neurovascular plasticity. Thus, we are developing a novel therapy, nano-neurological therapy, utilizing the body`s nano-lipid containers, exosomes, which contain and can be loaded with proteins, miRs and genetic instructions , to promote neurological recovery.

Special Issue on Controversies in Neurology. From the 10th World Congress on Controversies in Neurology (CONy), Lisbon, Portugal. 17–20 March 2016.

International Journal of Clinical Neurosciences and Mental Health 2016; 3(Suppl. 1):L4

Icon_pdf Download PDF

Lecture


Post-stroke cerebral reorganization - read full article

By: J.P. Mohr

In 1898 the Scottish neurologist Byron Bramwell described “A Unusual Case of Aphasia” an autopsy-documented infarct affecting Broca’s area in the hemisphere dominant for speech and language. His case had aphasic syndrome of brief duration. Few examples were reported prior to 1973. Thereafter, the short clinical course has become well-recognized, especially with modern brain imaging. At first considered exception to the rule, then as examples that Broca aphasia is less important than the Wernicke syndrome, criticisms have slowly faded as a similar short-lived syndrome can occur from focal infarcts for Wernicke aphasia as well. Sensory and motor syndromes from circumscribed infarcts are also now well-known. In large clinical trials the sensory component frequently has a short clinical course. Focal motor syndromes may present with a functionless limb, appearing normal on examination weeks later. For larger Rolandic infarcts or from war wounds, the classical syndrome of dystonic hemiparesis slowly emerges regardless of whether the injury is high or low in the rolandic system. These disparities in outcomes suggest a certain layering function in the Rolandic motor system, the major injuries allowing more primitive motor function to emerge, the perilesional functions or functional reorganization being prevented by the large size of the injury. By hemispheral functional magnetic resonance imaging of unilateral rolandic infarcts provides further support for perilesional activation: a focus of activation predicts functional improvement within 30 days in some patients; why only in some remains unknown. Arguments still exist whether focal infarction in the calcarine cortex itself can be associated with improvement in the visual fields, but there is little argument that a short clinical course may follow anopia from precuneus infarction. The classical disconnection model for alexia now seems established as a volumetric effect, by disruptions of trans-callosal and ipsi-hemispheral pathways. Formerly-acceptable simplistic explanations of peri-lesional edema may have been satisfactory when autopsy documentation was the limited data source. But high-quality modern imaging now also prevents speculation of extremely superficial cortical infarction, or absence of penetration of the lesion into the white matter. In retrospect many of von Monakow’s cases described as ‘diaschisis’ were among these syndromes. If by diaschisis he meant disturbance and remote structures from those damaged, he may have underemphasized the importance of functional reorganization tissue surviving a focal infarct. Focal tissue disruption from infarction or trauma is but one model testing functional reorganization: Transcranial magnetic stimulation maps of Rolandic convexity areas serving a limb to be surgically excised has demonstrated the area post-surgery to have shifted its function serve adjacent body parts. Ingenious studies of local limb anesthesia from arterial blood pressure cuff causing temporary ischemia has demonstrated the cortical reorganization begins almost immediately, and re-establishes its prior organization after blood flow is restored and the anesthesia fades. Not merely perilesional function, but regional cerebral blood flow (rCBF) alterations may create the appearance of focal syndromes. Infarcts in the capsular genu has interrupted neurotransmitter pathways important for frontal lobe responses, creating a blunting of behavior characterized as “strategic infarct dementia”. A dysphasic syndrome has also occurred from pulvinar infarction, blunting rCBF responses over the ipsilateral parietal lobe. For many generations, clinicians have been taking credit for the improvement following focal lesions, assuming it related to our interventional efforts. More attention to the occurrence of what appeared to be compensatory mechanisms could allow insights into their control and augmentation. We could take our inspiration from the knowledge by designers of Voyager 2, allowing them to reprogram some of the hardware with the spacecraft well beyond Pluto. We can look forward to the day when we may achieve similar restoration of performances to allow the brain to achieve its maximum potential after focal injury.

Special Issue on Controversies in Neurology. From the 10th World Congress on Controversies in Neurology (CONy), Lisbon, Portugal. 17–20 March 2016.

International Journal of Clinical Neurosciences and Mental Health 2016; 3(Suppl. 1):L5

Icon_pdf Download PDF

Lecture


The meeting of informatics with brain medicine: a vision for the future from the perspective of the human brain project - read full article

By: Richard Frackowiak

We now know that a single human gene mutation may present with any of multiple phenotypes, and vice versa, that a range of genetic abnormalities may cause a single disease phenotype. These observations lead to the conclusion that a deeper understanding is needed of the way changes at one spatial or temporal level of brain organisation integrate and translate into others, eventually resulting in behaviour and cognition or their abnormalities. The basic idea is that it is now possible to look for rules underlying the functional and structural organisation of the human brain, exhaustively, at all spatial scales, and eventually perhaps at all spatio-temporal scales. The methodological approach is to federate and integrate existing knowledge from bottom up using recent advances in information technologies, notably supercomputing and distributed and interactive data basing. The theory is that rules and constraints determining a particular structural and functional organisation at one level will limit what organisational principles are possible at the next. It has, for example, been shown that one can construct in silico models that look and behave remarkably like their ex vivo counterparts, up to the level of the cortical mini-column. The ambition therefore is to link genetic and proteomic levels by determining the rules that govern the segregation of protein expression. From protein expression we can start to extract rules that determine cellular morphology, which in turn predicts connectivity, and so on, until the mechanisms of emergent properties are discovered by a constructive process of reconstruction and predictive simulation, not as isolated modules but as interacting biological entities. Materials scientists discovered that the apparent simplicity of matter emerges from complex statistical combinations of subatomic particles and waves and have generated a rich theory to situate and interpret all new experimental results. They have done so by means of systematic deconstruction based on experimental hypothesis refutation—the classical reductionist approach. So it is perhaps unsurprising that in the case of the human brain, a similar approach has generated a mass of knowledge but no overarching theory explaining emergent behaviour. The response of brain scientists has been to generate more knowledge, hoping that a theory will eventually reveal itself. We argue that the degree of complexity represented by organic matter warrants an additional, complementary set of tools—tools that federate, integrate mine and simulate those data, thus discovering new patterns and rules that govern its organisation. The application of such tools is justified, we think, by one simple fact: every organic object, however complex, is generated from just four building blocks, the four base pairs of DNA. The HBP’s goal is to generate a draft blueprint that describes how the brain is constructed across all levels. The blueprint will provide a framework within which new and old theories can be tested and new hypotheses generated. An immediate aim is to create a federation of hospital databases, whilst respecting the imperatives of security and privacy of individuals. To this end the Medical Informatics Platform of the Human Brain Project brings together scientists and engineers from multiple domains including computer science, informatics, statistics, mathematics, clinical science, neurologists, psychiatrists, neuro-imagers and the like. We have specified and built together software that provides an Open Source distributed platform for use by European and other clinician scientists, population health scientists, epidemiologists, health economists and the like. All these and other health care related disciplines should in the long run be able to benefit from the very large, constantly accruing masses of clinical data that reside, currently grossly underused, in hospital databases. The federation will be distributed, eschewing the need for data warehousing and guaranteeing local control of access to data by every hospital, as presently. Another critical medicine-related research aim of the federated platform will be to use big data techniques and algorithms to fill the multi-dimensional brain disease space, which ranges from psychiatry through behavioural disorders to neurological diseases, with groups of like patients characterised by combinations of homogeneous features. We call such a group of specific features a “disease signature”. A disease signature brings together, in a systematic way, clinical features (phenomenology) and the results of genetic, biological, physiological and anatomical test results (biology). This reclassification should in the long-term supplant the symptom and syndrome based DSM and ICD disease catalogues by ones based on the same clinical features supplemented by patterns of abnormal investigations. This strategy has as its primary aim the definition of more precise diagnoses that reduce error variance in diagnostic categories for construction of clinical trial cohorts. A biological underpinning of phenomenological features may in combination with improved understanding of the functional and structural organisation of the human brain emanating from other parts of the Human Brain Project facilitate other aspects of brain medicine, such as identification of biological treatment targets, planning of potential benefits, risks and side effects of proposed treatments, as well as considerable reduction of clinical cohort sizes associated with more precise disease signature based definition of diagnosis and prognosis.

Special Issue on Controversies in Neurology. From the 10th World Congress on Controversies in Neurology (CONy), Lisbon, Portugal. 17–20 March 2016.

International Journal of Clinical Neurosciences and Mental Health 2016; 3(Suppl. 1):L6

Icon_pdf Download PDF

Lecture


Redefining Neurodegenerative Diseases through Epigenetics - read full article

By: Tiago Fleming Outeiro

Neurodegenerative disorders, such as Alzheimer’s (AD) and Parkinson's disease (PD), are highly complex conditions that affect a growing number of patients worldwide, due to the aging of the human population. These disorders have a multifactorial origin, depending not only on genetic but also on environmental factors. Several genetic risk factors have already been associated with both AD and PD, but the precise mechanisms through which the environment contributes to neurodegeneration are still unclear. Recently, epigenetic mechanisms, such as DNA methylation, chromatin remodelling or miRNAs, which induce alterations in gene expression, have been implicated in various neurodegenerative conditions. Given that epigenetic modulation is present from pre-natal stages and throughout life, and that it depends on lifestyle conditions and environmental factors, it might provide new insights into the molecular basis of neurodegeneration, opening novel avenues for therapeutic intervention.

Special Issue on Controversies in Neurology. From the 10th World Congress on Controversies in Neurology (CONy), Lisbon, Portugal. 17–20 March 2016.

International Journal of Clinical Neurosciences and Mental Health 2016; 3(Suppl. 1):L7

Icon_pdf Download PDF

Lecture


Is AD caused by viral infection? - read full article

By: Ruth F. Itzhaki

There are now about 100 experimental studies by several groups (including some 40 or so from RFI's group), using diverse approaches, which explicitly suppor—directly or indirectly—the hypothesis that herpes simplex virus type 1 (HSV1) is involved in AD. HSV1 is a neurotropic virus which infects 80-90% of humans by the age of about 60. Once infected, a person harbours the virus for life. It resides in latent form (i.e., dormant) in the peripheral nervous system (PNS) in the trigeminal ganglia but can reactivate under circumstances such as stress and immunosuppression, and in some 25% of infected people it then causes cold sores (herpes labialis). In very rare cases (~1-3/106), it causes the severe brain disease, herpes simplex encephalitis (HSE) The first relevant study, in 1991, revealed by PCR that HSV1 DNA is present in latent form in a high proportion of elderly brains, including those of AD patients. It was subsequently found that HSV1 in brain of carriers of an APOE-e4 allele confers a major risk of AD. The presence of HSV1 DNA in many elderly normal brains as well as in AD brains does not invalidate a role for HSV1; many microbes infect far more people than they affect, so "controls" might be infected but are asymptomatic; i.e., 'infect' does not necessarily mean 'affect'. Later, studies on intrathecal antibodies in the elderly (which are known to be long-lived after HSE), confirmed viral presence in brain, and showed also that HSV1 reactivation from latency can occur in brain (as well as in the PNS), quite probably recurrently; thus, HSV1 is not just an inert passenger in the aged brain. The main concept is that HSV1 reactivates periodically in brain under certain conditions such as stress, immunosuppression, peripheral infection etc. Reactivation leads to a productive infection, which causes both direct and also inflammatory damage, and viral spread. Repeated reactivation would cause cumulative damage - perhaps a limited, localised type of HSE, culminating in the development of AD in APOE-?4 carriers. (Significantly, APOE-e4 is a risk factor for cold sores.) HSV1 DNA presence in human brains has been confirmed by 5 other groups, another confirmed the HSV1-APOE-?4 association in AD, and yet another showed a trend. Further, studies on HSV1-infected APOE-transgenic mice found that APOE-e4 transgenic animals display a greater potential for viral damage. Diverse approaches—cell biological, genetic, epidemiological and virological—have subsequently been used to investigate the role of HSV1 in AD. These indicate that HSV1 does indeed reactivate in human brain and that it induces AD-type damage. Data on HSV1 DNA in CSF, which remains for only one week post-HSE (unlike long-lived HSV1 antibodies), suggest that reactivation of the virus is far more frequent than expected merely from the frequency of HSE. Other CSF studies have shown that biomarkers of AD are more similar to those of HSE patients than are those of patients with other brain infections. Also, in immunosuppressed leukaemic patients, brain specimens revealed HSV1 DNA in those who were seropositive, but not in those who were seronegative, nor in non-immunosuppresed subjects. HSV1 infection of a wide variety of cells in culture, including human neuronal-type, causes accumulation of beta amyloid (A?) and of abnormally phosphorylated tau (P-tau)—the main components respectively of the characteristic amyloid plaques and neurofibrillary tangles seen in AD brains. The increase in A? probably occurs via activation of PKR and de-repression of BACE1 expression. Implicating HSV1 further in AD is the finding that HSV1 DNA is very specifically localised in amyloid plaques in AD brains. This association of viral DNA with plaques does not prove causality, but considered together with the HSV1-induced formation of A?. It suggests that HSV1 is a major cause of A? formation in brain and of its toxic oligomers. Several genome-wide association studies (GWAS) have examined genetic links between HSV1 and its host cells. They show that a limited number of genes, when combined, are strongly associated with AD, even though the effect of any single gene or SNP is very weak. Possibly these genes code for proteins that interact in various processes, leading to a synergistic effect on AD pathogenesis. Also, HSV1 might bind to many cell proteins, thereby modulating their expression, including many encoded by susceptibility genes for various neurological diseases, including AD. Epidemiological studies have examined serum IgG and IgM, also IgG avidity index, and serological data relating to several different microbes; all show association between HSV1 reactivation and AD development, and between infectious burden and cognitive decline, with HSV1 particularly implicated. Cytomegalovirus (CMV) has been implicated also, possibly influencing immune response to other pathogens, thereby triggering the immune dysregulation involved in some age-related diseases, and suggesting specifically reactivation of HSV1 with CMV action and age. There is evidence that A? has anti-bacterial action, as part of the innate immune system, and recently it has been shown to have specifically anti-HSV1 action; however, it is likely that if eventually over-produced, it becomes toxic. Other relevant, harmful effects of infection include dynamic interactions between HSV1 and amyloid precursor protein (APP), the precursor of A?, which would facilitate viral transport and interfere with normal APP transport and distribution; induction of toll-like receptors in HSV1-infected astrocyte cultures, which has been linked to the likely effects of reactivated HSV1 in brain; infection-induced acute or chronic inflammation in triple-transgenic mice, which would exacerbate tau pathological features, further supporting the triggering of inflammation by infectious agents in brain, leading to cognitive impairment via effects on tau. Only 2 papers, 12 and 14 years ago, have challenged the data—specifically on viral presence in brain. No other opposing studies have since been published. One can conclude that there is overwhelming supportive evidence that HSV1 in brain of APOE-e4 carriers confers a major risk of AD.

Special Issue on Controversies in Neurology. From the 10th World Congress on Controversies in Neurology (CONy), Lisbon, Portugal. 17–20 March 2016.

International Journal of Clinical Neurosciences and Mental Health 2016; 3(Suppl. 1):L8

Icon_pdf Download PDF

Lecture


Beyond the horizon in dementia - read full article

By: George Perry and R. Castellani

Our nearly 35 year journey in Alzheimer disease (AD) began with the linkage of senile dementia to AD and the molecular dissection of genetics and proteins that revealed the central players. How could a cure or even effective therapy have eluded us for so long? Studying AD is like walking through the looking glass, for while everything is the same--e.g., there is no novel gene expression—it is also different in quantitative and qualitative relationships leading to endless studies suggesting therapeutic strategies. Do endless abnormalities mask the one distinct initiator or is the countless change instead the disease: possibly a single condition but made up of thousands of components that are touched by the key risk factor of AD—age—for we find the same changes in aged normal people. Could it be the same changes of aging are AD because they are what maintains normal function with aging but are insufficient in AD to maintain physiology. Removal of these changes has not restored normal function and could do harm. In Alois Alzheimer’s time treatments revolutionized medicine by curing most diseases from the outside, infections and injury, and corrected many of defect (mutations) but since then we have made but modest impact in diseases of normal aging, degenerative diseases. Instead progress has been made when we address the underlying issues: lifestyle, inflammation, and others, instead of eliminating the reactive changes. We might consider the same for AD as we work on more effective therapy.

Special Issue on Controversies in Neurology. From the 10th World Congress on Controversies in Neurology (CONy), Lisbon, Portugal. 17–20 March 2016.

International Journal of Clinical Neurosciences and Mental Health 2016; 3(Suppl. 1):L9

Icon_pdf Download PDF

Lecture


Beyond the horizon in neuropathology - read full article

By: Lea T. Grinberg

Neuropathology is a relatively old discipline known for still using methods developed over a century ago. Difficulties in procurement and examination of clinical specimens, the advent of high-throughput—omics, and advances in animal models with their ability to provide insight into the mechanisms of a disease process, led to a waning of interest in neuropathology that has been rendered obsolete. My talk will focus on the transformation of neuropathology into a 21st-century science on the forefront of advances in neurology. By incorporating elements of molecular biology, improved microscopy, advancing graphics, and technology to deal with big data in the study of human brain specimens, neuropathology is transforming biomarker discovery and treatment development in several areas of neurology and rapidly reinstating itself as a valuable player in the contemporary neurological research.

Special Issue on Controversies in Neurology. From the 10th World Congress on Controversies in Neurology (CONy), Lisbon, Portugal. 17–20 March 2016.

International Journal of Clinical Neurosciences and Mental Health 2016; 3(Suppl. 1):L10

Icon_pdf Download PDF

Lecture


Close encounter on chromosome 14 - read full article

By: Sergiu C. Blumen, Itzhak Braverman, and Tamar Ben-Yosef

Since the discovery of the large cluster of Oculopharyngeal Muscular Dystrophy (OPMD) among Uzbek (Bukhara) Jews, we noticed that some OPMD homozygotes had significantly reduced vision due to pigmentary retinopathy. Recent investigations in a newly identified OPMD homozygote, as well as in several Uzbek OPMD heterozygotes, revealed in this population, a high prevalence of a novel, autosomal recessive, mutation producing, adult onset, progressive visual loss in homozygotes; vision is not affected in heterozygote carriers. This mutation, occurring on chromosome 14q, in close proximity to PABPN1, was found neither among Uzbeks with two normal [(GCN)10] PABPN1 alleles nor in OPMD patients belonging to another ethnic group. We conclude that, during history, two founder mutations occurred on 14q in Uzbek Jews and they are closely linked.

Special Issue on Controversies in Neurology. From the 10th World Congress on Controversies in Neurology (CONy), Lisbon, Portugal. 17–20 March 2016.

International Journal of Clinical Neurosciences and Mental Health 2016; 3(Suppl. 1):L11

Icon_pdf Download PDF

Lecture


Effect of Glatiramer Acetate on Peripheral Blood Brain-Derived Neurotrophic Factor and Phosphorylated TrkB Levels in Relapsing-Remitting Multiple Sclerosis - read full article

By: Buzoianu Anca Dana, Vacaras Vitalie, Major Zoltan Zsigmond, Muresanu Fior Dafin, Krausz Ludovic Tibor, and  Marginean Ioan

Glatiramer acetate (GA) is one of the most widely used disease-modifying drugs for the treatment of relapsing-remitting multiple sclerosis; is assumed to have inductor effects on neurotrophic factor expression. One of these neurotrophic factor systems is the brain-derived neurotrophic factor (BDNF)/receptor tyrosine kinase B (TrkB) pathway. Peripheral blood is thought to contain soluble BDNF, and some blood cells express TrkB. We attempted to determine whether GA treatment leads to changes in plasma BDNF levels and TrkB activation. Such a phenomenon are relapsing-remitting multiple sclerosis patients is significantly reduced; GA treatment is not influencing peripheral BDNF levels, after one year of sustained therapy, not from the point of view of total free BDNF nor the phosphorylated TrkB.

Special Issue on Controversies in Neurology. From the 10th World Congress on Controversies in Neurology (CONy), Lisbon, Portugal. 17–20 March 2016.

International Journal of Clinical Neurosciences and Mental Health 2016; 3(Suppl. 1):L12

Icon_pdf Download PDF

Lecture


Does the diagnosis of AD implies immediate revocation of driving license? - read full article

By: Sokratis Papageorgiou

Successful driving requires various physical and mental capacities to: judge distances, simultaneously manage multiple incoming stimuli, maintain attention for long periods of time, perform sequencing skills, demonstrate immediate reaction in case of adverse events and succeed proper interpretation of traffic signs and signals. While patients with moderate to severe dementia should stop driving, some patients with mild Alzheimer’s Disease (AD) seem still capable to drive without an increased risk of accidents compared to healthy elderly. Performance on tests of visuospatial and attentional abilities, executive functioning and memory is associated with the ability to drive safely in these patients. However, due to the moderate relationships of the cognitive tests with driving measures and individual variability, relying only on these tests for making recommendations for restrictions in driving is not adequate and combination with other measures such as findings from neurological assessment is warranted. Research findings indicate that patients with Mild Cognitive Impairment (MCI) are at risk for driving difficulties although their performance on driving testing was not consistently found worse than that of healthy elderly. Nevertheless, cognitive measures appear to be associated with driving performance in patients with MCI. Our research results suggest that measures of information processing speed, visuospatial memory, psychomotor vigilance and also motor measures of balance and movement coordination (e.g. tandem walking test) as well as measures of quality of sleep and emotional state could serve as useful predictors of driving performance in individuals with MCI as they predict various indexes of driving performance: number of crashes, reaction time, average driving speed, lateral position variation, and headway average time. Finally, compared to healthy elderly, mild AD and MCI patients are more sensible to distraction while driving (e.g. use of mobile phone and conversation). Definition of successful predictors of driving ability in patients with mild AD or MCI will allow the development of thoughtful guidelines and national policies to improve public road safety.

Special Issue on Controversies in Neurology. From the 10th World Congress on Controversies in Neurology (CONy), Lisbon, Portugal. 17–20 March 2016.

International Journal of Clinical Neurosciences and Mental Health 2016; 3(Suppl. 1):L13

Icon_pdf Download PDF

Lecture


Should Vascular Dementia be treated with Cholinesterase Inhibitors? - read full article

By: Babek Tousi

holinesterase inhibitors are considered to be the first-line cognitive enhancer for Alzheimer's disease, but they do not have regulatory approval for treatment of vascular dementia in the United States and most of the Europe. There have been multiple studies of cholinesterase inhibitors in patients with vascular dementia over past decade. Cholinesterase inhibitors showed greater efficacy than placebo on ADAS-cog in some of these studies. However, these studies showed inconsistent benefit in global functioning of patients with vascular dementia. Eisai's applications (Manufacturer of Aricept) for regulatory approval of donepezil for vascular dementia in 2002 and 2003 were rejected both in the United States and Europe. The development for this indication stopped. Donepezil has been studied frequently for patients with vascular dementia. One of the largest studies on donepezil, sponsored by the manufacturer, was a combined analysis using 2 identical randomized trial, 24-week period7. Patients were randomized to receive donepezil 5 mg/day or 10 mg/day, after brief titration or placebo. Both donepezil groups showed significant improvements in cognition compared with placebo (ADAS-cog, MMSE, p < 0.01). There was inconsistency in the global benefit. The 5 mg/day group showed benefit on the CIBIC-plus and the 10 mg/day group showed benefit on CDR-SB. The authors concluded that donepezil improved cognition, global function and ability to perform IADL in patients with vascular dementia and was well tolerated. Kavirajan and Schneider did a meta-analysis of randomized controlled trials of cholinesterase inhibitors in vascular dementia from 1996-2006. Eight studies including the above double blind RCT studies comprising 5183 patients met their selection criteria. Their meta analysis attenuate the global effects of the 5 mg dose reported by published data. The Alzheimer’s Disease Assessment scale was significantly improved for all drugs but only 5 mg daily donepezil had an effect on the Clinicians’ Global Impression of Change scale. There was no behavioral or functional benefits on any of these drugs, except for 10 mg daily donepezil on the Alzheimer’s disease Functional Assessment and Change Scale. They concluded that Cholinesterase inhibitors produce small benefits in cognitive abilities in vascular dementia but the clinical significance is uncertain. As previous studies of Donepezil in vascular dementia showed inconsistent benefit in global functioning of patients with vascular dementia, the manufacturer sponsored another trial to further evaluate the potential benefits of donepezil in VaD. The participants were randomized only to donepezil 5 mg or placebo once daily. They achieved their previous results that patients treated with donepezil 5 mg/d had significant improvement in cognitive, but they did not show any improvement in global function. A double-blind trial of Donepezil in patients with subcortical vascular cognitive impairment (CADASIL) failed to show any effect on the primary endpoint, which was change from baseline in the score on the vascular AD assessment scale cognitive subscale (V-ADAS-cog) at 18 weeks. Some improvements on few measures of executive function did not reach the clinical significance. These initial studies used the now-outdated NINDS-AIREN criteria for probable VaD and the NINCDS-ADRDA4 criteria for possible AD, coupled with a requirement for radiological evidence of significant cerebrovascular disease for mixed dementia. Mixed dementia is now known to be very common. Both these criteria were prepared before this was recognized. When these criteria were prepared, small amounts of CVD were routinely ignored when seen in conjunction with what was otherwise thought to be AD. NINDS-AIREN criteria require an Alzheimer-like dementing process coupled with the presence of cerebrovascular disease. As such, these criteria are probably better criteria for mixed dementia than they are for VaD, There is some evidence from the both the galantamine and donepezil studies of a therapeutic effect for acetylcholinesterase inhibitors in VaD, or mixed AD and VaD, although in reality both studies are probably studies of mixed disease. When different sets of diagnostic criteria for Vascular dementia (ICD-10, DSM-IV and NINDS-AIRENS) have been compared against pathological findings as the gold standard, their sensitivity and specificity (in differentiating AD from VaD) are highly variable. These sets of criteria cannot be used interchangeably either. The overall design of efficacy trials in vascular dementia is questionable. A randomized, double-blind, placebo-controlled, parallel-arm design seems to be the most appropriate for AD with gradual worsening clinical course but a similar design may not be appropriate for vascular dementia. On current evidence, an acetylcholinesterase inhibitor could reasonably be considered for a patient with a spectrum of AD mixed with vascular disease. It is more important to emphasize the importance of early identification of cases with a vascular component to their cognitive decline, as these patients can benefit from prevention rather than just symptomatic treatment. Since many patients with Vascular dementia also suffer from cardiovascular disease, a potential drug–drug interactions between cholinesterase inhibitor and the medications used to treat heart conditions in these patients is alarming. The potential inconsistent mild benefit of a cholinesterase inhibitor should be weighed against the harms likely to be caused to patients with vascular dementia.

Special Issue on Controversies in Neurology. From the 10th World Congress on Controversies in Neurology (CONy), Lisbon, Portugal. 17–20 March 2016.

International Journal of Clinical Neurosciences and Mental Health 2016; 3(Suppl. 1):L14

Icon_pdf Download PDF

Lecture


Nanotechnology in early diagnosis and treatment of dementia - read full article

By: Jerzy Leszek

The lack of effective treatment for Alzheimer’s disease(AD) stems mainly from the incomplete understanding of AD causes. Currently there are several hypotheses which try to explain the early molecular mechanisms of AD pathogenesis. The current pathophysiologic approach is based on a number of common mechanisms of neurodegeneration, including accumulation of abnormal proteins(tau and ABeta), mitochondrial dysfunction, oxidative stress, impaired insulin signaling, calcium homeostasis dysregulation, imbalance of neurotransmitters, early synaptic disconnection and late apoptotic cell death. Considering that AD is a multi-factorial disease with several pathogenic mechanisms and pathways, a multifunctional nanotechnology approach may be needed to target its main molecular culprits. There are still no effective treatments to prevent, halt, or reverse AD. To very early diagnosis of AD we need to have an affordable, ultra sensitive and selective molecular detection methods. Nanomedicine as a biomedical and pharmaceutical application of nanotechnology for making nanocarriers for instance dendrimers has shown great potential not only for diagnosis but the treatment of many CNS diseases such AD. Ultra-low concentrations of protein biomarkers( eg. ADDL- amyloid-Beta-derived diffusible ligands) which have been implicated in the pathogenesis of AD, is possible to detect ,owing to carrier dendrimers. Dendrimers are polymeric molecules chemically synthesized with well defined shape size and nanoscopic physicochemical properties reminiscent of proteins. Recently an increasing number of studies have been focused on the potential of dendrimers to prevent aggregation and fibrillation of proteins involved in neurodegenerative disorders such as AD. Some of dendrimers were demonstrated to cross blood-brain barrier, which legitimized research on these compounds as potential drugs for neurological disorders. Recent our studies have revealed that dendrimers possess the intrinsic ability to localize in cells associated with neuroinflammation(activated microglia and astrocytes) and thus can be used in neuroinflammation therapy. Above/mentioned findings may be significance in the context of potential application of dendrimers as drug carriers or active compounds per se. According to the opinion the author’s of this presentation ,they are promising macromolecules for further investigations on their applicable in neurodegenerative disorders, for instance AD.

Special Issue on Controversies in Neurology. From the 10th World Congress on Controversies in Neurology (CONy), Lisbon, Portugal. 17–20 March 2016.

International Journal of Clinical Neurosciences and Mental Health 2016; 3(Suppl. 1):L15

Icon_pdf Download PDF

Lecture


The CGRP story and its role in migraine pathophysiology - read full article

By: Lars Edvinsson

Migraine is a painful, debilitating neurological disorder that manifests as a debilitating headache associated with altered sensory perception, having a huge impact on individual and public health. In a survey about years lived with disability, migraine was ranked on the third place. Although evidence suggest no increase in migraine prevalence in a ten year period, the cumulative lifetime incidence is very high (43% in women, 18% in men), affecting especially young adults. Great progress has been made in understanding the pathophysiology of migraine. However, there are still some questions regarding the origin of migraine pain and on its chronification. The neuropeptide calcitonin gene-related peptide (CGRP) is now firmly established as a key player in migraine. The first evidence was presented already 1984, showing that sensory nerves on cerebral arteries store calcitonin gene-related peptide (CGRP) using immunohistochemistry, performed surgical denervation and quantification of CGRP, did in vivo work and defined the trigeminovascular reflex with CGRP as the main molecule. In 1988, we observed upon operation of patients with trigeminal neuralgia that CGRP was released into the jugular venous blood and at the same time there was unilateral flushing. This was the start of our migraine project. CGRP was found to be released in acute migraine and cluster headache attacks and correlated with the pain, and that both pain and increased CGRP levels were aborted by a triptan. Thus, CGRP is a key molecule in primary headache disorders. Subsequent work provided a wealth of preclinical and clinical data in support (Ho et al, Nature Rev Neurol 2010). Industry picked up the idea and started developed CGRP blockers 10-15 years ago. After the first proof-of-concept study (2004) several trials using small molecules that could be given orally, revealed positive effects both in acute migraine attacks and in a prophylaxis study with gepants (Edvinsson & Linde, Lancet Neurol 2010). Due to liver toxicity this program was halted. However today this has been followed by 4 different companies using antibodies towards CGRP or the CGRP receptor and they have revealed positive results in phase 2 trials. It is expected that CGRP blockers may reach the market in about 2-3 years. The preliminary data show compared to placebo no significant side effects and good efficacy. Despite this progress in the clinical arena, the details of the mechanisms and involvement of CGRP in migraine pathophysiology remain unclear providing room for further research.

Special Issue on Controversies in Neurology. From the 10th World Congress on Controversies in Neurology (CONy), Lisbon, Portugal. 17–20 March 2016.

International Journal of Clinical Neurosciences and Mental Health 2016; 3(Suppl. 1):L16

Icon_pdf Download PDF

Lecture


Cortical Integrative Therapy: application of non-invasive brain stimulation in the treatment of pediatric brain injury and brain-based disorders - read full article

By: Victor M. Pedro

Cortical Integrative Therapy (CIT) is successful in treating a wide range of neurological conditions including traumatic and acquired brain injury as well as developmental disorders and learning disabilities. CIT utilizes the spatial and temporal specificity of sensory stimulation and motor signaling to initiate neuronal re-synchronization, restore hemispheric balance in functions, and drive neuronal plasticity so that long-term positive changes are implemented and maintained. CIT stimulates the brain by using a patient-specific set of simulative treatment therapies (visual, auditory, vestibular), physical exercises, and nutritional counseling. The purpose of this presentation is to illustrate the effectiveness of CIT in the treatment of pediatric and adult brain injury. We will introduce a conceptual framework of CIT, describe typical treatment modalities, and report patient outcomes.

Special Issue on Controversies in Neurology. From the 10th World Congress on Controversies in Neurology (CONy), Lisbon, Portugal. 17–20 March 2016.

International Journal of Clinical Neurosciences and Mental Health 2016; 3(Suppl. 1):L17

Icon_pdf Download PDF

Lecture


Development of the international pediatric acquired brain injury plain (iPABI plan) - read full article

By: Patrick B. Donohue

Pediatric acquired brain injury (PABI) is the leading cause of death and disability for American youth up to 25 years of age and is an international public health crisis. Over 765,000 American youth enter an Emergency Department each year with a new brain injury, over 80,000 are hospitalized and over 11,000 die annually. There is currently no evidenced-based system of care to prevent, identify, treat or cure PABI. The International Pediatric Acquired Brain Injury Plan (iPABI Plan) is developed from the $2.9 billion, seven-year National Pediatric Acquired Brain Injury Plan (PABI Plan) by the International Advisory Board of The Sarah Jane Brain Foundation. The PABI Plan develops a seamless, standardized, evidence-based system of care that is universally accessible for the millions of American families who have a child with a brain injury. This presentation will explain Who, What, Where, Why, When and How about the iPABI Plan.

Special Issue on Controversies in Neurology. From the 10th World Congress on Controversies in Neurology (CONy), Lisbon, Portugal. 17–20 March 2016.

International Journal of Clinical Neurosciences and Mental Health 2016; 3(Suppl. 1):L18

Icon_pdf Download PDF

Lecture


Can Neurology Solve the Free Will Paradox? - read full article

By: Mark Hallett

ne definition of a paradox is a proposition that arises from apparently sound premises leads to a conclusion that seems logically unacceptable. The paradox that arises in relation to free will is that studies of motor control do not obviously reveal the operation of free will, and there is a general view that people do have free will. Free will is a perception that people have that they choose to make (most of) their movements. This perception includes both a sense of willing the movement and self-agency that their act of willing was responsible for the movement that was made. Intrinsic to the perception of willing is the sense that the willing itself drives the movement. It is important to recognize that perceptions are purely passive. A critical question is whether there is any evidence for a “free will force” that plays a role in movement selection. The basic challenge to a relevant free will force is the experiment of Libet et al. (1983) that showed EEG activity well before the time of perception of willing (called W). A series of other experiments, less reliant on subjective and retrospective perceptions confirm this result. Moreover, the timing of W can be influenced by events, such as TMS, after the movement is made. The probable explanation of this is that perceptions must occur after physical events in the real world—consciousness is in the past. Evidence from neuroimaging and brain stimulation studies reveal that the sense of willing likely arises from regions in the brain including the temporoparietal junction area and supplementary motor area. Neuroimaging and brain stimulation studies have also been done investigating the sense of agency and similar regions appear relevant. Physiological studies of movement generation give a fairly clear account of how movement is produced, and a free will force has not been identified nor does it seem necessary. Much of what the brain does is unconscious and only some of its activity becomes passively experienced in consciousness. The brain event underlying the sense of willing is not a driving force. The paradox is solved with the recognition that a person “is” his/her brain. Then free will can be considered to exist if a person’s brain is functioning normally without coercion.

Special Issue on Controversies in Neurology. From the 10th World Congress on Controversies in Neurology (CONy), Lisbon, Portugal. 17–20 March 2016.

International Journal of Clinical Neurosciences and Mental Health 2016; 3(Suppl. 1):L19

Icon_pdf Download PDF

Lecture


Trophic factors for Parkinson's Disease: facts and dreams - read full article

By: Jose Martin Rabey

Since the discovery of the trophic effects of nerve growth factor by Nobel laureate Rita Levi-Montalchini in the 1970's numerous studies have demonstrated that many trophic factors can prevent neuronal degeneration and increase the function of both intact and degenerating nerve cells. Moreover trophic factors show great promise in laboratory studies as potential therapies for PD. However multiple double—blind clinical trials have failed to show benefits in comparison to a placebo control. With respect to developing a therapy for PD patients, the GDNF family of ligands (GFLs) that include glial cell-derived neurotropic factor (GDNF) and neurturin (NRTN) have received the most attention. Lin (1993) first discovered GDNF and demonstrated that it supports the viability of dopaminergic midbrain neurons in tissue culture. We will review in our presentation the scientific rationale for testing trophic factors in PD , the result of the different clinical trials that have been performed and the possible explanations for these failed outcomes. Future directions will be also considered.

Special Issue on Controversies in Neurology. From the 10th World Congress on Controversies in Neurology (CONy), Lisbon, Portugal. 17–20 March 2016.

International Journal of Clinical Neurosciences and Mental Health 2016; 3(Suppl. 1):L20

Icon_pdf Download PDF

Lecture


Clinical features and the natural history - read full article

By: T. Klockgether

Machado-Joseph disease/spinocerebellar ataxia (MJD/SCA3) is worldwide the most common autosomal dominantly inherited ataxia disorder. MJD/SCA3 is a multisystem disorder characterized by degeneration of spinocerebellar tracts, dentate nucleus, brainstem nuclei, and basal ganglia. In MJD/SCA3 mutation carriers, ataxia usually starts around 35 years with large variability that partly depends on the repeat length. The clinical syndrome is characterized by prominent cerebellar ataxia in combination with supranuclear gaze palsy and peripheral neuropathy. In addition, patients may present with pyramidal signs, basal ganglia symptoms, such as parkinsonism or dystonia, restless legs syndrome, urinary dysfunction, and mild cognitive dysfunction. As part of the EUROSCA study we followed a cohort of 139 MJD/SCA3 patients over a period of 8 years. The severity of ataxia at baseline, as measured by the Scale for the Assessment and Rating of Ataxia (SARA), was determined by repeat length and disease duration. Longer repeats and earlier age of onset were associated with the occurrence of pyramidal signs, whereas higher age was associated with clinical signs of peripheral neuropathy. SARA progression data were best fitted with a linear model. Annual SARA score increase was 1.56 (SE 0.08). We did not identify factors that affected progression of the SARA score. Progression rate in MJD/SCA3 was slower than in SCA1, but faster than in SCA6. Other than the SARA score, the increase of the number of non-ataxia signs reached a plateau.

Special Issue on Controversies in Neurology. From the 10th World Congress on Controversies in Neurology (CONy), Lisbon, Portugal. 17–20 March 2016.

International Journal of Clinical Neurosciences and Mental Health 2016; 3(Suppl. 1):L21

Icon_pdf Download PDF

Lecture


Machado-Joseph Disease—single center experience from Central Portugal - read full article

By: Cristina Januário, Joana Afonso Ribeiro, Ana Margarida Novo, Luciano Almendra, Anabela Matos, Luís Negrão, and João Lemos

We report on a series of 80 spinocerebellar ataxia type 3 (SCA 3) patients from 39 unrelated families followed in our clinic, focusing on novel clinical findings and phenotypical diversity. Demographic, clinical (scale for the assessment and rating of ataxia (SARA), Montreal Cognitive Assessment, clinical Total Neuropathy Score-cTNS scores), and genetic features were recorded. Neurophysiological evaluation included nerve conduction studies, needle electromyography and cutaneous sympathetic skin response (SSR). Functional imaging using the radioactive tracer 123I-ioflupane was performed to assess dopamine deficiency, exclusively in parkinsonian patients. Neuro-ophthalmological assesment including strabismus evaluation, and the use of binocular video-oculography video-horizontal head impulse test (vHHIT) were further performed. Patients’ median age was 53+/-14 years, mean duration of disease was 15 (± 8) (3 – 38) years, median SARA score was 15.4 +/-6, median number of CAG repeats was 71+/-8, and median MoCA score was 25 (18 -29). Three cases presented initially as a levodopa responsive parkinsonian syndrome, and one of them underwent successful deep brain stimulation. Peripheral neuropathy is frequent in our population (>50%), showing predominant sensory involvement. The presence of peripheral neuropathy positively correlates with age but not with triplet expansion size. Strabismus was a universal finding, particularly esotropia at near. Vestibular ocular reflex loss positively correlated with SARA score. A novel saccadic intrusion has been found. In our series we have identified potential oculomotor biomarkers of disease.

Special Issue on Controversies in Neurology. From the 10th World Congress on Controversies in Neurology (CONy), Lisbon, Portugal. 17–20 March 2016.

International Journal of Clinical Neurosciences and Mental Health 2016; 3(Suppl. 1):L22

Icon_pdf Download PDF

Lecture


Magnetic resonance imaging in Machado-Joseph disease - read full article

By: Marcondes C. França

Machado-Joseph disease (SCA3) is the most frequent spinocerebellar ataxia worldwide and caused by abnormal (CAG) expansions within the 10th exon of the MJD1 gene located at chromosome 14q. It is typically an adult onset ataxic syndrome, but there is remarkable phenotypic heterogeneity. Patients often present pyramidal signs, movement disorders (particularly dystonia) and peripheral manifestations. Current research efforts in SCA3 are directed towards understanding the pathophysiology of the disease and also to identify robust biomarkers for clinical trials. In this scenario, magnetic resonance imaging (MRI) emerged as a promising tool. It is a widely available and non-invasive technique that enables the evaluation of structural and functional changes related to the disease. Most available MRI-based studies focused in cerebral abnormalities and employed volumetric techniques. These studies revealed cerebellar (predominantly vermian) and brainstem atrophy in SCA3. More recently, studies using cortical thickness measurements also identified precentral, temporal and occipital volumetric reduction. Diffusion tensor imaging (DTI) is a MRI sequence that enables the evaluation of white matter integrity in the brain. In patients with SCA3, DTI-based studies essentially revealed damage to cerebellar and brainstem tracts, including the cerebellar peduncles. Spinal cord is another neural structure known to be affected in SCA3 from pathological reports. Current high-field scanners and protocols now enable adequate evaluation of the cord in vivo using MRI. Indeed, two reports showed cervical atrophy in the disease, and interestingly the extent of atrophy correlated independently with clinical severity. Overall, these results indicate that SCA3 is associated with multifocal damage to the central nervous system that goes far beyond the cerebellum and connections. It seems, however, that damage distribution is not homogeneous in every single patient. Some recent reports tried to compare MRI findings in patients with different phenotypes, such as dystonic vs non-dystonic. Results indicate that cerebellum is compromised in both situations, but the pattern of cortical and basal ganglia damage is clearly different. There are very few longitudinal MRI data in SCA3. Reetz et al reported progressive caudate and putaminal volumetric reduction after 2 years, but it did not correlate with clinical decline. In summary, MRI-based studies greatly improved our knowledge about disease mechanisms and genotype-phenotype correlation. The use of MRI parameters as clinical biomarkers for SCA3, however, still needs further studies with a longitudinal design. We strongly believe that DTI might prove more sensitive than volumetric techniques to detect subtle changes in the short-term.

Special Issue on Controversies in Neurology. From the 10th World Congress on Controversies in Neurology (CONy), Lisbon, Portugal. 17–20 March 2016.

International Journal of Clinical Neurosciences and Mental Health 2016; 3(Suppl. 1):L23

Icon_pdf Download PDF

Lecture


Mutational origins of Machado-Joseph disease - read full article

By: Sandra Martins

Machado-Joseph disease (MJD) is the most frequent dominant ataxia worldwide, but de novo mutational events (i.e. expansions from normal or intermediate to the pathological range of (CAG)n alleles) do not seem to explain disease relative high frequency and diffusion into many populations. Previously, we have identified two SNP lineages, each underlying an independent MJD origin: the most ancient and worldwide spread Joseph (TTACAC) lineage, originated probably in Asia more than 6000 years ago; and the more recent Machado (GTGGCA) lineage, predominant in families of Portuguese extraction. Interestingly, these two lineages display different repeat instability biases upon paternal transmission of expanded alleles. Taking into account that the CAG repeat size is the parameter that better explains age-of-onset and disease severity, the identification of MJD lineages becomes even more important at the clinical level. More recently, we have been studying families from more remote and isolated communities in order to discern whether the presence of MJD in these populations is due to new mutational events or to the introduction of expanded alleles from other populations. A total of 20 SNPs flanking the expanded repeat was analysed in Australian aborigines and African families. No new mutational origins have been identified, but a “Joseph-derived” lineage shared by Australian aborigines and 9 Asian families suggested an introduction of the mutation in this community via Asia. By inferring a phylogenetic tree from genetic distances, we estimated that the Australasian Joseph-derived lineage dates back to more than 100 generations.

Special Issue on Controversies in Neurology. From the 10th World Congress on Controversies in Neurology (CONy), Lisbon, Portugal. 17–20 March 2016.

International Journal of Clinical Neurosciences and Mental Health 2016; 3(Suppl. 1):L24

Icon_pdf Download PDF

Lecture


Planning and feasibility of clinical trials - read full article

By: T. Klockgether

Clinical trials in Machado-Joseph disease/spinocerebellar ataxia (MJD/SCA3) with neuroprotective drugs, such as lithium, or symptomatic drugs, such as varenicline have been performed, however with negative results. In the majority of recent clinical trials in ataxia, the Scale for the Assessment and Rating of Ataxia (SARA) is used as a primary outcome measure. The SARA score is highly correlated with activities of daily living, and it is a major determinant of health-related quality of life underlining the clinical relevance of SARA. SARA progression in MJD/SCA3 is comparably slow so that neuroprotective clinical trials require large numbers of patients. Based on the 8 year longitudinal data of the EUROSCA study, we calculated that more than 500 patients will be required to detect a 30% reduction in progression of the SARA score in a trial with a power of 80%. Before embarking on such large trials, smaller proof-of-concept trials are desirable. In such trials, biomarkers are used to provide evidence of target engagement and to indicate possible efficacy. Currently, however, validated biomarkers that could be used in MJD/SCA3 trials are lacking. To overcome some of these problems, we are launching the European Spinocerebellar Ataxia Type 3/Machado-Joseph Disease Initiative (ESMI) that aims at setting up a trial ready cohort by bringing together 7 European cohorts and 1 US cohort. ESMI plans to integrate the existing data in a common database and to apply standardized and quality-controlled clinical assessment, MRI and biobanking protocols. A major part of ESMI will be the development and validation of innovative assessment instruments and disease markers, including a new highly sensitive motor test battery, ambulatory sensor-based activity measurement, automated MRI volumetric evaluation, diffusion tensor imaging (DTI), and blood as well as CSF markers based on transcript profiling and disease protein (ataxin-3) measurement.

Special Issue on Controversies in Neurology. From the 10th World Congress on Controversies in Neurology (CONy), Lisbon, Portugal. 17–20 March 2016.

International Journal of Clinical Neurosciences and Mental Health 2016; 3(Suppl. 1):L25

Icon_pdf Download PDF

Lecture


Ataxin-3 phosphorylation decreases neuronal defects in spinocerebellar ataxia type 3 models - read full article

By: Carlos Andrade Matos, Clévio Nóbrega, Susana R. Louros, Bruno Almeida, Elisabete Ferreiro, Jorge Valero, Luís Pereira de Almeida, Sandra Macedo-Ribeiro, and Ana Luísa Carvalho

Different neurodegenerative diseases are caused by aberrant elongation of repeated glutamine sequences normally found in particular human proteins. Although the proteins involved are ubiquitously distributed in human tissues, toxicity targets only defined neuronal populations. Changes caused by an expanded polyglutamine protein are possibly influenced by endogenous cellular mechanisms, which may be harnessed in order to produce neuroprotection. Here, we show that ataxin-3, the protein involved in Spinocerebellar ataxia type 3, also known as Machado-Joseph disease, causes dendritic and synapse loss in cultured neurons when expanded. We report that S12 of ataxin-3 is phosphorylated in neurons and that mutating this residue so as to mimic a constitutive phosphorylated state counters the neuromorphologic defects observed. In rats stereotaxically injected with expanded ataxin-3- encoding lentiviral vectors, mutation of serine 12 reduces aggregation, neuronal and synapse loss. Our results suggest that S12 plays a role in the pathogenic pathways mediated by polyglutamine-expanded ataxin-3 and that phosphorylation of this residue protects against toxicity.

Special Issue on Controversies in Neurology. From the 10th World Congress on Controversies in Neurology (CONy), Lisbon, Portugal. 17–20 March 2016.

International Journal of Clinical Neurosciences and Mental Health 2016; 3(Suppl. 1):L26

Icon_pdf Download PDF

Lecture


Models of disease: C. elegans - read full article

By: A. Teixeira-Castro, A. Jalles, L. da Silva Santos, M.D. Costa, S. Oliveira, S. Vasconcelos, R.I. Morimoto, and P. Maciel

Caenorhabditis elegans has been successfully used to model neurodegeneration in vivo, mainly due to the conservation of basic cellular mechanisms such as neuronal signaling, cell death/survival, proteostasis and aging. Despite having relatively few neurons, C. elegans exhibit complex behaviors that can be assayed to monitor neuronal dysfunction, which can be combined with biophysical assays to examine protein aggregation in live neurons of interest. Here, we describe how the use of a C. elegans model of Machado-Joseph disease (MJD) pathogenesis allowed the identification of novel genetic modifiers of disease and promissing cellular targets for therapeutical intervention. Pan-neuronal expression of mutant ATXN3 led to a polyQ-length dependent, neuron subtype-specific aggregation and neuronal dysfunction. Wild-type ATXN3 is irreversibly recruited into polyQ-containing cellular aggregates, aggravating the animals’ motor dysfunction. Aging influenced the ATXN3 phenotypes which can be suppressed by lifespan increasing mutations in C. elegans. A drug repurposing screen identified pharmacological modulators of neurotransmission as potential treatment for MJD. Chemical genetics and validation in higher organisms will help to shed light into its mode-of- action in MJD.

Special Issue on Controversies in Neurology. From the 10th World Congress on Controversies in Neurology (CONy), Lisbon, Portugal. 17–20 March 2016.

International Journal of Clinical Neurosciences and Mental Health 2016; 3(Suppl. 1):L27

Icon_pdf Download PDF

Lecture


Potential Treatment on SCA3/MJD Drosophila Models and patients - read full article

By: Hong Jiang, Zhe Long, Qinghua Li, Jiping Yi, Dandan Jia, LIfang Lei, and Beisha Tang

We used several SCA3/MJD Drosophila models through which we determined that heat shock protein 22 (Hsp22), lithium chloride, and valproic acid (VPA) are potential therapeutic agents for the treatment of SCA3/MJD. Hsp22, a member of the small heat shock protein (sHsp) family, plays a significant role as chaperone. In the SCA3 Drosophila model, expression of the MJDtr-Q78 transgene—containing an expanded polyglutamine tract—showed a greater loss of cell integrity, and the pigmentation of adult flies was faded and showed black, point-like necrosis. Findings showed that Hsp22 expression impacted eye depigmentation, growth restriction, ability for eclosion, and average lifespan. We examined the effect of VPA and Li chloride (LiCl) in a Drosophila SCA3 model. We expressed the MJDtr-Q78 transgene both in the developing eyes and in neurons. Expression of the MJDtr-Q78 protein produced deleterious phenotypes including faded eye pigmentation, impaired climbing ability, and decreased mean lifespan, similar to the characteristics of human SCA3. To test the therapeutic potential of VPA and LiCl in vivo, a series of daily doses of VPA as well as LiCl were administered to SCA3 flies before cross-breeding. Results showed that long-term use of VPA and LiCl at an optimal dose partly prevented eye depigmentation, alleviated climbing disability, and extended the average lifespan of SCA3/MJD transgenic flies. Additionally, we performed a randomized, double-blind, placebo-controlled, dose-controlled study evaluated the safety and efficacy of multi-dose VPA in 36 SCA3/MJD patients and found VPA is a potentially beneficial agent for the treatment of SCA3/MJD.

Special Issue on Controversies in Neurology. From the 10th World Congress on Controversies in Neurology (CONy), Lisbon, Portugal. 17–20 March 2016.

International Journal of Clinical Neurosciences and Mental Health 2016; 3(Suppl. 1):L28

Icon_pdf Download PDF

Lecture


A transgenic zebrafish model of Machado-Joseph disease to test potential disease treatments - read full article

By: M. Watchon, K. Yuan, N. Mackovski, T.S. Becker, G.A. Nicholson, and A.S. Laird

Machado Joseph disease (MJD), also known as spinocerebellar ataxia-3 (SCA3) is a hereditary neurodegenerative disease that affects muscle control and coordination. The disease is caused by an extended trinucleotide repeat region (CAG) in the gene ATXN3/MJD1, encoding a polyglutamine (polyQ) region within the ataxin-3 protein. Whilst the wild-type (WT) ataxin-3 protein contains 12-44 glutamine residues, as many as ninety glutamines are found in the ataxin-3 protein of MJD patients. We have successfully established the first transgenic zebrafish model of MJD. These zebrafish express human ataxin-3 containing either 19Q (WT) or 84Q (MJD). Immunoblot analysis of protein lysates extracted from our transgenic SCA-3 zebrafish revealed the presence of ataxin-3 cleavage products similar to those found in MJD patient samples. These fragments were present at all ages examined from three days post fertilization (dpf) through to 12 months old. We identified a marked motor phenotype developed in ataxin-3-84Q zebrafish from 4 months old, with ataxin-3-84Q zebrafish swimming slower than ataxin-3-19Q fish. A more sensitive behavioural test (escape response during darkness) detected reduced swimming speeds in ataxin-84Q zebrafish than ataxin-19Q as early as 6dpf. This motor phenotype provides a useful readout for drug screening assays because it is easily quantified and occurs at an age that zebrafish larva can be treated in small multi-well plates. Our results indicate that our transgenic zebrafish model of MJD is relevant to the human disease and will be a valuable tool for testing potential disease treatments.

Special Issue on Controversies in Neurology. From the 10th World Congress on Controversies in Neurology (CONy), Lisbon, Portugal. 17–20 March 2016.

International Journal of Clinical Neurosciences and Mental Health 2016; 3(Suppl. 1):L29

Icon_pdf Download PDF

Lecture


Humanized SCA3 knock-in mouse: progress in identification of new deregulated molecules by high throughput NGS and proteomic studies - read full article

By: Maciej Figiel, Malgorzata Kurkowiak, Kalina Wiatr, Pawel M. Switonski, Lukasz Marczak, Agnieszka Zywert, Marek Figlerowicz, Pawel Wojciechowski, Rafal Ploski, Malgorzata Rydzanicz, and Luiza Handschuh

Humanized SCA3 knock-in ataxin-3 mouse model (Ki91) contains the following hallmarks of the disease: instability of the CAG mutation, ataxin-3 positive inclusions, astrogliosis, purkinje cell degeneration and early transcriptional changes. To provide a more holistic view of the neurodegenerative process in SCA3 Ki91 knock-in model we proposed to identify the deregulated molecules using transcriptome, proteome, phosphoproteome and ubiqiutome profiling by NGS and mass spectrometry. The homozygous k300 knock-in animals containing the CAG repeats without Ataxin-3 protein were also included in NGS transcriptome studies. The NGS of cerebellum and cortex of pre-symptomatic Ki91 (mut/mut) 8-week old animals has shown deregulation of several genes on mouse chromosome 12 and 19. Serpina3n which is located at chromosome 12 was deregulated in both Ki91 and K300 mouse. The induction of Serpina3n in both models increased when both alleles contained CAG repeat tract. Moreover the increased expression of Serpina3n was identified in astrocytes but not in granular cell neurons in the cerebellum. The enrichment and profiling of phosphoproteins was performed in pre-symptomatic Ki91 (mut/mut) 8-week old animals and identified number of deregulated phosphoproteins. Among deregulated proteins the GO analysis identified RNA binding, axon and dendrite development, regulation of synaptic transmition, learning, regulation of cytoskeleton organization. Summarizing young presymptomatic homozygous Ki91 animals reveal limited number of transcriptional changes predominantly clustering on mouse chromosome 12 and 19 and show greater scale of phosphoproteins deregulation in cerebellum and cerebral cortex.

Special Issue on Controversies in Neurology. From the 10th World Congress on Controversies in Neurology (CONy), Lisbon, Portugal. 17–20 March 2016.

International Journal of Clinical Neurosciences and Mental Health 2016; 3(Suppl. 1):L30

Icon_pdf Download PDF

Lecture


Nuclear localization and transport: a critical pathomechanism in Machado-Joseph disease - read full article

By: Thorsten Schmidt

Machado-Joseph disease (MJD) or Spinocerebellar ataxia type 3 (SCA3) is caused by a polyglutamine expansion in the ataxin-3 protein. In controls, ataxin-3 is predominantly located in the cytoplasm but forms protein aggregates in the nucleus of neurons in MJD/SCA3 patients. We recently demonstrated in vivo that the toxicity of expanded ataxin-3 is linked to its intracellular localization: Targeting ataxin-3 to the nucleus gave rise to a strong phenotype with a high number of protein aggregates. Purely cytoplasmic ataxin-3, however, even with a highly expanded polyglutamine repeat (148 glutamines), was not able to induce a phenotype and even did not aggregate. Only nuclear ataxin-3 gave rise to a phenotype. Purely cytoplasmic ataxin-3, however, even with a highly expanded polyglutamine repeat, remained harmless. In addition, we identified and characterized intracellular transport signals (two nuclear export signals, NES, and one nuclear localization signal, NLS) within the coding sequence of ataxin-3. Therefore, it is evident that proteins involved in the nucleocytoplasmic transport machinery recognize these localization signals, control the intracellular localization of ataxin-3, thereby influence the toxicity and aggregation of Ataxin-3 and, thus, the pathogenesis of MJD/SCA3. We further dissected the nucleocytoplasmic transport mechanisms of ataxin-3 and identified a transport protein whose critical importance for the nuclear import of ataxin-3 we confirmed in vitro and in vivo: Knocking down this protein alleviates the symptoms induced by expanded ataxin-3 both in transgenic Drosophila and mouse models. As pathologically ataxin-3 remains harmless as long as it is kept in the cytoplasm, we further anticipated the intracellular localization of ataxin-3 as a target for a possible therapeutical intervention. For this reason, we generated an assay allowing us to easily monitor the intracellular localization of normal or expanded ataxin-3, screened a library of FDA-approved compounds and indeed identified compounds impacting the nuclear translocation of ataxin-3 and validated them in vivo. As the compounds we identified are already FDA-approved and on the market, they could be transferred to the clinics comparatively fast. We believe that our results will improve the understanding of pathological mechanisms influencing the progression of the disease and are an important contribution towards a treatment of SCA3.

Special Issue on Controversies in Neurology. From the 10th World Congress on Controversies in Neurology (CONy), Lisbon, Portugal. 17–20 March 2016.

International Journal of Clinical Neurosciences and Mental Health 2016; 3(Suppl. 1):L31

Icon_pdf Download PDF

Lecture


Transcriptional dysregulation in SCA3 - read full article

By: Bernd Evert

Ataxin-3 (ATXN3) the disease protein in spinocerebellar ataxia type 3 (SCA3) can act as a transcriptional repressor through inhibition of histone acetyltransferases (HATs) and blocking access of HATs to histone acetylation sites suggesting that transcriptional dysregulation contributes to SCA3 pathogenesis. Indeed, cell models of SCA3 showed differential expression of several genes encoding transcription factors, inflammatory cytokines and cell surface proteins prior to cell death. Also, in cerebella of transgenic SCA3 mice, altered expression of genes involved in glutamatergic and calcium signalling, GABA receptor subunits, transcription factors and heat shock proteins regulating neuronal survival and differentiation occurs before the onset of neurological symptoms. On the one hand, transcriptional dysregulation in SCA3 may be caused by depletion of transcriptional components into nuclear inclusions formed by mutant ATXN3. On the other hand, polyQ expansion in ATXN3 may alter its normal function in transcriptional regulation. Previously, we found that ATXN3 binds to target genes and represses transcription by interaction with transcriptional corepressors and histone deacetylation whereas mutant ATXN3 has a reduced ability to form deacetylating repressor complexes at target genes. Moreover, ATXN3 interacts with specific transcription factors and synergistically enhance transcription of target genes in response to oxidative stress compared to a reduced capability of mutant ATXN3 to activate transcription at target genes. These findings suggest that ATXN3 apart from its role in protein quality control is a component of transcriptional complexes regulating the activity of specific genes in response to different stimuli. To identify target genes of ATXN3, we undertook chromatin immunoprecipitation sequencing of genomic fragments bound by ATXN3 using induced pluripotent stem cell-derived neurons from control and SCA3 patients. Currently, we are analyzing identified ATXN3-bound genomic regions to distinguish genes and pathways modulated by normal and mutant ATXN3.

Special Issue on Controversies in Neurology. From the 10th World Congress on Controversies in Neurology (CONy), Lisbon, Portugal. 17–20 March 2016.

International Journal of Clinical Neurosciences and Mental Health 2016; 3(Suppl. 1):L32

Icon_pdf Download PDF

Lecture


Regulation of translation of Ataxin-3 by Ataxin-2 - read full article

By: Clévio Nóbrega, Sara Carmo-Silva, David Albuquerque, Ana Vasconcelos- Ferreira, Udaya-Geetha Vijayakumar, Liliana Mendonça, Hirokazu Hirai, and Luís Pereira de Almeida

In polyglutamine disorders, proteins carrying abnormally long polyglutamine tracts interact aberrantly with other proteins contributing to neurodegeneration. In this work we focus on Machado-Joseph disease (MJD), a disorder associated to the polyglutamine-expanded ataxin-3 (Atx3MUT). Aiming at clarifying the mechanism of neurodegeneration we investigated the interaction of Atx3MUT with wild-type ataxin-2, a protein recently involved in ALS and PD pathogenesis, and whose mutated form causes spinocerebellar ataxia type 2. Using cell and animal models of MJD, we found that Atx3MUT aggregation in the cell nucleus leads to re-location of Atx2 to the nucleus and a downregulation of its mRNA and protein levels. Importantly, our results suggest a role of Atx2 in translational regulation of specific transcripts, by reducing the protein synthesis through interaction with PABP. Accordingly, abnormal reduction of Atx2 cytoplasmic levels, by freeing its natural interactor and translation activator PABP, leads to an overactive protein translation of specific transcripts, particularly of Atx3MUT. Conversely, the restoration of Atx2 levels represses Atx3MUT translation and rescues neuropathological MJD-related abnormalities, due to interaction with PABP through PAM2 motif. These data indicate a clear function of Atx2 in the regulation of the translation of specific mRNAs, particularly ataxin-3 and point to a key physiological role of ataxin-2 in MJD pathogenesis opening a new avenue for therapeutic intervention in this and potentially other polyglutamine disorders.

Special Issue on Controversies in Neurology. From the 10th World Congress on Controversies in Neurology (CONy), Lisbon, Portugal. 17–20 March 2016.

International Journal of Clinical Neurosciences and Mental Health 2016; 3(Suppl. 1):L33

Icon_pdf Download PDF

Lecture


Mechanisms of disease: proteolysis of ataxin-3 - read full article

By: Jonasz Jeremiasz Weber

Proteolytic cleavage of disease-causing proteins is a widely discussed mechanism in neurodegenerative disorders, which gives rise to toxic fragments and thus may amplify the formation of protein aggregates. This molecular model - known as the toxic fragment hypothesis - was also proposed to play a crucial role in Machado Joseph Disease (MJD) and several studies have reported on the proteolysis of polyglutamine-expanded ataxin-3, the causative protein in MJD. Hitherto two classes of enzymes, caspases and calpains, were linked with the proteolytic processing of ataxin-3, triggering neurotoxicity and cell death. Inhibition of protease activity and mutation of caspase or calpain cleavage sites within mutant ataxin-3 was shown to reduce toxicity and neuronal death in cell and animal models of MJD. Our better understanding of proteolytic events in MJD has opened new possibilities to identify therapeutic targets as a treatment for this fatal disorder.

Special Issue on Controversies in Neurology. From the 10th World Congress on Controversies in Neurology (CONy), Lisbon, Portugal. 17–20 March 2016.

International Journal of Clinical Neurosciences and Mental Health 2016; 3(Suppl. 1):L34

Icon_pdf Download PDF

Lecture


Drug discovery for MJD—Low molecular weight drugs - read full article

By: Patrícia Maciel

Machado-Joseph disease or spinocerebellar ataxia type 3 is a late-onset neurodegenerative disorder caused by expansion of a polyglutamine tract within the protein ataxin-3, for which there is no effective treatment. We have developed transgenic animal models expressing the mutant human ataxin-3 cDNA for the study of this disorder, in the mouse (CMVMJD135) and in the nematode Caenorhabditis elegans. These models show marked neuronal dysfunction, with loss of motor coordination, and the typical pathological feature of ataxin-3 aggregation, and can be used both to study the mechanisms of disease and to test therapeutic strategies in vivo. In this presentation I shall discuss our drug discovery efforts and most recent findings using hypothesis-based as well as unbiased hypothesis-free approaches (drug repurposing screenings), in these transgenic models. We have identified hsp90 inhibitors and serotonin signaling modulators as promising candidates for pharmacotherapy in MJD, but also discovered the beneficial impact of neuroprotective compounds such as tauroursodeoxycholic acid (TUDCA) and creatine in delaying disease onset and progression. The results of such preclinical studies inform us on the therapeutic efficacy of specific compounds but also provide important clues to the key aspects of pathogenesis that are amenable to therapy. Translation of the most promising findings to the clinic is challenging but also warranted.

Special Issue on Controversies in Neurology. From the 10th World Congress on Controversies in Neurology (CONy), Lisbon, Portugal. 17–20 March 2016.

International Journal of Clinical Neurosciences and Mental Health 2016; 3(Suppl. 1):L35

Icon_pdf Download PDF

Lecture


Trehalose reverses the phenotype of Machado-Joseph disease models - read full article

By: Magda M. Santana, Susana L. Paixão, Teresa Silva, Janete Cunha-Santos,Cláudia Cavadas, Hagar Greif, and Luís Pereira de Almeida

Machado–Joseph disease (MJD), also known as spinocerebellar ataxia type 3, is the most common of the dominantly inherited ataxias worldwide and is characterized by mutant ataxin-3 misfolding, intracellular accumulation of aggregates and neuronal degeneration. No treatment able to modify the disease progression is available. In the present study, we evaluated whether trehalose, a natural occurring alpha-linked disaccharide, could rescue the disease phenotype of cell and mouse models of MJD. N2A cells, stably expressing human mutant ataxin-3, were treated with trehalose (1 mM and 10 mM) for 24h, 48 h and 72 h. By western blot, we observed a clearance of mutant ataxin-3 protein after 48h and 72 h treatment with trehalose (10 mM). Furthermore, MJD transgenic mice were orally treated with 2% trehalose for a period of 30 weeks. Motor behavior was measured at different time points during lifetime and neuropathological features were evaluated after sacrifice. We observed that trehalose treatment significantly improved the motor and coordination behavior in both males and females MJD transgenic mice. Moreover, trehalose effects on behaviour were associated with a reduction of the MJD-associated neuropathology as MJD transgenic mice treated with 2% trehalose presented a reduced atrophy of cerebellar layers and a decrease in the size of protein aggregates in Purkinje cells. In conclusion, we show that trehalose induces the clearance of mutant ataxin-3 in N2A cells and alleviates motor impairments and neuropathological features in a mouse model of MJD, suggesting that trehalose is a promising pharmacological drug for therapy of this disease.

Special Issue on Controversies in Neurology. From the 10th World Congress on Controversies in Neurology (CONy), Lisbon, Portugal. 17–20 March 2016.

International Journal of Clinical Neurosciences and Mental Health 2016; 3(Suppl. 1):L36

Icon_pdf Download PDF

Lecture


Blood-based trancriptional biomarkers of Machado-Joseph disease - read full article

By: Mafalda Raposo and Manuela Lima

Whereas Machado-Joseph disease (MJD) remains an untreatable disorder, disease-modifying compounds have begun being tested in the context of clinical trials; their success is dependent on the sensitivity of the methods used to measure subtle therapeutic benefits. Thus, efforts are being made to propose a battery of potential outcome measures, including molecular biomarkers (MBs), which remain to be identified. MBs are particularly pertinent if trials are expected to enrol preclinical subjects. Our group has been investigating MJD-specific expression patterns, with the aim to identify novel MBs, studying patients in distinct stages of disease severity, as well as asymptomatic and preclinical subjects. Results of an exploratory whole-genome expression microarray allowed us to identify a set of genes whose expression was deregulated in patients blood samples (Raposo et al., 2015). Data from this array was combined with information from the literature concerning molecules whose levels were described as altered in the presence of mutated ataxin-3. In this candidate study we were able to confirm, using quantitative real-time PCR, that levels of HSPB1 and BCL2 were found to be significantly deregulated. We have further performed a pilot longitudinal study, using patient’s samples collected at two moments of disease progression. BCL2 and DNAJB14 adjusted mRNA levels were found to be significantly different between the baseline and the second moment. In an additional microarray experiment, in which different stages of disease progression were included, a set of deregulated genes, currently being analysed, was identified. Candidate MBs will have to be further tested by analysing independent cohorts of patients and evidencing the correlation with clinical as well as imaging data.

Special Issue on Controversies in Neurology. From the 10th World Congress on Controversies in Neurology (CONy), Lisbon, Portugal. 17–20 March 2016.

International Journal of Clinical Neurosciences and Mental Health 2016; 3(Suppl. 1):L37

Icon_pdf Download PDF

Lecture


The Lithium clinical trial - read full article

By: Jonas Alex Morales Saute and Laura Bannach Jardim

In a recent phase II clinical trial in Machado-Joseph disease/Spinocerebellar ataxia type 3 (MJD/SCA3), a disorder without specific therapy, no significance on primary efficacy outcome —NESSCA score—was obtained. However, after 48 weeks of double-blind observation, possible benefit of lithium carbonate therapy appeared on secondary outcomes related to ataxia—SCAFI and CCFS. These apparently conflicting results may suggest that the study protocol should be revisited before ongoing on further studies. Therefore, unplanned subgroup analysis of this data was performed, as hypothesis generating technique for future studies. Treatment response modifiers and metric properties of clinical scales were also done. Sixty-two MJD/SCA3 patients had been randomly assigned (1:1) for the 48 weeks, single center (Hospital de Clínicas de Porto Alegre, Brazil), double-blind, placebo-controlled trial. We performed additional analysis with the subscores of the Neurological Examination Score for the Assessment of Spinocerebellar Ataxia (NESSCA) and the Scale for the Assessment and Rating of Ataxia (SARA) and with the subgroup of patients with independent gait. Potential interactions of clinical/molecular findings with treatment response; minimally important differences (MID); and sample size estimations (with placebo data) of NESSCA, SARA, Spinocerebellar Ataxia Functional-Index (SCAFI) and Composite-Cerebellar Functional-Score (CCFS) were evaluated. Interventions were Lithium carbonate (target serum level of 0.5- 0.8 milliequivalents per liter) or placebo tablets. Cerebellar NESSCA (range: 0-7 points) differed between groups 0.64 points (95% CI 0.23 to 1.05, p<0.001) over the whole 48 weeks of study, favoring lithium. NESSCA (p=0.010) and SCAFI (p=0.015) differed between groups in the subgroup of patients able to perform the 8-meters walking-time, favoring lithium. Estimated sample sizes with the evaluated scales were provided for future trials with lithium or other candidate drugs. Lithium efficacy on cerebellar NESSCA and on SCAFI and CCFS in the primary analysis suggests lithium efficacy on cerebellar features of MJD/SCA3. The interaction of disease severity with treatment response on SCAFI and NESSCA indicates that early stages patients should be preferentially recruited in future studies. We suggest that SCAFI should be utilized as the primary outcomes for phase 2 studies. SARA data from this phase 2 study with positive results on SCAF should provide sample size estimations for phase 3 trials with the same intervention, where SARA should be the primary outcome. The inclusion of independent walking patients only (according to 8MW) is advisable. And finally, taking SARA MID and SARA progression in the placebo group as references, we suggest that future phase 3 studies should be planned for lasting at least 18 or 24 months.

Special Issue on Controversies in Neurology. From the 10th World Congress on Controversies in Neurology (CONy), Lisbon, Portugal. 17–20 March 2016.

International Journal of Clinical Neurosciences and Mental Health 2016; 3(Suppl. 1):L38

Icon_pdf Download PDF

Lecture


Preliminary results of intravenous trehalose for the treatment of Spinocerebellar Ataxia type 3 (SCA3) - read full article

By: C.R. Gordon, R. Zaltzman, C. Klein, H. Greif, I. Gliko-Kabir, and Z. Argov

Background: Trehalose is a disaccharide with protein stabilizing and autophagy enhancing properties. It showed efficacy in reducing abnormal protein aggregation in animal models of several human poly A- and poly Q- mediated hereditary neurological disorders. In animal models of SCA3, oral trehalose showed reduction of lesion size in a lentivirus model and improved motor function in an ongoing study in transgenic animals. The safety and pharmacokinetics of high dose IV trehalose in humans was recently studied in patients with Oculopharyngeal Muscular Dystrophy (OPMD). Objective: To report preliminary results of a phase 2 trial of trehalose 9% IV in SCA3 patients. Design and Methods: This is a proof of concept, phase 2 study to determine and compare the safety, tolerability and efficacy of 52 weekly IV administration of Trehalose 9% IV solution, 13.5 gr vs 27 gr in SCA3 patients. Primary endpoints will be the SARA score with several secondary endpoints (NESSCA scale, 9 hole peg test, 8 meters walk). Safety and tolerability is assessed by various clinical and laboratory tests. Results: We have recruited 15 clinically and genetically confirmed SCA 3 patients who are currently under treatment. No drug-related adverse events were noted. This is in accordance with the reported safety profile of our OPMD study. Efficacy data is very limited data and at the moment is not reportable. Conclusions: Based on these preliminary findings, trehalose 9% IV solution seems to be safe in humans. A further planned phase 2b multi-center clinical trial in SCA3 will be discussed.

Special Issue on Controversies in Neurology. From the 10th World Congress on Controversies in Neurology (CONy), Lisbon, Portugal. 17–20 March 2016.

International Journal of Clinical Neurosciences and Mental Health 2016; 3(Suppl. 1):L39

Icon_pdf Download PDF

Lecture


TTR amyloidosis: a scientific journey - read full article

By: Maria João Saraiva

Mário Corino de Andrade described in 1952 in the journal “Brain” the first form of an hereditary amyloidosis, Famlial Amyloidotic Polyneuropathy, FAP—affecting the peripheral nervous system, also known as Andrade´s disease. In 1939, Andrade observed different patients complaining of loss of sensitivity to temperature and pain and suspected the clinical symptoms were peculiar and belonged to a rare hereditary disease. To understand in depth what he considered a new endemic clinical entity, he asked the collaboration of experts in different fields, such as biochemistry, genetics, pathology, who confirmed the genetic nature of the disease and the presence of systemic amyloid deposits, that we know since 1984 to be constituted by mutant transthyretin (TTRV30M), particularly in the peripheral nervous system. Explosion of molecular biology tools provided identification worldwide of more than 100 TTR mutations, most of them associated with amyloid neuropathies and cardiopathies as well as perspectives for their clinical improvement. Molecular and cellular in-depth studies are underway in several laboratories to dissect underlying ethiopathogenic mechanisms in TTR related amyloidoses; in particular: (1) consequences of protein aggregation on peripheral nerve and other organs and tissues; (2) development of improved/alternative therapies in pre-clinical models; (3) biomarker identification for therapy follow-up.

Special Issue on Controversies in Neurology. From the 10th World Congress on Controversies in Neurology (CONy), Lisbon, Portugal. 17–20 March 2016.

International Journal of Clinical Neurosciences and Mental Health 2016; 3(Suppl. 1):L40

Icon_pdf Download PDF

Lecture


TTR-FAP: diagnosis of familial and sporadic cases - read full article

By: Isabel Conceição

Transthyretin-related familial amyloid polyneuropathy (TTR-FAP) is a rare, autosomal- dominant, adult-onset, systemic disease caused by mutations in the transthyretin (TTR) gene that lead the TTR protein to misfold and deposit as insoluble amyloid fibrils in peripheral and autonomic nerves, the heart, gastrointestinal tract, kidneys, eyes, and connective tissue of the transverse carpal ligament. Initial clinical symptoms may appear between the second and ninth decade of life and, without treatment, TTR-FAP leads to death on average within 10 years of symptom onset. The disease can be difficult to recognize due to extreme phenotypic heterogeneity and nonspecific clinical symptoms. Because of the late onset and low penetrance of TTR mutations in some areas, TTR FAP can present as sporadic cases leading to frequent misdiagnosis. As a result of such misdiagnoses, definitive diagnosis can be delayed for as much as 2–6 years, postponing adequate management and genetic counseling and leading to possible irreversible damage.

Special Issue on Controversies in Neurology. From the 10th World Congress on Controversies in Neurology (CONy), Lisbon, Portugal. 17–20 March 2016.

International Journal of Clinical Neurosciences and Mental Health 2016; 3(Suppl. 1):L41

Icon_pdf Download PDF

Lecture


Molecular aging: a primary or secondary trigger in late onset myopathies? - read full article

By: Vered Raz

The genetic cause for OPMD is an alanine expansion in PABPN1. PABPN1 encodes for RNA binding protein, involved in multiple steps of RNA processing. The protein is ubiquitously expressed but symptoms in OPMD start only from midlife onwards, and initially are limited to only few muscles. This enigma is not fully understood. Recent data correlating molecular and pathological changes with symptoms reveals the most prominent affected molecular pathway in OPMD and key regulators that cause muscle weakness in OPMD. A better understanding of OPMD pathology could lead to better therapeutic developments.

Special Issue on Controversies in Neurology. From the 10th World Congress on Controversies in Neurology (CONy), Lisbon, Portugal. 17–20 March 2016.

International Journal of Clinical Neurosciences and Mental Health 2016; 3(Suppl. 1):L42

Icon_pdf Download PDF

Lecture


OPMD therapy progress - read full article

By: Aida Abu-Baker

Oculopharyngeal muscular dystrophy (OPMD) is a late-onset muscular dystrophy caused by a polyalanine expansion mutation in the first exon of the poly (A) binding protein nuclear 1 (PABPN1) gene. It is characterized by progressive eyelid drooping, swallowing difficulties and proximal limb weakness. Currently there is no effective treatment for OPMD. Here, we will highlight the current translational research research advances in the treatment of OPMD. Both In vitro and in vivo OPMD disease models will be described. We will discuss different experimental therapeutic approaches for OPMD including gene editing, RNA molecules, and drug therapies.

Special Issue on Controversies in Neurology. From the 10th World Congress on Controversies in Neurology (CONy), Lisbon, Portugal. 17–20 March 2016.

International Journal of Clinical Neurosciences and Mental Health 2016; 3(Suppl. 1):L43

Icon_pdf Download PDF

Debate


Is beta-amyloid still a relevant target in AD therapy? - read full article

By: Paulo Fontoura

Point of view: Yes 
The development of disease modifying therapies for Alzheimer disease (AD) is an extremely important goal that has become the focus of major public health initiatives involving governments, civil society, academia and the pharmaceutical industry. The “amyloid cascade” hypothesis of AD is one of the best understood elements of the pathophysiology of this disease, and is based on strong pathological, preclinical and genetic data, including familial and early onset AD and the role of risk factors associated with the production and clearance of amyloid protein, such as ApoE4 genotypes and variants in the APP associated with BACE cleavage. Based on this hypothesis, amyloid-targeting therapies have been the focus of drug development for the past 2 decades. Several different approaches to remove amyloid, employing both active and passive immunization therapies, as well as enzymatic inhibition of the production of amyloid-beta peptides have been tested in large scale clinical trials. So far all these trials failed to produce clinically meaningful results, or have highlighted significant safety risks for gamma secretase and BACE inhibitors. This has led many in the field to question the validity of the amyloid hypothesis and to calls to abandon pharmaceutical research on this target. However, the other side of the story of amyloid-targeting therapies has been one of continuous improvement and learning about AD. Data from several of the recently reported trials with anti-amyloid antibodies have shown consistent trends for efficacy in earlier stages of AD, especially in patients receiving higher doses of antibody. At the same time, key advances in diagnostic criteria, including the use of high quality molecular testing of CSF for amyloid and tau proteins, and the widespread use of PET imaging for amyloid (and development of ligands for Tau), have made it operationally feasible to identify the right patients for trials, and to use pharmacodynamic measures to predict therapeutic doses. Finally, our understanding of trial methodology, including the selection and behavior of clinical endpoints in these populations, and identifying predictors of progression, has improved significantly. While there are still doubts about which of the amyloid species in the cascade is the optimal target for therapy, there is founded hope that current trials being conducted with high-dose anti-amyloid antibodies and BACE inhibitors in prodromal and mild AD will be successful. Nonetheless, the pathophysiology of AD is very complex and involves several other mechanisms and targets beyond amyloid (e.g. p-Tau, inflammation, ER stress, authophagy), and the future of AD treatment will likely be in combination therapies that include targeting amyloid and some if not all of these additional mechanisms to maximize efficacy. Therefore, even if anti-amyloid therapies may not provide a cure for AD, they are very likely to be the first medicines to show disease modifying properties and will remain one of the cornerstones of therapy in the future.

Special Issue on Controversies in Neurology. From the 10th World Congress on Controversies in Neurology (CONy), Lisbon, Portugal. 17–20 March 2016.

International Journal of Clinical Neurosciences and Mental Health 2016; 3(Suppl. 1):D1

Icon_pdf Download PDF

Debate


Amyloid reducing therapies: do they still have a future? - read full article

By: Amos D. Korczyn

Point of view: No 
There is widespread recognition in the urgency to understand the causes and mechanisms of senile dementia. Attempts to find cures for Alzheimer's disease (AD) have, however, failed so far, in spite of enormous investments, intellectual and financial. We therefore have to reconsider the problem from new angles. AD is regarded as a disease because of its clinical manifestations and underlying pathology. However, this combination does not define a disease but rather a syndrome, in analogy with hepatic cirrhosis in which liver pathology causes metabolic changes, but which can result from many different etiologies. It is unlikely that attacking a downstream phenomenon, like apoptosis or beta-amyloid accumulation, can cure AD, or prevent the progression of the disease. It is probable that senile dementia is the result of a combination of several processes, working differently in each person. Epidemiological studies have identified many risk factors for "senile dementia of the Alzheimer type", some genetic but most environmental and thus modifiable. Therefore a concerted action to fight the dementia epidemic must be made by aggressive action against its risk factors, and this battle must begin in midlife, not in old age.

Special Issue on Controversies in Neurology. From the 10th World Congress on Controversies in Neurology (CONy), Lisbon, Portugal. 17–20 March 2016.

International Journal of Clinical Neurosciences and Mental Health 2016; 3(Suppl. 1):D2

Icon_pdf Download PDF

Debate


Is NEDA a clinically relevant endpoint for therapeutic decisions? - read full article

By: Hans-Peter Hartung

Point of view: Yes 
The gratifying development of new drugs for the treatment of MS has greatly broadened our therapeutic armamentarium over the past 10 years. Availability of more efficacious agents has also raised the bar and prompted definition of more ambitious treatment goals. Following an approach adopted by rheumatologists some time ago, the concept of treating to target has also been introduced in the management of MS. In the absence of curative therapies, earlier goals to reduce relapse rate and slow progression have been abandoned and redefined with the aim of silencing disease activity and halting disease progression. Proof of this comes from clinical assessment and MRI evaluation of disease activity and burden. The Disease activity freedom status (DAF) was first analyzed posthoc in the AFFIRM trial of natalizumab. Freedom from disease was operationally defined as absence of relapses, disease progression, gadolinium enhancing T1 lesions and new or enlarging T2 lesions. Havradova et al could show superiority of natalizumab to placebo in attaining disease free status. Subsequently, completed phase 3 trials of new drugs were also analysed to determine what now is termed NEDA, no evidence of disease activity. Clearly, this aggregate outcome provides a more comprehensive view of the efficacy of a drug and is more sensitive to register impact of an agent than clinical or MR outcomes looked in isolation. More recently, in recognition of the importance of brain volume loss as a surrogate marker of the overall pathologic process and a predictor of disability, the composite NEDA 4 has been introduced integrating brain atrophy into the equation. There is discussion whether it might be possible to further enlarge the concept by adding measures of cognition, a very significant domain of neurological functioning impacted by the disease process. Looking at NEDA also aids in assessing relative efficacies of drugs in the absence of head-to-head trials.s

Special Issue on Controversies in Neurology. From the 10th World Congress on Controversies in Neurology (CONy), Lisbon, Portugal. 17–20 March 2016.

International Journal of Clinical Neurosciences and Mental Health 2016; 3(Suppl. 1):D3

Icon_pdf Download PDF

Debate


Is NEDA a clinically relevant endpoint for therapeutic decisions? - read full article

By: Friedemann Paul

Point of view: No 
With the advent of more efficacious MS therapies in recent years, a mere reduction of relapse rate is no longer considered a satisfactory therapeutic goal. Moreover, recent data on MS disease course suggest that probably only relapse rates in the first few years from onset are associated with long-term disability and prognosis, thus underscoring the necessity for additional measures of disease activity and progression that could help guide treatment decisions. Therefore, the concept of “no evidence of disease activity” (NEDA) which roots in the field of rheumatology were disease-free status is an accepted goal for clinical trials and patient care was transferred to MS and first applied in 2009 to the AFFIRM trial (“disease activity free status”), one of the pivotal natalizumab trials. NEDA was defined as a composite score comprising the criteria “No EDSS worsening”, “Freedom from relapses”, “No new/enlarging T2 lesions” and “No gadolinium-enhancing lesions”. 37% of study participants who received natalizumab in the AFFIRM trial were “disease activity free” over 2 years according to this definition. Subsequent analyses for dimethyl-fumarate, fingolimod, cladribine and the combination of glatiramer acetate / interferon beta-1a reported NEDA rates ranging from 28 to 44%. However, despite the beneficial promotional aspect of such a composite score for pharmaceutical companies, the clinical relevance for individual patient management and treatment decisions has not been proved. Moreover, NEDA has been criticized because it heavily relies on radiographic measures whose correlation with clinical measures is only moderate and whose relevance for long term prognosis is equivocal. Most NEDA data are derived from very short follow-up periods and lack comparability between studies which questions the long term importance and predictive value of this measure. Moreover, the NEDA concept disregards relevant features of disease pathology (diffuse tissue damage, grey matter atrophy, retinal atrophy etc.) that are probably more relevant for disease prognosis and long term disability than focal T2/gadolinium-enhancing lesions. Even more serious is the fact that it is totally unclear what the clinical meaningfulness of NEDA is from the patients’ perspective as it does not entirely reflect the clinical need by not taking “intangible” but often severely debilitating symptoms like fatigue, depression, cognitive impairment, pain and sleep disorders into account. Moreover, a recent study from the US has shown that NEDA is hardly an achievable goal in clinical practice as only 7.9% of more than 200 RRMS patients retained NEDA status after a period of observation of 7 years. Recent attempts to overcome some of the criticism by including brain atrophy measurements into the concept (NEDA-4) fall short as standardized brain volume assessments in clinical routine are probably not feasible in the nearer future. In sum, NEDA is currently not relevant for therapeutic decisions.

Special Issue on Controversies in Neurology. From the 10th World Congress on Controversies in Neurology (CONy), Lisbon, Portugal. 17–20 March 2016.

International Journal of Clinical Neurosciences and Mental Health 2016; 3(Suppl. 1):D4

Icon_pdf Download PDF

Debate


My MRI worsened but I didn't. Should I change my disease-modifying treatment? - read full article

By: Mark S. Freedman

Point of view: Yes
We cannot ignore the power of the MRI today which detects clinically relevant changes in the absence of clinical signs or symptoms. Subclinical (MRI only) disease activity is relevant enough to be included in all current renditions of the new diagnostic criteria for MS, fulfilling all the requirements now for ‘dissemination in space’ (DIS) and ‘time’ (DIT) in the absence of any clinical signs or symptoms. In fact, a recent MAGNIMS publication has raised that diagnostic criteria should be even further changed calling for a more simplified, less ambiguous definition of DIS; meeting DIT criteria whether or not the lesions are symptomatic; and indicating the lack of value of non-enhancing hypointense lesions on T1- weighted images (i.e. T1 black holes) in predicting conversion to clinically definite MS when added to the current DIS criteria. They go on to make further recommendations regarding the use of MRI in both CIS and RIS. When it comes to prognosis or monitoring response to therapy, the same MAGNIMS consortium have also addressed this and indicated clearly that MRI also makes an important contribution to the monitoring of treatment, and can be used to determine baseline tissue damage and detect subsequent repair. This use of MRI can help predict treatment response and assess the efficacy and safety of new therapies. They build upon the seminal study by Prosperini et al which was used to establish the cut-off of new lesion development over a year of treatment which by itself (in the absence of any clinical signs or symptoms of relapse or progression) should prompt consideration for switching therapies in the Canadian Treatment Optimization Recommendations. The recommendations for monitoring also require strict adherence to an informative standardized MRI set of acquisition sequences, which offer accuracy in terms of follow-up comparisons to allow for making recommendations based on new lesion development while on a DMT, but furthermore are vital to detecting relevant safety concerns such as the development of an atypical lesion that might suggest PML. It is therefore quite clear that if we are to embark on expensive and sometimes risky medications in order to get a foothold on MS disease, that we intercede and determine as quickly as possible that the medication is not futile and switch to one that will make a difference. MRI monitoring will now allow us to do this with accuracy and in a shorter time than waiting for clinical signs or symptoms of the disease to develop.

Special Issue on Controversies in Neurology. From the 10th World Congress on Controversies in Neurology (CONy), Lisbon, Portugal. 17–20 March 2016.

International Journal of Clinical Neurosciences and Mental Health 2016; 3(Suppl. 1):D5

Icon_pdf Download PDF

Debate


My MRI worsened but I didn't. Should I change my disease-modifying treatment? - read full article

By: Uros Rot

Point of view: No
It is imperative to recognize multiple sclerosis (MS) patients with high risk of disability progression as soon as possible and offer them more potent treatment. Conventional (enlarging T2, novel T2 and Gd lesions) and unconventional (brain atrophy) MRI parameters are putative biomarkers of the disease progression. The data about influence of early conventional MRI parameter worsening (without clinical progression or relapses) on early or late disability in treated MS patients are controversial and available mainly for interferons beta. Some of the studies showed that the development of new T2 or Gd enhancing lesions in the first year of interferon beta treatment predicted second and third year disease activity or worse late clinical outcome, but some of the studies were negative. In a single study from Barcelona the first-year MRI activity did not predict clinical worsening of the disease in the next two years in patients treated with glatiramer acetate. There are many caveats which need to be considered when interpreting comparative MRI data in the treated MS patients. How many novel silent T2 MRI lesions have to be present in the first year for a poor early or late prognosis? One, two or three? In the interferon beta studies different number of early new T2 lesions predicted worse future outcome. One has to be aware that the clinical effects of interferons beta and glatiramer acetate are delayed therefore novel T2 lesions could appear before the start of efficacy of the agents. The substantial problem of all injectable drugs is adherence to the therapy. In a large recent study from Germany only 30-40% from more then 50.000 patients were adherent to the injectables. Furthermore, there is also a problem of an interpretation reliability of paired MRI data among neuroradiologists. In a study from Cleveland for example between-rater variability was high for enlarging T2 lesions, intermediate for novel T2 lesions and low only for Gd enhancing lesions. So far there are no data which would indicate that patients treated with oral drugs or monoclonal antibodies have a poor prognosis with ´MRI only´ worsening. It is even more difficult to include unconventional MRI parameters, such as brain atrophy measurements into early therapeutic decision making. The majority of disease modifying drugs have moderate and inconsistent effect on brain volume which is often delayed (e.g. pseudoatrophy). Therefore, taking into account also a less favorable safety profile of more potent drugs, common clinical reasoning is crucial in the management of an individual with MS and escalation therapy should be given to patients with more realistic risk of poor prognosis.

Special Issue on Controversies in Neurology. From the 10th World Congress on Controversies in Neurology (CONy), Lisbon, Portugal. 17–20 March 2016.

International Journal of Clinical Neurosciences and Mental Health 2016; 3(Suppl. 1):D6

Icon_pdf Download PDF

Debate


Is vitamin D a substantial disease modifier in patients with MS? - read full article

By: Jacek Losy

Point of view: No
Vitamin D can modulate the innate and adaptive immune responses. Existing data show that vitamin D supplementation has major effect in determining MS risk. Data from two large prospective cohorts of woman ( Nurses´ Health Study, 92.253 followed from 1980-2000) and Nurses´ Health Study II ( 95.310 woman followed from 1991-2001) has shown that woman who used supplemental vitamin D had a 40% lower risk of MS, that woman who did not use vitamin D supplements. In the prospective cohort study of 145 participants with relapsing-remitting MS higher 25-OH-D levels were associated with a reduced hazard of relapse. Also the relative risk of developing MS has been found to be lower among woman born to mothers with high vitamin D intake during pregnancy. Controversies exist regarding the therapeutic effect of vitamin D supplementation on the course of MS and not allow conclusion that vitamin D can be regarded as a substantial disease modifier in patients with MS. In a small prospective study 15 MS patients were treated with vitamin D3 2.5 mcg/d for 48 weeks showing that the on study exacerbation rate was lower than baseline. Also in a randomized, double-blind, placebo controlled trial with vitamin D3 as an add on treatment to interferon beta 1b in patients with MS, patients in the vitamin D group have shown a significant reduction of MRI activity in comparison with group of patients only treated with interferon beta 1b. But in a 96-week randomized controlled trial in 68 MS patients , supplementation with 20.000 IU vitamin D3 weekly did not result in beneficial effect on the relapse rate, EDSS , MSFC components or fatigue. Some clinical trials are ongoing. Large prospective trials are needed to resolve this issue.

Special Issue on Controversies in Neurology. From the 10th World Congress on Controversies in Neurology (CONy), Lisbon, Portugal. 17–20 March 2016.

International Journal of Clinical Neurosciences and Mental Health 2016; 3(Suppl. 1):D7

Icon_pdf Download PDF

Debate


Patients with radiologically isolated demyelinating syndrome should be considered for MS disease modifying therapy - read full article

By: Brian Weinshenker

Point of view: No
MS is mainly a silent disease in its early phases. Furthermore, most inflammatory disease MS activity detected by MRI scans is subclinical. Hence, it is not surprising that a clinically silent phase precedes overt manifestations of MS in most patients. What was needed to prove this hypothesis was: 1) unfettered access to MRI technology in large numbers of individuals with symptoms irrelevant to MS (e.g. migraine headaches and other non-MS related symptoms) and 2) an interest in the MS community to follow patients with silent MS-suggestive lesions. In recent years, both these requirements have been satisfied, and there is now a robust interest in the early subclinical phase of MS within the MS community. The term most widely applied to this condition is radiologically isolated syndrome (RIS), and it is clear that it can be the precursor of relapsing remitting MS, and in some prospectively documented cases of primary progressive MS. Wisely, experts have cautioned against making the diagnosis in a confident way in individuals without symptoms of neurological disease and to avoid disease modifying treatment. They have recognized the lack of specificity of MRI markers of MS. While no doubt some will “convert” to MS, it is unclear whether this is the majority. Even if the majority eventually convert, it is not justifiable to expose all patients with subclinical white matter lesions who might eventually manifest symptoms to extremely expensive, indefinitely prescribed and potentially hazardous treatments. In this debate, I will argue against institution of treatment or conducting clinical trials with outcome measures that are predictable (e.g. reduced risk of “conversion to MS”) but should not, in their own right, lead to inappropriate practice recommendations if the trials were to yield positive results. While strong arguments can be made against instituting long term MS disease modifying treatment (DMT) in every patient with early demyelinating disease until it is clear that relapses occur, the strongest argument against use of DMT in patients with RIS is that the diagnosis is uncertain. Nonspecific white matter lesions are extremely common. While current criteria for RIS proposed by Okuda use the more rigorous criteria of Barkhof rather than the more liberal Swanton criteria that have replaced the Barkhof criteria in the latest (2010) version of the McDonald criteria, even the Barkhof criteria have not been rigorously assessed in a general practice setting. The criteria were based on predicting whether dissemination in time and space will be satisfied in patients presenting with typical clinical characteristics of MS such as optic neuritis. A far more common problem occurs in patients who have anything less than an unequivocal presentation of demyelinating disease (e.g. major visual loss and afferent pupillary defect in a patient with optic neuritis). Many patients experience symptoms (e.g. visual migraine, paresthesias in the context of fibromyalgia) that are mistaken for symptoms of demyelinating disease. It is very common to detect nonspecific white matter lesions in the brain that are touted as evidence that patients have radiological evidence for “dissemination in space” and hence MS. Often, the diagnosis is not removed even when the patient sees an expert who is strongly convinced that the diagnosis was made in error and even when the patient is on long term immunomodulators. While many neurologists may argue that the correct diagnosis will eventually declare itself and modifications in therapy will be made, some conditions such as fibromyalgia lead to continuing but unchanging symptoms; definitive evidence of an alternative neurological diagnosis will never emerge. Such patients are at risk of being left on disease modifying therapies (DMT’s) for lengthy periods of time until the diagnostic error is identified, if it ever is. As is the case for MS, but even more convincingly for RIS, the prognosis is indeterminate. Many patients with MS have lengthy periods of remission with no or punctuated by only small numbers of attacks with few sequelae. Benign MS, while only diagnosed confidently retrospectively, is nonetheless common. While it is difficult, if not impossible, to reliably assign a prognosis early, continued observation clinically and monitoring with MRI’s generally permits early detection of recurrent disease activity and institution of DMT’s at a point when the diagnosis is convincing and the prognosis is clearer. The point at which therapy should be introduced is still not well-defined, although there is a trend for treatment to be instituted as soon as a diagnosis of MS is satisfied using McDonald criteria. While perhaps more aggressive than can be justified, even such this approach is preferable to routine institution of treatment before a confident diagnosis of MS is established. Patients are understandably concerned when they are told that they have RIS that they might suffer a devastating demyelinating attack from which they may not recover. It is possible to monitor patients with RIS and identify informative lesions. The benefits of being sure that a long term DMT is necessary outweigh any realistic concerns about a patient experiencing a devastating clinical attack that will not respond to rescue treatment. It is difficult to know after initiating treatment whether a patient’s course deviates from what might be expected for that patient give the variability in the natural course of MS and the incompleteness and variability of outcomes of patients on virtually all DMT’s for MS. It is easy to attribute success to a drug that is unwarranted especially without a period of prior observation to gauge the natural course of disease in a given patient. Furthermore, there are no guidelines for stopping of DMTs, so at the present time, commitment of a patient to a course of therapy is for an indefinite period, a further argument in favor of being certain about the indications for treatment.

Special Issue on Controversies in Neurology. From the 10th World Congress on Controversies in Neurology (CONy), Lisbon, Portugal. 17–20 March 2016.

International Journal of Clinical Neurosciences and Mental Health 2016; 3(Suppl. 1):D8

Icon_pdf Download PDF

Lecture


Disease modifying therapy should be stopped in secondary progressive MS - read full article

By: Abhijit Chaudhuri

Point of view: Yes
Disease modifying therapies (DMT) are not effective in non-relapsing secondary progressive multiple sclerosis (SPMS). Despite the recent progress in the treatment of relapsing remitting multiple sclerosis during the past two decades which has seen the introduction of several drugs, similar success has not been achieved for SPMS. This is primarily due to the intrinsic neurodegenerative process that drives the accumulation of disability in SPMS which is independent of focal inflammatory changes where DMT seem more effective. The underlying pathology in the progressive formof the disease is not unitary and neurodegeneration in SPMS is considered to be multi-factorial, diffuse and significantly influenced by metabolic neuroaxonal changes. One of the characteristic features of SPMS is the involvement of normal-appearing cerebral white and grey matter which worsens in severity with disease progression over time. Current selection of DMT does not influence the wider pathology in SPMS, which is attested by the failure of treatment benefit in several completed randomised controlled clinical trials. These trials have involved over 6000 patients since 1988 and included immunosuppressive agents (Azathioprine, Ciclosporin, Cyclophosphamide, Sulfasalazine, Linomide, Mitoxantrone and Cladribine), first line DMT (Interferon beta 1-a, 1-b, and Glatiramer Acetate), human IVIg, anti-CD20 monoclonal antibody (Rituximab), Myelin Basic Protein and Cannabinoid (Dronabinol). The European and North American placebo-controlled study of interferon beta-1b in SPMS showed divergent results in the primary outcome measure (sustained EDSS progression), while treatment effects were similar on relapse and MRI-related endpoints, confirming the dissociation between disease progression, relapse and MRI markers of inflammation (Enhancing and T2 lesions). There was no clinical benefit of Alemtuzumab in a small trial of SPMS and despite a reduction in inflammatory activity,with no benefit in terms of EDSS progression or rate of brain atrophy in MRI. Fingolimod, an oral DMT approved in relapsing remitting MS (RRMS) for patients failing first line DMT, was not shown to be effective in a large trial of patients with primary progressive multiple sclerosis (PPMS) which shares the disease pathology of SPMS. The clinical trial of Siponimod, an oral S1P superagonist similar to Fingolimod, in SPMS patients is expected to be completed in 2016, and the trial of Rituximab in SPMS will finish in 2017. An interim result of Ocrelizumab, a humanised anti-CD20 monoclonal antibody, found treatment benefit in younger (<55 years) ambulatory PPMS patients with MRI evidence of disease activity (enhancing brain lesions). Several other clinical trials in SPMS are currently ongoing, but very few of these trials are testing currently approved DMT with the exception of Natalizumab (ASCEND trial, estimated completion date in 2017). There is clearly an unmet need of effective treatment in SPMS. This is largely due to the incompleteness in our understanding of the progressive disease pathology in MS. By the exacting standards of “no evidence of disease activity (NEDA), the goal is achieved at best in about 45% of RRMS patients in the clinical trials of DMT and in 15% of placebo-treated patients; the relative size of the difference (30%) is small compared to the size of relative risk reduction of relapse with DMT. This implies that despite the huge success of current DMT with containment of MS relapse, a larger proportion of disease pathology still remains untouched and contributes to the disability progression and transition to SPMS. There is thin evidence, little therapeutic benefit and no cost-effectiveness to support the continuation of existing DMT in patients with established SPMS. A small subgroup of patients with so called progressive-relapsing phenotype with MRI evidence of enhancing or new lesions may in theory continue to experience some benefit from current DMT but this number is small and the presumed treatment benefit in this subgroup should not be extrapolated to all SPMS patients. The recommended stopping criteria for disease modifying therapy (DMT) in patients currently receiving treatment for relapsing remitting disease are: walk for reasons other than MS; which would imply an EDSS score >6.5, and (sustained disease progression) over a 6-12 month period. The disability progression is reflected in MRI as progressive loss of brain volume and cervical spinal cord atrophy without evidence of lesion enhancement. Many patients develop psychological dependence on DMT after having taken it for many years, and feel apprehensive when advised to stop treatment. SPMS patients meeting stopping criteria should be counselled and withdrawn from treatment gradually over a period of 3-4 months to avoid the risk of “rebound” and pseudorelapses; these patients should ideally be offered the opportunity to enrol in new treatment trials of SPMS. Quite appropriately, new treatment trials in SPMS are moving away from the immune-inflammatory focus and aiming at neuroprotection, mitochondrial function, neuroaxonal metabolic reserve and ion transport function with promising early results reported in clinical trials of Simvastatin and Biotin. Such treatments are likely to be introduced early in the future, possibly in combination with DMT in RRMS, to arrest disease progression and conversion to SPMS.

Special Issue on Controversies in Neurology. From the 10th World Congress on Controversies in Neurology (CONy), Lisbon, Portugal. 17–20 March 2016.

International Journal of Clinical Neurosciences and Mental Health 2016; 3(Suppl. 1):D9

Icon_pdf Download PDF

Debate


Should disease-modifying therapies be stopped in patients who have developed secondary progressive MS? - read full article

By: Jacek Losy

Point of view: No
The answer to this dilemma depends on the two fundamental issues: if it is active or nonactive form of secondary progressive (SP) MS and what type of disease-modifying therapies was introduced in the early stages of the disease. Active SPMS is defined as form with relapses and presence of MRI activity in the CNS. In SPMS IFN beta 1b and IFN beta 1a s.c are approved by European Medicines Agency (EMA) and mitoxantrone by FDA and EMA. In the European SPMS study the significant positive effects on disease progression, number of attacs and several MRI parameters was observed in patients treated with IFN beta 1b. Contrary, in the North American SPMS study with IFN-beta 1b no treatment benefit was seen on the time to confirmed progression of disability, relapse- and MRI-related outcomes. A comparison of the both studies revealed that the European trial with positive results included patients with more active MS than the North American trial. The subgroup analysis in SPECTRIMS study (with IFN beta 1a s.c in SP MS) has shown that patients who still had attacs benefit from the medication in terms of disease progression. So existing data indicate that only patients with active form of SPMS should continue treatment with described immunomodulatory treatment. In the MIMS study patients with worsening RRMS or SPMS were assigned placebo or mitoxantrone. At 24 months the mitoxantrone group experienced benefit compared to placebo group for disability progression. The characteristics of the patients included in the MIMS trial however does not allow conclusions to be made in relation to the efficacy of mitoxantrone in SPMS patients without relapses.

Special Issue on Controversies in Neurology. From the 10th World Congress on Controversies in Neurology (CONy), Lisbon, Portugal. 17–20 March 2016.

International Journal of Clinical Neurosciences and Mental Health 2016; 3(Suppl. 1):D10

Icon_pdf Download PDF

Debate


Anti B cell or non specific anti B+T therapy - read full article

By: Hans-Peter Hartung

Point of view: Pro Anti B
More than a decade ago the dominant theories on the etiology and pathogenesis of MS revolved around a prime role of T cells that would recognize target autoantigens in the brain and orchestrate inflammatory insults on CNS parenchyma. Subsequently, numerous lines of research advanced robust evidence for a role of humoral autoimmunity and B lymphocytes in driving or contributing to the disease process. These included histopathological analyses of MS brains detecting immunoglobulin and complement deposits as well as B cells in lesions, and the retrieval of myelin-reactive antibodies and B cells in blood and CSF. The most convincing evidence came from therapeutic studies with the B cell depleting monoclonal anti-CD20 antibody rituximab in RRMS. This highly effective monoclonal induced early suppression of inflammatory disease activity. This temporal profile suggested an action on B cell function as antigen presenters and instructors of T cells rather than a modifying effect on autoantibody production. The clinical development of the humanized anti-CD 20 antibody ocrelizumab culminating in the two OPERA studies in RRMS completed last year replicated the marked therapeutic effects achieved with rituximab in the earlier phase 2 trial. Very interestingly, ocrelizumab also appeared effective in a recently completed phase 3 trial in PPMS. These results raise a number of questions as to the role of B cells in the pathogenesis of this disease type.

Special Issue on Controversies in Neurology. From the 10th World Congress on Controversies in Neurology (CONy), Lisbon, Portugal. 17–20 March 2016.

International Journal of Clinical Neurosciences and Mental Health 2016; 3(Suppl. 1):D11

Icon_pdf Download PDF

Debate


Anti B cell or non specific anti B+T therapy - read full article

By: Bruno Gran

Point of view: Pro Anti B+T
Multiple sclerosis (MS) is a multifactorial disease, with complex aetiology driven by genetics and the environment. Pathogenesis is clearly immune-mediated, as had been suspected for a long time. In this respect, findings from genome-wide association studies (GWAS; Sawcer et al. 2011; Nature 476:214), the pathology of MS brain lesions (Kutzelnigg and Lassmann 2014; Handb Clin Neurol 122:15), animal model studies (Constantinescu et al., 2011; Br J Pharmacol 164:1079), and the response to immunotherapies (Nylander and Hafler 2012; J Clin Invest 122:1180) have confirmed that the immune system is the effector of central nervous system (CNS) tissue damage. In progressive disease, it is likely that neurodegenerative mechanisms are also important. I will argue that MS is driven by potent T-cell and B-cell cooperative mechanisms. Activated T cells are thought to be essential. They enter the CNS through its microvasculature, forming characteristic perivascular cuffs, and are re-activated by CNS-resident antigen-presenting cells to trigger an inflammatory and autoreactive cascade (Hohlfeld et al 2016; Lancet Neurol 15: 198). Such mechanisms have been interfered with, most specifically and successfully, by designing natalizumab as an effective anti-integrin Mab that blocks T-cell entry into the CNS (Yednock et al 1992; Nature 356:6; Polman et al 2006; N Engl J Med 354:899). CD4+ T cells, crucial coordinators of the adaptive immune response, can activate or inhibit other immune cells as they respond to foreign or self antigens in physiological or pathological responses. CD8+ T cells are also well represented in MS lesions and could potentially target oligodendrocytes and neurons directly, through HLA class I-restricted antigen recognition (Friese et al 2008; Nat Med 14:1227). B cells are involved in an immune signature of MS in >90% of patients, namely cerebrospinal fluid oligoclonal IgG bands (OCB; Housley et al 2015; Clin Immunol 161:51). Although the specificity of such oligoclonal response remains unclear, we know from its molecular features that it is antigen-driven, quite possibly by one of more viruses, such as Epstein-Barr virus (EBV, HHV-4). The importance of B cells is also emphasised by their targeting for infection by EBV, a virtually essential factor in susceptibility to MS (Pakpoor et al 2013; Mult Scler 19:162). Production of antibodies by B-cell derived plasma cells is also known to promote more efficient myelin damage by monocyte-derived CNS-infiltrating macrophages, chemo-attracted by activated T cells (Hohlfeld et al 2016; Lancet Neurol 15:317). In addition to their productive interactions in peripheral lymphoid organs and the “classic” perivascular cuffs that characterise MS lesions (immune pathogenesis “from the inside”), T and B cells also interact in the subarachnoid spaces adjacent to the pial surface of the cerebral cortex, most likely leading to different types of cortical lesions “from the outside” (Calabrese et al 2015; Nat Rev Neurosci 16:147). This is most evident, but not necessarily limited to, the tertiary lymphoid follicles observed in advanced progressive cases (Pikor et al 2016; Front Immunol 6:657). Crucially, not only GWAS, but also epigenetic studies indicate unequivocally that MS susceptibility genes are most highly expressed in both T cells and B cells (Farh et al., 2015; Nature 518:337). The excitement for the success of B-cell targeting therapies that started with rituximab (Hauser et al 2008; N Engl J Med 358:676) and led to ocrelizumab (Sorensen and Blinkenberg 2016; Ther Adv Neurol Disord 9:44) and other potential Mabs, should not hinder our efforts to control disease by thoughtful, pathogenesis-driven approaches. We know that the effects of anti-B cell treatments are too fast to be mediated by antibody production and that plasma cells are not even depleted by such antibodies. It is likely that antigen presentation by B cells to T cells is inhibited instead, as are other pro-inflammatory, antibody-independent B-cell functions. We should also keep in mind that drugs that we consider as mainly targeting B cells are in fact also affecting T cells – consider for example the depletion of CD20dim T cells by rituximab (Palanichamy et al 2014; J Immunol 193:580). Conversely, treatments that we consider as aimed at T cells, also have effects on B cells. For example, natalizumab affects the levels of circulating B cells with different naive/memory profiles depending on its effects on the mobilization of hematopoietic stem cells (Mattoscio et al 2015; Neurology 84:1473). In addition, fingolimod promotes a regulatory phenotype and function of B cells (Gruetzke et al 2015; Ann Clin Transl Neurol 2: 119) and reduces the repertoire diversity of newly produced T as well as B cells (Chiarini et al 2015; Mult Scler 21:726). The most effective disease-modifying treatments, either licensed for use (alemtuzumab) or experimental (hematopoietic stem cell transplantation), potently deplete both T cells and B cells, the latter recovering more quickly in subsequent months (Jones and Coles 2014; Exp Neurol 262:37; Sullivan et al 2010; Biol Blood Marrow Transplant 16: S48; Mancardi et al 2015; Neurology 84:981). In conclusion, on the basis of the above mentioned observations, it would be unwise to exclusively target B cells in MS. We are in fact not even able to do so – and until more crucial disease mechanisms are clarified, we probably should not.

Special Issue on Controversies in Neurology. From the 10th World Congress on Controversies in Neurology (CONy), Lisbon, Portugal. 17–20 March 2016.

International Journal of Clinical Neurosciences and Mental Health 2016; 3(Suppl. 1):D12

Icon_pdf Download PDF

Debate


Can we expect long-term clinical improvement through remyelination? - read full article

By: Olaf Stuve

Point of view: No
The pathological hallmarks of all multiple sclerosis (MS) subtypes are focal areas or of demyelinating plaques in the central nervous system (CNS), with surrounding inflammation and neurodegeneration. Demyelination leads to decreased nerve conduction velocity, and predisposition of the axons to neurodegeneration due to lack of physical and metabolic support. In fact, axonal loss can be detected at the earliest stages of MS. In addition, accelerated rates of brain atrophy on magnetic resonance imaging (MRI) is evident at all stages of MS in patients with all clinical phenotypes. The pathological substrate of neurological disability is likely the damaged myelin sheet, and, to a larger extend, the loss of intact axons. Damage to axons in the CNS may be acute or subacute, and very likely irreversible. Thus, remyelinating strategies will have very limited efficacy.

Special Issue on Controversies in Neurology. From the 10th World Congress on Controversies in Neurology (CONy), Lisbon, Portugal. 17–20 March 2016.

International Journal of Clinical Neurosciences and Mental Health 2016; 3(Suppl. 1):D13

Icon_pdf Download PDF

Debate


Long term clinical improvement with remyelination is less likely in MS - read full article

By: Abhijit Chaudhuri

Point of view: No
The precise cause of multiple sclerosis (MS) is still unknown and the disease pathology is complex. Despite the long held assumption of a primary myelin-specific autoimmune process in MS, no myelin-specific autoimmune reaction has so far been identified. Demyelination is one of the key pathological changes in MS, but not the only one. Disability progression in MS is the cumulative effect of chronic and diffuse neurodegenerative process in the grey and white matter of the brain and spinal cord. This is clearly shown in primary progressive multiple sclerosis (PPMS) where the burden of cerebral demyelinating lesion is relatively low. Multi-focal demyelination in brain is considered to be the hallmark of relapsing remitting MS but functional improvement after a clinical demyelinating episode occurs spontaneously over time, even in patients with large (tumefactive) cerebral demyelination. Spontaneous remyelination in MS lesions is either restricted to the lesion edge or extends through the entire lesion area (shadow plaques); these remyelinated plaques may become the future target of new demyelinating events. Shadow plaques are commonly observed in the brain and spinal cord of MS patients and in one post-mortem study, white matter lesions were remyelinated in nearly half of all cases (47%) on average and 22% of them were found to be fully remyelinated. Even during plaque development, remyelination may occur very rapidly and ongoing myelin breakdown may coexist with areas of remyelination. There is no evidence that the number of shadow plaques or early remyelination correlated with better functional preservation in patients with any form of MS. Several attempts have been made over the years to promote remyelination in MS. The concept that remyelination would prevent axonal loss and neuronal degeneration in MS leading to long term improvement however is not established in clinical studies. In animal models of EAE, natural occurring autoantibodies or intravenous immunoglobulins (IVIg) have been shown to successfully induce remyelination; however, human IVIg is not effective as a treatment in MS. Several remyelination pathways have recently become targets of new drug development in MS, including those of LINGO-1, hyaluronan, Notch-1, retinoid X receptor; targets also include pathways involving chemokine receptor type 4 and G protein-coupled receptor 17. There are also a number of existing (“re-purposing”) drugs claimed to enhance remyelination, such as benztropine, clemastine, quetiapine, olesoxime, and ibudilast. However, there is not enough evidence that any of these drugs could be effective in promoting remyelination beyond the level that naturally occurs in MS. Therapeutic attempt at remyelination in MS is at best likely to be partial or incomplete; remyelination alone would not prevent recurrent myelin injury or restore axonal integrity that has already been lost or irreparably damaged. If one takes the view that MS being primarily a neurodegenerative disease with secondary inflammation leading to focal perivenous demyelination in metabolically vulnerable areas of brain and spinal cord, then it is even more difficult to speculate meaningful and long term clinical improvement from therapeutic remyelination in MS. Cortical atrophy occurs before substantial white matter demyelination in MS and predicts future disease progression. A characteristic feature of MS is the disease pathology involving normal-appearing cerebral white and grey matter which inexorably increases in severity with disease and disability progression. It seems unlikely that remyelination will reverse these changes and reduce long term disability progression. The likely physiological benefit of remyelination would be improved nerve conduction and reduced ephaptic transmission rather than protection of cerebral grey or white matter from progressive MS pathology. The recently reported clinical trial outcome of anti-LINGO antibody in acute optic neuritis showed electrophysiological improvement in about 40% patients without clinical benefit; it is not known if some of the treated patients enrolled in this trial might have progressed to relapsing remitting MS. LINGO-1, its signalling partner proteins and pathways have been implicated in several neuropsychiatric disorders and antagonists of LINGO-1 may clinically benefit MS patients possibly for reasons other than remyelination. The appropriate imaging marker of remyelinating lesions in MS is not yet established and its correlation with conventional MRI parameters of disease progression (brain volume loss and spinal cord atrophy) is still completely unknown. Until there are robust clinical trial data supported by imaging markers to confirm sustained functional recovery and prevention of disease progression in MS, the expectation of long term clinical improvement from remyelination therapy would be purely speculative.

Special Issue on Controversies in Neurology. From the 10th World Congress on Controversies in Neurology (CONy), Lisbon, Portugal. 17–20 March 2016.

International Journal of Clinical Neurosciences and Mental Health 2016; 3(Suppl. 1):D14

Icon_pdf Download PDF

Debate


Placebo controlled treatment in neuromyelitis optica (NMO) are unethical and not needed - read full article

By: Ron Milo

Point of view: Yes
Neuromyelitis optica (NMO) and its spectrum (NMOSD) are rare antibody-mediated autoimmune conditions of the central nervous system (CNS) characterized by recurrent aggressive inflammatory attacks causing demyelination and axonal loss mainly in the spinal cord, optic nerves and other brain areas rich in the water channel aquaporin-4 (AQP4). Recovery from attacks is only partial and the devastating nature of the disease may result in high mortality rate or permanent and severe loss of function such as paralysis, blindness and respiratory failure. In contrast to multiple sclerosis (MS), where disability is dissociated from relapses and accumulates mainly in the later progressive phase of the disease, disability in NMO arises solely from cumulative relapse-related injury. Therefore, effective treatment to prevent relapses and associated disability should be initiated as early as possible. Most patients, especially those with the relapsing phenotype, are sero-positive for a pathogenic autoantibody directed against AQP4 located on astrocyte foot processes, known also as NMO-IgG. This antibody is highly specific and helps distinguish NMO from MS, where attacks involving the optic nerves and spinal cord are also common. Immunosuppressive therapies in other rare antibody-mediated autoimmune conditions such as myasthenia gravis and the autoimmune encephalopathies are well-accepted as beneficial although their use is mainly empirical. Standard therapies for these conditions include corticosteroids (CS), plasma exchange (PE), azathioprine (AZA), mycophenolate mofetil (MMF), mitoxantrone or methotrexate (MTX), and their safety profiles are well-established. It seems unnecessary to reinvent the wheel by performing randomized controlled trials each time a new auto-antibody is identified. Although all therapeutic studies in NMO to date have been either small, retrospective case series or uncontrolled prospective studies, they have been consistent with supporting a beneficial response of NMO to immunosuppressants including B-cell targeted therapies and established their use as standard of care in NMO. This is reflected in European Guidelines and a consensus document produced by an international group of NMO experts, which support the initiation of preventive treatment with immunosuppressive drugs as soon as the diagnosis of NMO is made. The European guidelines recommend first-line therapy with azathioprine in combination with prednisolone, or rituximab for B-cell depletion, and second line therapy with cyclophosphamide, mitoxantrone or MMF and potentially with MTX or IVIg, with optional PE for treatment escalation. The International Group of NMO Experts concludes that 6 treatments appear to be likely effective in preventing attacks and stabilizing disability in NMO patients and that the currently available studies provide a limited but helpful insight on treatment effect and tolerability. The expert panel provides recommendations for doses and regimen for 4 first line treatments (azathioprine, MMF, rituximab, or prednisone) and 2 second line treatments (MTX and mitoxantrone), as well as guidelines for monitoring and treatment change considerations. Indeed, several studies have shown that relapses respond to CS and PE, earlier diagnosis and treatment of NMO after the discovery of NMO Ab’s resulted in reduction in the mortality rate over the past 20 years, relapses recover better while on immunosuppressive therapy and treatment with AZA+CS or rituximab is associated with a longer time to next attack. Therefore, a standard of care exists for NMO, which is widely accepted. Still, Prospective trials in treatment-naive patients are required to corroborate the efficacy suggested from nonrandomized studies, compare the effectiveness of various regimens to each other, and determine optimal first-line treatment. New potential therapies for NMO need also to be tested in well-designed controlled trials, which may require participation of many centers, and the issue of comparing them to placebo or to one of the recommended first-line therapies is valid for ethical, scientific and clinical reasons. The rarity of the disease, severity and lack of reversibility of the relapses, early morbidity and mortality in untreated NMOSD suggest that placebo-controlled trials may be unethical. The rationale for comparator rather than placebo-controlled trials may extend beyond the lack of ethics in preventing patient from being treated with recommended therapies, thus exposing them to unnecessary risks of relapses and irreversible neurological damage: The key question about the potential superiority of new agents over the current standard of care will remain unanswered in placebo-controlled trials; Investigators may be under subtle pressures to recruit for a placebo study against their expert opinion and the expected recommendation to start treatment immediately; Recruitment may be slow and insufficient as both clinicians and patients will be reluctant to delay treatment initiation or to take patients off their treatment before enrolling them into the study, and there are likely to be "selection biases", favoring milder patients or those who are unresponsive to standard therapies. Moreover, after study completion, the "better than placebo" and more expensive drug with higher class of evidence but limited safety data may become preferable over currently available effective treatments. The risk of placebo-controlled trials in NMO can be reduced by shortening the time in the comparative phase, and allowing immediate switch to the active drug after the occurrence of a relapse. However, this may lead to earlier escape from the randomized placebo phase of the study and to insufficient comparative safety data on the new treatment. The claim that total number of relapses required to show a statistically significant difference between the study drug and the placebo is smaller and thus more ethical than when comparing active to current treatment may also be misleading, as this may not be the case if current therapies lack evidence of efficacy (thus providing the ground for "clinical equipoise"), a statement that constitutes the main argument for placebo trials in NMO. Even if it is true and less harm may be caused to the whole group, the risk for the individual patient is greater both in terms of the risk to experience a relapse and the severity of the relapses which have been shown to be milder and recover better with immunosuppressive treatment. Although there may be a case for clinical equipoise in NMO and a need for treatments with higher level of evidence and a better benefit/risk ratio, clinical trials in NMO should adopt a design other than a placebo-only control design that is too risky and unethical.

Special Issue on Controversies in Neurology. From the 10th World Congress on Controversies in Neurology (CONy), Lisbon, Portugal. 17–20 March 2016.

International Journal of Clinical Neurosciences and Mental Health 2016; 3(Suppl. 1):D15

Icon_pdf Download PDF

Debate


Placebo controlled treatment in neuromyelitis optica (NMO) are unethical and not needed - read full article

By: Eliezer Katz

Point of view: No
Many considerations are in play when exploring the most appropriate design for a randomized, controlled study in NMO, a design that balances the need for scientific rigor with the safety of participating patients. The two most significant considerations related to placebo-controlled design are those related to the ethics of clinical trials and those related to what constitutes “standard of care.” These two issues, ethics and standard of care, are closely related to each other in the context of assessing the appropriateness of clinical trial design. NMO is a serious disease, and attacks may lead to devastating neurological consequences. There have been no randomized, controlled trials in this disease to direct decision-making; physicians committed to treating patients have adopted immunosuppressive medications approved for use in other autoimmune diseases. The fundamental question is whether the use of a number of available immunosuppressive medications, unapproved for NMO/NMOSD, constitutes a “standard of care” and can be used as an active control and/or background therapy in randomized, controlled trials for new treatments for NMO/NMOSD. The WMA Declaration of Helsinki #33, October 2013 states: “Use of placebo is appropriate where no proven intervention exists and where for compelling and scientifically sound methodological reasons, the use of any intervention less effective than the best proven one is necessary to determine the efficacy and safety of an intervention. In this systematic review, out of 2,438 citations noting NMO/NMOSD, 77 primary studies met the inclusion criteria. Of those, 49 were studies of maintenance therapy to prevent NMO/NMOSD relapses. The systematic review demonstrated that ALL studies that assessed current unproven treatments to prevent NMO/NMOSD attacks are Class IV studies (the lowest) which includes all published Rituximab, AZA, and Mycophenolate Mofetil studies. This means that all published studies were uncontrolled, small, retrospective observational studies. Also, benefit/risk assessment for NMO/NMOSD maintenance therapies cannot be determined based on the published studies because of the minimal reporting of safety evaluations. Therefore, based on this systematic review, all current unproven treatments used to prevent NMO/NMOSD relapses meet Level “U” of the AAN treatment guidelines and do not meet the criteria for establishing clinical guidelines, and probably cannot be referred to as “standard of care”. It is clear that the lack of evidence for treatments in NMO/NMOSD is a significant factor in establishing the ethical basis for a placebo-controlled study. A low level of evidence and lack of “standard of care” are grounds for reasonable professional disagreement among physicians as to the appropriate clinical approach for this disease. The status of disagreement, the “Clinical Equipoise,” provides for an ethical argument that aims at reconciling the overall needs and interests of the “NMO society” with the duties and rights of physicians and patients. When equipoise exists, it is considered ethical to offer physicians and patients the option to participate in a placebo-controlled study, and at the same time, the option to not participate in such a study. To enhance open discussion and the exchange of ideas on the ethical grounds for a placebo controlled study in NMO, a sponsored public open symposium was held at the European and American Committee on Treatment and Research in Multiple Sclerosis (ECTRIMS/ACTRIMS) meeting in Boston on 11 September 2014. This open forum provided a stage for the spectrum of opinions related to the ethical grounds for a placebo-controlled design, which were presented by a range of established experts in NMO and ethics. This symposium highlighted the current state of disagreement among the main stakeholders of this important dilemma, and concluded with the recognition that the current state of clinical equipoise gives ethical legitimacy to a placebo-controlled design for those physicians and patients who decide to participate in such a study. The European Medicine Agency (EMA) conducted a NMO workshop in October 2014 in London which included the participation of NMO expert physicians, ethicists, pharmaceutical representatives, European regulators and patient advocacy group representatives. In this workshop, Dr. Simon Woods, co-director of the policy ethics and life sciences research institute at Newcastle University, summarized what would be required for giving a placebo-controlled design to be ethically justified: Clinical equipoise in place, least possible exposure to placebo, Cross-over/open-label extension, appropriate form of ethical review, consultation with patient groups. Dr. Woods concluded that indeed clinical equipoise is in place in the case of NMO, and those public forums like the EMA NMO workshop, and the ethical symposium in Boston are an appropriate way of ethical review. The use of a placebo controlled trials in NMO and its inherited ethical controversies have led to several recent publications from NMO experts and ethicists analyzing the acceptability of such trial design in this disease (Cree B, 2015; Rhodes R, 2015; Greenberg B, 2015; Weinshenker B, 2015; Palace J, 2015; Levy M, 2015). The authors also analyzed the ethical concerns regarding the harm, benefit and justice of a placebo design in NMO patients as individuals and as the population living with the disease and its implications to treating physicians. Rhodes and Cree concluded that ultimately the choice to participate in a placebo trial comes down to the patient and physician after providing a full informed consent. Rhodes concluded that reluctance to undertake these types of studies benefits neither the potential subjects of the study nor the patients outside the study living with NMO and provides a barrier to the advancement in NMO research. Placebo designed study in NMO should be done with the aim of striking a balance between patient safety and clinical/scientific integrity. Specific measures should be implemented into the study design to mitigate the concerns related to a placebo-controlled study such as short exposure to placebo, unequal randomization, immediate access to rescue therapy, and occurrence of a single relapse as a primary endpoint. In summary, a placebo design study in NMO is ethical and meets all GCP guidelines. This type of a study should be offered to patients and physicians and although not all physicians and patients will choose to participate in such a study, they should have the opportunity to make this decision,

Special Issue on Controversies in Neurology. From the 10th World Congress on Controversies in Neurology (CONy), Lisbon, Portugal. 17–20 March 2016.

International Journal of Clinical Neurosciences and Mental Health 2016; 3(Suppl. 1):D16

Icon_pdf Download PDF

Debate


NMO-IgG is sufficient to cause the pathology of an NMO lesion without participation of T cells - read full article

By: Olaf Stuve

Point of view: No
Neuromyelitis optica (NMO) is a demyelinating inflammatory disorder of the central nervous system (CNS) that is clinically and pathologically defined as the co-occurrence of optic neuritis and myelitis. Aquaporin (AQP)4 is considered a potential autoantigen in patients with NMO after an autoantibody, designated NMO-IgG, that binds to human (h) AQP4 was detected in the serum of the vast majority of patients with NMO. The presence of the NMO-IgG has led many neurologist and neuroimmunologists to believe that NMO may be a primarily B cell-mediated disease. However, there is evidence to suggest a cellular immune response in NMO during disease initiation or perpetuation. HLA haplotype analyses of patients with NMO suggest a positive association with HLA-DRB1* 03:01 (DR17), a gene that codes for a major histocompatibility class (MHC) II molecule that presents linear antigens to CD4+ T cells. Also, NMO-IgG is undetectable in a substantial number of patients with NMO. A NMO-IgG, antibody isotype switch from IgM to IgG could not occur without CD4+ T cell involvement, which are abundantly present in NMO lesions. B cell–depleting therapies are not consistently beneficial in patients with NMO. Finally, transfer of AQP4-reactive T cells into wild-type mice and rats results in neurological deficits and CNS inflammation.

Special Issue on Controversies in Neurology. From the 10th World Congress on Controversies in Neurology (CONy), Lisbon, Portugal. 17–20 March 2016.

International Journal of Clinical Neurosciences and Mental Health 2016; 3(Suppl. 1):D17

Icon_pdf Download PDF

Debate


Treatment of chronic inflammatory demyelinating polyradiculoneuropathy (CIDP): steroids versus IVIg - read full article

By: Eduardo Nobile-Orazio

Point of view: Steroids
Chronic inflammatory demyelinating polyradiculoneuropathy (CIDP) is a chronic and often disabling neuropathy that often respond to immune therapies including corticosteroids, plasma exchange and high-dose intravenous immunoglobulin (IVIg) as also summarized in recent Cochrane reviews. It is however difficult to decide what therapy should be first used in CIDP. This decision should consider the short-term and long–term efficacy, the cost and side effects of each these therapies. A few randomized trials have shown a comparable short-term efficacy of IVIg and oral corticosteroids and of IVIg and plasma exchange in CIDP. Plasma exchange is considered however less suitable for long–term treatment than IVIg and is often reserved to patients with an insufficient response to IVIg or corticosteroids. A randomized trial comparing the six-month efficacy of monthly therapy with IVIg or intravenous methylprednisolone (IVMP) showed that IVIg was more frequently effective and tolerated (87.5%) than corticosteroids (47.6%) during the first six month of treatment. When effective however, corticosteroids were less frequently associated with deterioration than IVIg in the six months following therapy discontinuation. This was confirmed in the follow-up extension of the study showing that the median time to deterioration was significantly longer after discontinuing IVMP (14 months) than IVIg (4.5 months). A similar proportion of patients however eventually deteriorated in the 42 months of median follow- up after discontinuing IVIg (87%) or IVMP (79%) confirming that none these therapies eventually cured CIDP. A similar discrepancy in the prolonged efficacy of steroids and IVIg can be derived from previous studies individually assessing the frequency of deterioration after IVIg or corticosteroids discontinuation. In a study comparing six-month treatment with IVIg and placebo, discontinuation of IVIg was followed by deterioration in 45% of the patients after 24 weeks (5.6 months). Similar data were obtained in a study comparing the efficacy of interferon-beta and placebo in preventing disease progression after IVIg suspension. Clinical deterioration was observed within 16 weeks (3.7 months) in 48% of the patients suspending IVIg in the placebo group. On the other hand the extension of the PREDICT study that compared the efficacy of six month therapy with pulsed oral dexamethasone and daily oral prednisolone in CIDP showed that the median time to relapse after therapy discontinuation was 11 months for oral prednisolone and 17.5 months for pulsed oral dexamethasone, similar to the 14 months of our study. A similar more prolonged efficacy of steroids than of IVIg can be also assumed from a five year follow-up study of 70 patients with CIDP showing that the possibility to stop treatment tended to be more frequent in patients who responded to steroids than to IVIg. The long-term efficacy of continuous treatment with steroids was also shown in an uncontrolled retrospective study on 20 patients with CIDP, 15 of whom were continuously treated for 5 years with monthly high-dose of intravenous methylprednisolone irrespective of the possible phase of reactivity or remission of the disease. The improvement in these patients was maintained up to 5 years and, in those further treated, up to 10 years. Considering the safety of therapy, no significant differences in the proportion of patients experiencing adverse events was observed after six month therapy with IVIg or IVMP, even if it is not possible to exclude that this might occur after a more prolonged use of these therapies. In addition it was recently confirmed that the annual cost per patient was considerably higher for patients with CIDP treated with IVIg (49,000£) than with other therapies (9400£). In conclusion, even if IVIg are more frequently effective and possibly safer than steroids as initial treatment in CIDP, the latter have a more prolonged efficacy and consistently lower cost than IVIg.

Special Issue on Controversies in Neurology. From the 10th World Congress on Controversies in Neurology (CONy), Lisbon, Portugal. 17–20 March 2016.

International Journal of Clinical Neurosciences and Mental Health 2016; 3(Suppl. 1):D18

Icon_pdf Download PDF

Debate


Therapies in chronic inflammatory demyelinating polyneuropathy (CIDP) - read full article

By: Marinos C. Dalakas

Point of view: IVIg
Chronic inflammatory demyelinating polyneuropathy (CIDP) is the most common chronic, acquired immune-mediated disease of the peripheral nervous system with a prevalence of up to 9/100,000. Because it is a treatable form of chronic polyneuropathy, prompt recognition is needed to improve outcome. In CIDP, motor and sensory signs develop slowly, over months, with a minimum of 2 months from the outset. Patients with typical CIDP present with symmetrical proximal and distal weakness, diminished or absent tendon reflexes, symmetrical distal sensory deficits, elevation of the spinal fluid (CSF) protein, demyelination with conduction block on electrophysiology and histological signs of demyelination. Disease variants characterized by asymmetry, prominent motor or sensory deficits and multifocal symptoms are increasingly recognized and may generate diagnostic challenges. About 10-15% of CIDP patients may present acutely resembling Guillain Barré syndrome (GBS) and require early recognition because therapeutic strategies in this subset may be different from the outset. Both cellular and humoral factors have been implicated in the immunopathogenesis of CIDP. T cells, activated macrophages, cytokines, costimulatory molecules and antibodies operate in concert with each other. The increasingly recognized concomitant axonal loss secondary to primary demyelination remains an important factor in therapeutic approaches. Up to 10% of CIDP patients have IgG4 antibodies to paranodal proteins, neurofascin-155 and contacting/Caspr 1(CNTN1), and may represent a distinct subset relevant to therapies because many of them are suboptimally responding to IVIg. Control trials have demonstrated the efficacy of IVIg, plasmapheresis and corticosteroids in most patients. Results and lessons learnt from the largest ever conducted study with IVIg (the ICE trial) after which IVIg gained FDA-approval, suggest that early treatment with IVIg is effective, well tolerated and prevents axonal degeneration; it is therefore preferable to corticosteroids or plasmapheresis. Controlled trials with beta-interferon and Methotrecxate have failed; the other immunosuppressants such as Cyclosporin, Mycophenolate, Rituximab, or Cyclophosphamide may occasionally offer some benefit but controlled studied have not been performed. At least 15% of CIDP patients initially responding to IVIg, continue receiving it for long periods and seem to be “over-treated” because their disease has been in remission or burnt-out; periodic checks to assess whether further treatment with IVIg is needed is therefore essential . Up to 30% of CIDP patients do not adequately respond to available therapies, and new therapeutic strategies are explored in ongoing clinical trials.

Special Issue on Controversies in Neurology. From the 10th World Congress on Controversies in Neurology (CONy), Lisbon, Portugal. 17–20 March 2016.

International Journal of Clinical Neurosciences and Mental Health 2016; 3(Suppl. 1):D19

Icon_pdf Download PDF

Debate


Carbamazepine is an outdated drug that should never be used first line - read full article

By: Martin Brodie

Point of view: Yes
Carbamazepine was synthesised by Schindler at Geigy in 1953, when the company was investigating tricyclic analogues of the recently introduced chlorpormazine. It was first licensed for the treatment of epilepsy in 1965. Carbamazepine is no more effective for focal and generalised tonic-clonic seizures than any of its appropriate competitors. Common side effects include dizziness, fatigue, diplopia, nausea, vomiting, drowsiness and ataxia. It produces dose-dependent hyponatraemia, which can be a particular problem for the elderly and patients taking diuretics and other drugs known to reduce serum Na+. Life threatening idiosyncratic adverse reactions, such as aplastic anaemia, hepatotoxicity and Stevens-Johnson syndrome can be an unusual complication of its introduction. Serious drug rashes are substantially more common in Asian patients possessing the HLA-B*1502 and in Europeans possessing the HLA-A* 3101 alleles. Carbamazepine is also a dose dependent teratogen. The main reason, however, that carbamazepine is now an outmoded drug for first line use is the increasing appreciation of the adverse effects of its enzyme inducing properties on exogenous and, particularly, endogenous substrates. It has the property of increasing the synthesis of a wide range of oxidative and conjugating metabolic enzymes in the liver and throughout the body. Most therapeutic drugs are substrates for these pathways, resulting in a reduction in their elimination half-life and bioavailability by around 50-66%. This substantially reduces their efficacy unless the dose is appropriately increased, which can have major cost implications. Potential problems include unwanted pregnancy in patients taking oral contraceptives, increased cancer mortality, progressive AIDs, transplant rejection, uncontrolled hypertension, breakthrough pain etc. Doses of many other AEDs that are metabolised in the liver also need to be increased when combining them with carbamazepine. Withdrawal of carbamazepine, in addition, can more than double the circulating levels of all of these medicines leading to unexpected toxicity if their doses are not appropriately reduced. This too can be a problematic process. More recently there has been increasing awareness of the effects of longterm enzyme induction with carbamazepine on vitamin D resulting in reduced bone density with subsequent osteoporosis and an increased propensity for fractures. The drug can also produce sexual dysfunction in both men and women by inducing the breakdown of a range of sex hormones. Lastly, and arguably most worrying, treatment with carbamazepine increases cholesterol levels leading to higher risks of myocardial infarction and stroke. Enzyme induction with carbamazepine continues as long as the patient takes the drug. No one can predict what health problems lie in wait down life’s journey. Managing concomitant treatment in enzyme-induced patients can be difficult and withdrawing the drug can have disastrous consequences, since many doctors across a range of clinical disciplines will be unaware of its pitfalls. In conclusion, enzyme induction with carbamazepine can subtly and unpredictably complicate the lives of people with epilepsy. I would not take the drug myself nor would I prescribe it for a member of my family and so why would I offer carbamazepine to my epilepsy patients when a number of other equally effective, safer and user-friendly alternatives are available?

Special Issue on Controversies in Neurology. From the 10th World Congress on Controversies in Neurology (CONy), Lisbon, Portugal. 17–20 March 2016.

International Journal of Clinical Neurosciences and Mental Health 2016; 3(Suppl. 1):D20

Icon_pdf Download PDF

Debate


Carbamazepine is an outmoded drug and should never be used as a first-line drug - read full article

By: Cigdem Ozkara

Point of view: No
Carbamazepine (CBZ) is a major first-line AED for partial seizures and generalized tonic-clonic seizures. It is a tricyclic compound discovered by chemist Walter Schindler at J.R. Geigy AG, Switzerland, in 1953 while they were searching for more active psychotrphic drugs. It was first marketed as a drug to treat epilepsy in Switzerland in 1963 and its use for trigeminal neuralgia was introduced at the same time. In 1968, (CBZ) was approved, initially for the treatment of trigeminal neuralgia; later, in 1974, it was approved for partial seizures in USA. CBZ’s main mode of action is to block sodium channels during rapid, repetitive, sustained neuronal firing and to prevent posttetanic potentiation. It is available in immediate and extended release and syrup formulas CBZ is one of the most widely used AEDs in the world. It is highly effective for partial-onset seizures, in both adults and children. It also has demonstrated good efficacy in the treatment of generalized tonic-clonic seizures.. Although it is considered to be a first-generation drug, studies failed to show any superior efficacy of second- generation drugs over CBZ. Adverse effects were more common with CBZ in some studies however majority of them used immediate release formulas which can cause unwanted effects more than extended release formulations. It is among the first line recommended drugs for partial and generalized tonic clonic seizures even in recent updated guidelines. Its psychotropic effects is also very important as many newer drugs such as VGB, TPM and LEV have serious behavioral and cognitive side effects which may complicate the treatment of patients with epilepsy who very frequently suffer from various psychological problems. The therapeutic range is considered between 4-12 mcgr/ml and available for monitoring in almost everywhere which may ease the drug management. The drug is highly effective and well tolerated. Its major disadvantages are transient adverse dose-related effects at initiation of therapy and occasional toxicity. Potential dose-related adverse effects include dizziness, diplopia, nausea, ataxia, and blurred vision. Rare idiosyncratic adverse effects include aplastic anemia, agranulocytosis, thrombocytopenia, and Stevens-Johnson syndrome. Asymptomatic elevation of liver enzymes is observed commonly during the course of therapy in 5-10% of patients. Rarely, severe hepatotoxic effects can occur. Nevertheless, long term usage yielded an accumulated information about the long and short term side effects related to dosage or idiosyncratic reactions which helps the physician to warn and monitor the patients. Moreover recent advances in pharmacogenomics studies showed serious hypersensitivity reactions in patients with HLA B* 1502 from Han Chinese and South Asian populations. Therefore performance of specific tests can improve the safety of the drug in suspected groups. On the other hand all new drugs have unwanted side effects i.e. renal stones with TPM and ZNM, retinal problems with VGB, hypersensitivity reactions with LTG, psychiatric disorders with LEV etc. Third generation more newer drugs are so recent that we have to be very careful for unexpected events such as skin discoloration and retinal changes happened with retigabine which limited its usage. The teratogenic effect may differ among the pregnancy registries between 2- 6% where dosage below than 400mg seems to be relatively safe but coadministration with PB or VPA increases the risk of malformations. In addition the newer drugs can be significantly more expensive and there is no clear evidence that they are more cost effective. Finally because of its wide availability, relative inexpensiveness and proven efficacy, CBZ continues to be widely used for epilepsy.

Special Issue on Controversies in Neurology. From the 10th World Congress on Controversies in Neurology (CONy), Lisbon, Portugal. 17–20 March 2016.

International Journal of Clinical Neurosciences and Mental Health 2016; 3(Suppl. 1):D21

Icon_pdf Download PDF

Debate


Can we predict with reasonable confidence which patients with idiopathic generalized epilepsy will remit? - read full article

By: Elinor Ben Menachem

Point of view: Yes
Iopathic generalized epilepsies (IGEs) are genetically determined forms of epilepsy. They are age specific and can start in infancy, childhood, adolescence, and even in adulthood. The age related IGE’ s are usually life long and comprise about 1/3 of all epilepsies. According to the ILAE the following are the major types are benign myoclonic epilepsy in infancy (BMEI),generalized epilepsies with febrile seizures plus (GEFS+), epilepsy with myoclonic-astatic seizures (EMAS), epilepsy with myoclonic absences (EMA), childhood absence epilepsy (CAE), and IGEs with variable phenotypes that include juvenile absence epilepsy (JAE), juvenile myoclonic epilepsy (JME), and epilepsy with generalized tonic-clonic seizures only (EGTCSO). Some of these syndromes that are more common in the adolescent and adult patient are CAE, JME, JAE, and EGTCSO. In theses syndromes withdrawal of AEDs can be successful in certain instances. In CAE only without GTCs, medication can be withdrawn, most commonly after 2 years. However, newer results suggest that withdrawal after 5 or 6 years might be more reliable as GTCs can appear at 5 years. For JME, about 30% can remain seizure free after drug withdrawal. Seizure freedom can even be more successful in JAE and EGTCSO after an extended period of seizure freedom with AEDs.

Special Issue on Controversies in Neurology. From the 10th World Congress on Controversies in Neurology (CONy), Lisbon, Portugal. 17–20 March 2016.

International Journal of Clinical Neurosciences and Mental Health 2016; 3(Suppl. 1):D22

Icon_pdf Download PDF

Debate


Can we predict with reasonable confidence which patients with idiopathic generalized epilepsy will remit? - read full article

By: Martin Holtkamp

Point of view: No
The subgroup of generalized epilepsies which for decades has been known as ‘idiopathic’ has now been suggested to be termed ‘genetic’. Beyond terminology, the conceptual considerations however are very similar, and idiopathic / genetic epilepsy is, ‘as best as understood, the direct result of a known or presumed genetic defect in which seizures are the core symptom of the disorder’. Prevalence studies consistently demonstrate that idiopathic generalized epilepsies (IGE) make up 15 to 20 % of all epilepsies. IGE subsyndromes are characterized and defined by age at onset of epilepsy and by the predominant seizure type. Three IGE subsyndromes commonly commence in adolescence, i.e. between the age of 12 and 18 years. These comprise juvenile absence epilepsy (JAE), juvenile myoclonic epilepsy (JME), and epilepsy with grand mal only either manifesting on awakening (EGMA) or by random (EGMR). Long-term seizure outcome in regard of remittance even after withdrawal of antiepileptic drugs may be non-congruent in these subsyndromes. In IGE, long-term seizure outcome data are not available from prospectively followed incidence cohorts, but only from retrospective prevalence cohorts. In an Austrian study, 64 JAE patients had a follow-up of 22 years, 37 % were seizure free in the terminal 2 years, the vast majority was still treated antiictally. A meta-analysis on childhood absence epilepsy and JAE with 27 % of patients being adolescents or adults at absence epilepsy onset revealed terminal seizure freedom (duration depended on time of follow-up which was heterogeneous) in 59 % of patients. Absence epilepsies without generalized tonic clonic seizures had a more favorable outcome (78 % seizure-free) than those with generalized tonic clonic seizures (35 %). Another predictor for long-term seizure freedom in absence epilepsies was older age; the older the patients were and thus the longer epilepsy has lasted, the less likely they still had seizures. Until some years ago, the axiomatic dogma was that JME requires lifelong antiictal treatment, otherwise seizure recurrence would be almost inevitable. In the last couple of years, five retrospective studies on long-outcome of JME have been published. A total of 208 patients were followed up for at least 20 years. Five-year seizure remission was seen between 27 and 68 %, and for at least 5 years, 8 to 26 % of all patients in addition to seizure freedom were off antiictal medication. Out of 45 patients who were off medication at the end of the study, 31 were seizure free for at least 5 years. However, it is unclear how many patients in the course of their disease had seizure relapse after withdrawal of antiictal medication and then restarted regular drug intake. Our center identified manifestation of additional absence seizures at onset of JME as an independent predictor for lack of terminal 5-year seizure remission. In univariate analysis, other studies demonstrated that long duration of epilepsy with unsuccessful treatment, antiictal polytherapy, and generalized tonic clonic seizures preceded by bilateral myoclonic seizures are significantly associated with lack of seizure freedom. There was a general trend that the older the patients were, the more likely they were in remission. In the early course of EGMA, favorable treatment response to antiictal substances is well known, but until recently long-term data on seizure prognosis had not been available. We reported 42 patients with a ‘pure’ form of EGMA lacking absence seizures and myoclonia. Patients had a mean follow-up of 40 years, and 26 subjects (62 %) had been seizure-free for at least the last 5 years. Only five seizure-free patients were off antiictal medication. We identified current age to be the only independent predictor for lacking seizure freedom in the terminal 5 years. Remission rates were 35.7% in patients 55 years and younger (n = 14), 66.7% in patients aged between 56 and 65 years (n = 12), and 81.3% in patients older than 65 years (n = 16). Withdrawal of antiictal substances had been performed in 19 patients (45.2%), 12 of which had seizure relapse (63.2%). Mean time between withdrawal and relapse was 22 ± 31 months (median 7 months). We do not know how many of the 23 continuously treated patients would still be seizure free, if antiictal drugs had been withdrawn in the course of the disease. This, however, was done rather reluctantly due to our early experiences regarding seizure relapse after withdrawal of antiictal agents. In a Canadian population-based study, 40 patients with epilepsy with grand mal by random were reported. In 33 patients, antiictal drugs had been withdrawn and 27 of those patients (75 %) were seizure-free for more than 15 years. These findings are in line with 15 of our patients with EGMR, 12 of those (80 %) were seizure-free in the last 5 years. To conclude, currently available data are based on single-center retrospective studies revealing heterogeneous findings in regard of seizure remittance. Roughly speaking, probability of seizure freedom within the last 5 years is determined by higher age, but the majority of patients are still on antiepileptic drugs. Up to now, published data do not allow to sufficiently predict which IGE patients will remain seizure-free after antiepileptic drug withdrawal.

Special Issue on Controversies in Neurology. From the 10th World Congress on Controversies in Neurology (CONy), Lisbon, Portugal. 17–20 March 2016.

International Journal of Clinical Neurosciences and Mental Health 2016; 3(Suppl. 1):D23

Icon_pdf Download PDF

Debate


Should we regularly check for autoimmune causes in patients with refractory epilepsy without other obvious causes? - read full article

By: William Theodore

Point of view: No
Autoimmune epilepsy exists when seizures are accompanied by evidence of autoimmune-mediated central nervous system inflammation. Seizures have long been known to occur as part of the spectrum of a variety of systemic autoimmune disorders, particularly systemic lupus erythematosus. More recently, an increasing number of ‘autoimmune encephalitis’ syndromes have been identified, with seizures either as the major manifestation, or accompanying other presentations such as psychiatric disorders. Both intracellular (such as Hu and Ma) and surface antigens (for example GABAR or LGI1) may be antibody targets in autoimmune encephalitis. The former are more likely to be associated with tumors although NMDAR antibodies may be particularly associated with ovarian teratomata. The overall incidence of autoimmune encephalitis is unknown. Surveys such as the California Encephalitis project may only test patients with specific symptoms or signs suggesting an immune etiology. For example, of 761 patients with encephalitis of unknown origin, only 47 were tested fro NMDAR antibodies; 32 were positive. Twenty-one percent of patients in another survey had immune-mediated encephalitis. These patients, however, all had symptoms of acute encephalitis, rather than seizures alone. Other antibodies are much rarer. GABAB receptor antibodies were detected in seven of 3989 patients evaluated for autoimmune encephalopathy; five of them had small cell lung cancer. AMPA receptor antibodies were found in 1% of patients with suspected encephalitis/encephalopathy. In the Bethel Antibody laboratory from 2012-2014, 4.7% of 6893 patients with epilepsy had positive tests (NMDAR and GAD65 antibodies the most common). Some clinical features may suggest that autoimmune encephalitis should be considered as a potential seizure etiology. Some patients have signs or symptoms of 'limbic encephalitis' in addition to seizures, such as psychiatric manifestations or increased hippocampal signal. Other explanations such as bone marrow transplant-associated HHV6 encephalitis need to be excluded as well. Adults presenting with new-onset seizures, particularly if frequent or status epilepticus occurs, and there is no other explanation such as a tumor, should be considered for evaluation. Young women with a suspected ovarian teratoma and new-onset seizures should be tested for NMDA receptor antibodies. There are a few specific seizure syndromes, such as 'faciobrachial dystonic seizures,' that have been associated with autoimmune encephalitis due to LGI1 antibodies, as well as the 'extreme delta brush' EEG pattern in NMDAR encephalitis. CSF may show non-specific markers of 'inflammation. Although detection of some antibodies has high specificity for the diagnosis of autoimmune encephalitis, others have less certain implications, particularly when tiers are low. Treatment involves combinations of IVIG, plasmapheresis, and steroids as well as other drugs such as cyclophosphamide or rituximab that have serious potential toxicity. Moreover, controlled trial data are limited. These considerations suggest that testing all patients with seizures of uncertain etiology for possible autoimmune encephalitis may well lead to overdiagnosis and treatment, with increased adverse effects, as well as delay in furthering understanding of the best therapeutic approach. Only patients whose signs and symptoms lead to reasonable suspicion of the diagnosis should be tested.

Special Issue on Controversies in Neurology. From the 10th World Congress on Controversies in Neurology (CONy), Lisbon, Portugal. 17–20 March 2016.

International Journal of Clinical Neurosciences and Mental Health 2016; 3(Suppl. 1):D24

Icon_pdf Download PDF

Debate


Can the Wada test be replaced by fMRI and other techniques? - read full article

By: Andrew C. Papanicolaou

Point of view: Yes
The Wada test is typically used for identification of the language- and memory-dominant cerebral hemisphere. The test is considered the “gold standards”—a term implying that the evidence it furnishes is trust worthier than evidence from other methods. The advent of noninvasive functional neuroimaging now raises the possibility of replacing this “gold standard” pro-vided it offers equally trustworthy results. It will be argued here that these methods, namely functional magnetic resonance imaging fMRI, magnetoencephalography (MEG), and transcranial magnetic stimulation (TMS) do provide equally trustworthy results, and that therefore they may replace the Wada test in many if not most cases. The compatibility of the language lateralization results of the Wada and the fMRI procedure has been shown in a number of studies reporting perfect concordance or high concordance equally high is the compatibility between the results of the Wada and MEG with respect to language lateralization. Fewer studies, however, report comparisons of laterality estimates for memory between fMRI and Wada, with some reporting high and others also low concordance raising the questions as to which method is to be trusted. Given that the degree of concordance between the Wada and the noninvasive methods is not perfect (and sometimes low as in the case of memory lateralization) the question becomes: The results of which method is to be considered valid? On the basis of the assumption that the Wada is the “gold standard,” the tendency is to consider discordant estimates as failures of the neuroimaging methods. However, when that assumption is put to the empirical test it becomes obvious that the results of the Wada should not be considered any more valid than the results of the noninvasive methods. For example, the efficacy of the Wada procedure is lower than would be expected for a gold standard procedure for predicting the likelihood of postoperative language and memory deficits. In contrast, fMRI has shown better predictive efficacy than the Wada. In addition, many studies are conducted every year for the purpose of fine tuning the noninvasive methods in revealing with increasing reliability brain regions involved in different aspects of memory and language performance using fMRI, MEG and, lately, TMS and verifying the validity of the findings, mainly against prior knowledge gained from lesion studies. Therefore, given that the validity of the data of the Wada is limited, there is no justification in considering them more trustworthy than data supplied by neuroimaging, in those few cases that the results are in fact discordant. The practical question of course remains: Given that both types of methods are suboptimal, which type should be used preoperatively? But, given the compatibility of the two sets of methods, both in terms of their concordance in most cases and their imperfections in few cases, the noninvasive methods should be used as a matter of course because, in case their results are ambiguous, testing can be repeated and the results of the different ones cross-validated (e.g. of fMRI or MEG against TMS for expressive language; MEG and fMRI for receptive language, and so on). And only if the ambiguity is still not resolved should the Wada test be performed in the hope that they may resolve it. Moreover, although both types of methods have limitations, the following ones, specific to the invasive but not to the non-invasive methods, render the latter preferable. First, the Wada is associated with appreciable morbidity, ranging between 3 and 5%. Second, it is associated with patient discomfort. In contrast, no morbidity and only minor discomfort is associated with neuroimaging. Third, the results of the Wada procedure may not suffice for assessing memory laterality because delivery of the sodium amobarbital to the hippocampal formation is not always possible and because the structure of the Wada protocol does not allow for separate estimation of hemispheric dominance for verbal and for nonverbal encoding, although there is evidence of stimulus modality–specific encoding in the left and the right hippocampus. Needless to say, fMRI can discern the involvement of all brain structures associated with memory, both neocortical and paleo-cortical, and because it can be repeated, it can identify distinct components of the memory-specific brain circuitry. A fourth and a fifth limitation of the Wada test are due to the narrow time window in which it must be performed and its repetition for establishing reliability of the results is impractical. Moreover, the Wada may not probe for the mechanisms of a host of different cognitive operations that are subsumed under “language” and “memory.” Yet, the neuronal networks of such operations can be assessed separately in the context of several neuroimaging sessions. A seventh problem, also reducible to the time constraints, is the inability to control for situational variables that may corrupt the integrity of the data. Attention lapses on the part of the patient in the crowded Wada suite where a number of tasks have to be done under time constraints may well produce misleading data. Eighth, the Wada test cannot supply information about the primary visual and auditory cortex that both MEG and fMRI can readily supply. Finally, the Wada test requires alertness and cooperation on the part of the patient. Thus it cannot be used with patients with attention deficit and hyperactivity problems, patients in a state of confusion, patients with encephalopathies, or patients who are very young. None of these limitations apply to neuroimaging, where localization of sensory, motor, and even receptive language cortex can be accomplished with the patient under sedation. For all the preceding reasons it is proposed that the Wada may be replaced as the methods of choice in many if not most cases where the non-invasive methods are available.

Special Issue on Controversies in Neurology. From the 10th World Congress on Controversies in Neurology (CONy), Lisbon, Portugal. 17–20 March 2016.

International Journal of Clinical Neurosciences and Mental Health 2016; 3(Suppl. 1):D25

Icon_pdf Download PDF

Debate


Combination therapy should be used after failure of one or two antiepileptic drugs - read full article

By: Martin Brodie

Point of view: Yes
Over the past 20 years, more than 15 new antiepileptic drugs (AEDs) have been introduced globally many possessing unique mechanisms of action. Despite this plethora of novel agents, outcomes for the common epilepsies in children and adults have not substantially improved, largely because all AEDs are symptomatic anti-seizure and not anti-epilepsy drugs. Three main patterns of response have been identified with just less than 60% of patients having a good prognosis once an appropriate well tolerated AED has been successfully introduced, with another 25% developing refractory epilepsy probably de novo. The remainder of the patient population demonstrate a relapsing/remitting course with around half being seizure free at any one time. Very few patients attain remission after failing their first 2 AED schedules particularly due to lack of efficacy. The International League against Epilepsy (ILAE) defines drug resistant epilepsy as “failure of adequate trial of two tolerated, appropriately chosen and used AED schedules (whether as monotherapies or in combination) to achieve sustained seizure freedom”. If treatment fails at a low dosage due to poor tolerability or following the development of an idiosyncratic reaction, another AED should be substituted. Similarly if the patient documents worsening in seizure control or no useful improvement, another drug, arguably possessing a different mechanism of action, should be tried. However, if there is good response to treatment falling short of seizure freedom with the first or second AED, another drug should be added, again with a different mechanism of action. Attention should be paid particularly to drug burden, which is a function of high dosage as well as number of AEDs. Different mechanistic groups of AEDs include those affecting the fast and/or slow inactivated state of the Na+ channel, e.g. lamotrigine, oxcarbazepine and lacosamide, calcium channel blockers e.g gabapentin and pregabalin, GABA-ergic drugs e.g clobazam, those that modulate SV2A, e.g levetiracetam, Kv7 neuronal potassium channels e.g retigabine, or AMPA receptors e.g perampanel. Alternatively, the addition of a broad spectrum AED with multiple mechanisms of action can be tried, such as sodium valproate, topiramate or zonisamide. In clinical practice more than 50 combinations of AEDs have been reported to be successful in individual patients. The approach of combining rather than substituting AEDs in patients with difficult to control epilepsy is more likely to be effective and is a safer option than switching randomly from one drug to another, which carries with it the risk of seizure exacerbation and/or acute neurotoxicity. The most successful duotherapy is lamotrigine with sodium valproate, for which there is good evidence of synergism. There are increasing data supporting the use of AEDs possessing different mechanisms of action in combination. Keeping doses low allows combinations of 2 or sometimes 3 AEDs to be tried in the hope of attaining sustained seizure freedom without unacceptable toxicity. In addition the patient is more likely to retain confidence in their physician if a clear plan of action is laid out early for those who are most likely to have pharmacoresistant epilepsy. The major problem in this setting is the lack of good evidence in support of either course of action in the population at large or for the individual patient and so clinical experience is the driver in this setting.

Special Issue on Controversies in Neurology. From the 10th World Congress on Controversies in Neurology (CONy), Lisbon, Portugal. 17–20 March 2016.

International Journal of Clinical Neurosciences and Mental Health 2016; 3(Suppl. 1):D26

Icon_pdf Download PDF

Debate


Should combination therapy be used after failure of one or two antiepileptic drugs? - read full article

By: Elinor Ben Menachem

Point of view: No The case scenario of this debate from my side is an adult patient with new onset focal seizures. Earlier studies of Brodie (2001, 2012) lead us to believe that there is no use of trying the third antiseizure drug (commonly called antiepileptic drug-AED) if the first two fail before going on to polytherapy and that the whole exercise is rather useless. This is not, however, correct because there is still a lot that can be done before going on to polytherapy with all the side effects that can occur with combinations. First an assumption before the argument: The correct AEDs are given to the patient in the first place and that the patient actually takes the drugs and that the patient actually has focal onset epilepsy. First of all, when 2 drugs fail, then the patient needs to be referred to an epileptologist who understands the full range of AEDs for further dose adjustments or change of medication. Some of the adjustments that can be done are switching to a drug with another mechanism of action, or dose increases up to higher drug concentrations of the drug that the person is currently taking. Time of dosing can also be an important factor in seizure control. Environmental stressors should be analyzed and corrected when possible. According to other studies, a significant minority of patients (about 16%) can be rendered seizure free by changing up to 3-5 AEDs. Recent examples that even refractory patients can become seizure free are the new down-titration to monotherapy drug trials that have shown success for some new AEDs as lacosamide and eslicarbazepine. Patients should be given more than 2 chances of trying more than 3 AEDs before calling them refractory.

Special Issue on Controversies in Neurology. From the 10th World Congress on Controversies in Neurology (CONy), Lisbon, Portugal. 17–20 March 2016.

International Journal of Clinical Neurosciences and Mental Health 2016; 3(Suppl. 1):D27

Icon_pdf Download PDF

Debate


Should responsive neurostimulation be offered in preference to other forms of neurostimulation when a well defined focus is known? - read full article

By: Martin Holtkamp

Point of view: No
Multiple subcortical brain structures and cortical epileptogenic foci have been targeted for invasive—deep or subdural—brain stimulation in epilepsy. Most data on efficacy are derived from small, uncontrolled clinical studies hampering the significance of reported findings. Reliable data are available for continuous stimulation of the anterior nucleus thalamus and for responsive stimulation of the seizure onset zone in neo- or archicortical structures. Whether positive results of regulatory trials can be translated to the broad spectrum of difficult-to-treat epilepsies in the community, needs to be assessed at best by use of large international multi-centre registries. Prerequisite for successful invasive brain stimluation in epilepsy is ineligibility for possibly curative resective surgery and—most importantly—accurate phenotypisation of patients; different clinical forms of epilepsy may respond differently to individual targets and stimulation parameters. The general concept of deep brain stimulation in epilepsy is continuous electrical stimulation in order to increase neuronal inhibition independent of the state of cortical excitability or seizure occurrence. An alternative approach is to continuously record electrocorticographically neuronal activity in the supposed seizure focus and to stimulate the epileptogenic zone responsively only in the case of abnormal activity. In clinical practice, induction of stimulation can be rather frequent, and up to 3,000 trains of stimulation have been observed within 24 h questioning the concept of responsiveness. In a large randomised controlled trial on patients with intractable partial epilepsy, 109 adult patients from 17 centres in the U.S. underwent either 3-month bilateral electrical stimulation of the anterior thalamus or no stimulation starting 1 month after electrodes had been implanted. Compared to a 3-month prospective baseline period, patients with stimulation on had a reduction of seizure frequency of 40.4% while patients with stimulation off had a reduction of 14.5%, indicating significant efficacy of chronic ANT stimulation. The two most common self-reported adverse effects were depression (14.8%) and memory impairment (13.0%), both of which were significantly more common compared to non-stimulated controls (1.8%, resp.). This regulatory clinical trial resulted in receipt of the CE certification (CE = Conformité Européenne) in the year 2010 in Europe that allows for ANT implantation in patients with refractory epilepsy. So far, there is no approval by the Food and Drug Administration in the U.S. After the end of the 3-month blinded period, all patients were offered open-label ANT stimulation. One year after electrode implantation, median reduction in seizure frequency compared to baseline was 41%, and after 5 years, frequency reduction was 69%. Along with reduced seizure frequency, clinical variables such as seizure severity, quality of life, and neuropsychological test composite scores including depression, anxiety, and subjective cognitive function significantly improved. In another randomized controlled trial, eventually 191 patients underwent intracranial implantation of a neurostimulator directly addressing the seizure onset zone. Responsive stimulation was successful, 3-month stimulation resulted in a significant reduction of median seizure frequency of 38% vs. 17% in the non-stimulated group. In four out of the 191 patients, the stimulation had to be explanted due to infections all of which involved soft tissue and not the brain or the skull. This NeuroPace RNS® system has been approved by the U.S. Food and Drug Administration in 2013 but so far not in Europe. Recording and stimulation algorithms have not been disclosed by the above named company. Long-term follow-up data confirm increased efficacy over time with reduction of median seizure frequency of 53% after 2 years and 63% of 4 years. Along with decreased seizure frequency, quality of life improved. To conclude, efficacy data on continuous deep brain stimulation and on responsive direct stimulation of the seizure focus seem to be similar. A clinical trial directly comparing the two approaches—in particularly in patients with well defined seizure focus—is desirable, but for various reasons this is unlikely to happen. Against this background, there is currently no indication to prefer craniectomy with implantation of the recoding and stimulation system within the skull to the less invasive approach requiring only two small skull boreholes.

Special Issue on Controversies in Neurology. From the 10th World Congress on Controversies in Neurology (CONy), Lisbon, Portugal. 17–20 March 2016.

International Journal of Clinical Neurosciences and Mental Health 2016; 3(Suppl. 1):D28

Icon_pdf Download PDF

Debate


Should non-convulsive status epilepticus (NCSE) be treated aggressively? - read full article

By: Manjari Tripathi

Point of view: Yes
There are several clinical challenges in the diagnosis and management of NCSE .The working definition involves a prolonged state of impaired consciousness or altered sensorium, associated with continuous paroxysmal activity or electrographic discharges on the EEG. This mandates the need for continous EEG monitoring of these patients. NCSE may be more common than thought: 25 % of all SE, about 27% of ICU pts with altered mental status and 8% of pts in coma /critically will have NCSE. NCSE often has the following problems. Frequent subtle/no clinical manifestations except altered sensorium, a need for EEG confirmation of ongoing epileptic activity, physicians lack of awareness of the possibility of NCSE, underdiagnosis and deleterious consequences with increased mortality and morbidity. NCSE has steadily became a therapeutic Pandora’s box and often is a nightmare to manage due to its unusual clinical features requiring an high index of suspicion, challenging EEG patterns, controversial/unclear treatment paradigms & prognosis. Response to treatment is one of the modes of confirming the diagnosis a positive response to antiseizure and antistatus medication would go in favour of the diagnosis. Hence treatment is a part and parcel of the diagnosis. Response to anticonvulsants both clinical and EEG is controversial,and sadly often initiated after long delay. It is recommended to initiate treatment quickly—when NCSE developed out of convulsive status epilepticus (CSE) as per accepted guidelines for the management of CSE and as soon as it is suspected when happening denovo. Treatment recommendations are different for the various subtypes. Absence SE: BZD, if resistant VPA / PB Discontinue / Avoid AEDs which trigger SE Complex partial NCSE (CPNCSE) : similar to CSE NCSE in coma: dilemma about diagnosis and treatment exist but aggressive treatment similar to that for subtle SE epilepticus, Intravenous AEDs are a must because the response to first-line treatment may be poor (IV benzodiazepine must be used for both diagnostic and therapeutic purposes under EEG surveillance ) many AEDs must be tried. There is a scope for a good outcome with aggressive treatment approach Response to treatment may be quite delayed, often as much as 24 h or longer in NCSE and depends on the subtype, underlying etiology & timing of treatment. Mortality rates of 20-30% may be due to the underlying etiology itself or the complications of disease / treatment. In CPSE a mortality of 18% is based on etiology. In Children a mortality rate of 25 %, and in elderly it is higher to about 56%. Cognitive sequel are found after 15-30 % of adults and would be worse if no aggressive management is done. Unfortunately it will not be prudent to miss or under treat these patients with uncertainty in approach and this be realised retrospectively. It is hence necessary to have a deft and all FIRE BRIGADES blazing approach to put out the fire in NCSE.

Special Issue on Controversies in Neurology. From the 10th World Congress on Controversies in Neurology (CONy), Lisbon, Portugal. 17–20 March 2016.

International Journal of Clinical Neurosciences and Mental Health 2016; 3(Suppl. 1):D29

Icon_pdf Download PDF

Debate


Should non-convulsive status epilepticus be treated aggressively? - read full article

By: Ilan Blatt

Point of view: No
Generalized convulsive status epilepticus (GCSE) is a life-threatening medical emergency. Realizing that "time is brain", modern treatment protocols are quite aggressive, and after failure of a benzodiazepine and one intravenous (IV) antiepileptic drug (AED) the protocols call for induction of generalized anesthesia with drugs such as midazolam, propofol, thiopental or pentobarbital. Non-convulsive status epilepticus (NCSE) is different from GCSE. It can be defined as a change in behavior and/or mental processes from baseline associated with continuous epileptiform discharges on the EEG. It may or may not include dyscognitive features ("complex partial status" - CPSE). The compromise between the danger related to untreated SE and danger of damage induced by possibly unnecessary aggressive treatments may prove difficult. Available human data indicate that many clinical forms of NCSE are benign in terms of morbidity and mortality. Poor outcome may be attributed to the etiology and to associated complications. The evidence for neuronal damage induced by NCSE in humans is scant. Mortality in patients with NCSE due to pre-existing epilepsy is as low as 3%; in patients with NCSE due to acute medical disorders mortality reaches 27%, and the cause has a major effect on NCSE outcome. For most forms of NCSE that persist after treatment with BZD and an AED, additional trials of IV AEDs should be preferred, rather than early escalation to anesthetics. This strategy is especially relevant in cases of NCSE in which consciousness is somewhat preserved, and the risks of anesthetics (including arterial hypotension, respiratory depression, gastroparesis, paralytic ileus, immunosuppression, infections, propofol infusion syndrome and prolonged sedation due to drug accumulation) might outweigh the risks of continued seizure activity. EFNS guidelines (2010) state the therapeutic decision should be based on the type of SE, age, comorbidity and prognostic issues, and that this is of special relevance in patients with CPSE because the risks of anesthesia may be greater than the risks of ongoing non-convulsive epileptic activity.

Special Issue on Controversies in Neurology. From the 10th World Congress on Controversies in Neurology (CONy), Lisbon, Portugal. 17–20 March 2016.

International Journal of Clinical Neurosciences and Mental Health 2016; 3(Suppl. 1):D30

Icon_pdf Download PDF

Debate


Is imaging of tau the preferable marker of cognitive impairment in AD? - read full article

By: Panteleimon Giannakopoulos

Point of view: Yes
Early clinic-pathological studies demonstrated that the two cardinal lesions associated with Alzheimer disease (AD), neurofibrillary tangles (NFT) and amyloid deposits, have a differential impact on cognition both at early and late stages of the neurodegenerative process. In contrast to ß-amyloid (Aß) deposition that occurs diffusely in the human brain over 60 years of age, NFT formation follows hierarchical schemes of regional and cellular vulnerability affecting first the entorhinal cortex and parahippocampal formation before moving in adjacent neocortical association areas. Long before the emergence of novel imaging techniques, it was clear that Aß deposits correlate very weekly with cognition and downstream neurodegenerative biomarkers. In contrast, NFT and associated synaptic loss is strictly related to the loss of cognitive functions not only at late but also at early stages of AD. The last decade was characterized by the exponential increase of knowledge in the field of AD predictive biomarkers and, most importantly, characterization of tracers for ß-amyloid (Aß). It is now widely acknowledged that amyloid deposits in positron emission tomography (PET) with Pittsburg compound B (PiB; a marker of Aß fibrillar deposits) precede dementia by 5-10 years, and PiB burden inversely correlates with concentration of A?42 in the cerebro-spinal fluid. However, increased PiB burden was reported in nearly 20% to 30% of controls in the general population pointing to the fact that Aß deposition is not sufficient to cause cognitive decline in AD. Moreover, the rate of Aß accumulation is not related to neurodegeneration at baseline and only 8% of controls display both decreased hippocampal volume and increased PiB signal. According to Jack’s model, all of the aforementioned markers become positive well before dementia onset, and the ones related to amyloid pathology already reach their plateau at the time of first cognitive deficits. More recently, selective tau tracers became available for clinical research. Although a PiB equivalent is not yet ready for tau imaging, the recent development of tau tracers with higher selectivity, reduced non-specific binding and improved tracer kinetics compared to the first molecules raise increasing expectations among the scientific community. Given the tight association between tau deposition, cognition and neurodegeneration, and unlike Aß imaging, tau imaging will be essential for assessing disease progression. Furthermore, they may help to resolve the controversy about the temporal sequence of tau pathology in AD. The new diagnostic criteria by Dubois and collaborators consider that the development of tau pathology, at least under its fibrillar forms, is a late phenomenon in AD dependent, at least partly, on the Aß deposition in prodromal states. Recent contributions showed that tau-related markers (but also structural MRI changes) might become positive in the absence of PiB deposits mainly in preclinical cases. Ultimately, tau imaging will provide the tool to change the landscape and explore whether or not presymptomatic administration of anti-Aß therapy impacts on the progression of tau pathology that determines the clinical expression of AD.

Special Issue on Controversies in Neurology. From the 10th World Congress on Controversies in Neurology (CONy), Lisbon, Portugal. 17–20 March 2016.

International Journal of Clinical Neurosciences and Mental Health 2016; 3(Suppl. 1):D31

Icon_pdf Download PDF

Debate


Is imaging of tau the preferable marker of cognitive impairment in AD? - read full article

By: Giancarlo Logroscino

Point of view: No
The number of individuals affected by dementia is increasingly growing worldwide. Based on the Global Burden of Disease study (GBS), more than 130 millions of people affected by dementia by the year 2050. About at least seventy per cent of these cases are AD or mixed dementia. A definitive AD diagnosis, according to the 1993 NINDS-NIA criteria is achievable only by postmortem examination. On the other hand, the clinical diagnosis of dementia is still challenging for the dementia specialists applying both the old and the new clinical criteria. It is clear that the diagnostic accuracy can be improved by the support of paraclinical investigations such as imaging (structural and functional) plus fluid biomarkers (biomarkers of pathological specific process, neuronal damage, and inflammation). This is important for clinical work especially in the differential diagnosis process but probably essential to anticipate the diagnosis after first symptom and in the preclinical stage, as required in the recent classification systems and in trials for new therapies. The advancement of imaging Alzheimer disease pathology has included several markers for PET ?-amyloid imaging agents. The recognized growing importance of neocortical neurofibrillary tangles as marker of disease progression and pathology has determined the development of several tau imaging compounds such as [(18)F]T807, [18F]THK523, [18F]THK5117, [18F]THK5105 and [18F]THK5351, [18F]AV1451(T807) and [11C]PBB3. In particular F T807 binding has been described as associated with clinical impairment particularly in the inferior temporal gyrus, stronger than the association of beta-amyloid marker in the cortex with the same clinical features. In this direction several cell and animal studies suggest that tau propagation from cell to cell along specific anatomic pathways with a prion like mechanism may favour the aggregation and region-to-region spread of tau pathology within the central nervous system, determining the clinical phenotype. The pathological accumulation of the tau protein is important not only for other dementias both mainly environmental like chronic traumatic encephalopathy and others of more complex clinical and genetic classification such as frontotemporal dementias, progressive supranuclear palsy, and corticobasal degeneration. In AD, It has been clearly shown that the hyperphosphorylated tau tangles and not beta amyloid accumulation, correlates with neuronal dysfunction and death. Therefore also the clinical stage and severity of AD seem more closely correlate to tau load and spreading than with beta-amyloid accumulation. The pathogenesis and some data on the clinical progression seem to suggest that tau imaging, a surrogate in vivo of tau accumulation, may be instrumental in the classification and staging of dementias. On the other hand recent neuropathological studies in subjects over 85 with samples collected in population-based studies show that for older subjects the relationship between clinical features and tau accumulation may be non linear. This is particularly important in subjects with dementia where the correlation is lost after diagnosis. Therefore, the benefit of follow -up of patients with dementia and in some cases even the diagnosis may be less significant in subjects in advanced age. The age structure of people with dementia is rapidly changing with 2/3 of subjects being 85 and older. The challenge is therefore to obtain a valid and early diagnosis taking into account the changing pattern of disease phenotype of subjects with dementia. Subjects with dementia, being mostly in late stages of life, are going to have more than one pathological condition (more likely several pathological conditions and furthermore to be frail and with a short expectation of life , in most of cases less than ten years). Diagnostic and therapeutic research, including imaging in the area so dementia should carefully taking account this shift to determine improvement of clinical management and prognosis of patients. In this conceptual framework the challenge of early diagnosis should look carefully at change in tau accumulation with age. For disease progression other markers may be important: imaging markers of inflammation may be at least as important as tau deposition. Both genetic (particularly GWAS) and epidemiological studies have shown a link between neuroinflammation and neurodegeneration in AD. Microglial activation and reactive astrocytes have been described in critical area for dementia. Inflammatory genes like IL6r and C9 genes in particular have been associated with A? and tau burden. Recent work has shown that PET ligands for neuroinflammation may act as good markers of disease progression, allowing for the development of more complex and integrated model of AD natural history. PET tau imaging probably enables the assessment of the longitudinal pattern of tau deposition. This is, however, not the only imaging marker important for the assessment of the clinical evolution of disease. There are however significant problems that needs to be addressed before considering tau imaging key in diagnostic and especially in the follow-up of subject with dementia . These controversial issues will be discussed in the presentation.

Special Issue on Controversies in Neurology. From the 10th World Congress on Controversies in Neurology (CONy), Lisbon, Portugal. 17–20 March 2016.

International Journal of Clinical Neurosciences and Mental Health 2016; 3(Suppl. 1):D32

Icon_pdf Download PDF

Debate


Dementia with Lewy bodies and Parkinson’s disease dementia: part of one continuum or two distinct entities? - read full article

By: Laura Parkkinen

Point of view: Continuum
Dementia with Lewy bodies (DLB) and Parkinson’s disease dementia (PDD) are the second most common type of degenerative dementia after Alzheimer’s disease (AD) in patients older than 65 years. For years, there has been an ongoing debate whether DLB and PDD should be considered as part of one spectrum of dementia related to cortical Lewy body disease or whether they are two distinct conditions. One’s position on this debate in normally reflected by viewpoint on the disease itself whether it’s clinical, pathological or genetic. The current consensus criteria recognize the clinical distinction between DLB and PDD using the timing of the onset of cognitive symptoms in relation to motor symptoms (i.e. diagnosis of DLB is assigned when dementia and motor symptoms appear together within 1 year, PDD when dementia occurs >1 year after motor impairment). This “one-year” rule regarding temporal relationship between dementia and parkinsonism is however considered artificial and cognitive impairment is recognized to occur not only in more advanced PD, but also in early, untreated PD patients, and even in those patients with pre-motor syndromes such as REM sleep behaviour disorder (RBD) and hyposmia. There are no clinical symptoms that categorically distinguish DLB and PDD as both may show visual hallucinations, autonomic symptoms, RBD, cognitive fluctuations, and neuroleptic sensitivity. Regarding motor symptoms, DLB patients have been described with more symmetrical parkinsonism, relatively higher rigidity and lower resting tremor but this generally would not lead to high sensitivity in diagnosis. In addition to the clinical similarity, DLB and PDD also share a common neuropathological feature of cortical alpha-synuclein-positive Lewy bodies (LBs) and neurites that does not differentiate DLB from PDD or in fact even from Parkinson’s disease (PD) without dementia. This is reflected in the overlapping staging criteria of the two syndromes that both examine the topographical distribution of alpha-synuclein pathology (i.e. Braak PD stages 1-3= McKeith’s brainstem DLB, Braak stages 4-5= McKeith’s limbic DLB, Braak stages 5-6= McKeith’s neocortical DLB). Generally, most DLB, PDD and PD patients die with end-stage disease at which point the brain is diffusely involved. Some studies have suggested that there is more beta-amyloid accumulation in DLB causing a more aggressive course of disease (i.e. shorter time to dementia) but concomitant Alzheimer-type pathology is also very common in PDD and thus cannot be used as a diagnostic marker to distinguish the two syndromes. The only difference appears to be the nigral neuronal loss which can be more significant in PDD than in DLB suggesting that the most vulnerable neurons may differ between these disorders; however this has not been systematically studied. Genetic factors may also play a role in the expression of cognitive deficits in DLB and PDD, as suggested by dominant familial forms of DLB/PDD. Notably, missense mutations in the alpha-synuclein gene (SNCA) and locus multiplications are associated with clinical and pathological phenotypes ranging from PD to PDD to DLB. In world-wide populations SNCA genetic variability remains the most reproducible risk factor for idiopathic PD and SNCA gene has recently been also associated to DLB. However, only few investigators have looked at SNCA variability in terms of the different clinico-pathological groups. We used targeted next-generation sequencing to comprehensively characterize the 135kb SNCA locus in a large multi-national cohort of patients with PD, PDD, DLB and healthy controls. An analysis of 44 tagging single nucleotide polymorphisms (SNPs, with MAF>5%) across the entire SNCA locus showed two distinct association profiles for parkinsonism and dementia, respectively towards the 3’ or the 5’ of the SNCA gene. In addition, we defined a specific haplotype in intron 4 that is directly associated with PDD. The PDD risk haplotype has been interrogated at single nucleotide resolution and is uniquely tagged by an expanded TTTCn repeat. Our genetic study suggests that there may be specific haplotypes that have functional consequences in both mRNA and protein level that explain where in the continuum patients would fall. The fundamental question is the mechanism(s) whereby these subtle allelic differences lead to mismetabolism of alpha-synuclein responsible for the neurodegeneration and subsequent clinical presentation. In order to unravel this, it is important that clinicians, pathologists and geneticists work together each describing the variables they can measure reliably in optimal detail rather than obscuring subtle differences by trying to fit subjects into certain disease categories. Thus, the question whether DLB and PDD are on a continuum or distinct entities is rather moot. Single Lewy body disorder model however is more useful for studying disease pathogenesis with an ultimate aim of developing disease-modifying therapies that target the alpha-synuclein-related neurodegeneration.

Special Issue on Controversies in Neurology. From the 10th World Congress on Controversies in Neurology (CONy), Lisbon, Portugal. 17–20 March 2016.

International Journal of Clinical Neurosciences and Mental Health 2016; 3(Suppl. 1):D33

Icon_pdf Download PDF

Debate


Dementia with Lewy bodies and PD dementia: Part of one continuum or two distinct entities? - read full article

By: Robert Perneczky

Point of view: Two distinct entities
Age-related neuropsychiatric disorders such as Parkinson disease with and without dementia (PDD and PD, respectively), dementia with Lewy bodies (DLB), and Alzheimer disease dementia (AD) represent a growing socioeconomic challenge. These disorders show substantial clinical and neuropathological overlap, limiting diagnostic accuracy and questioning the concept of distinct clinical entities. Indeed, the notion that PD and AD may be extremes of a spectrum of neurodegenerative diseases, with DLB and PDD presenting overlapping neuropathologic and clinical features within this spectrum, has received growing attention in recent years. Although pathophysiologically and clinically different, PD and AD share some aspects in common; both are age-related neurodegenerative disorders characterized by aggregation of pathologic proteins leading to dysfunction of cerebral networks and distinct patterns of metabolic changes. Cases characterized by pure PD (?-synuclein aggregation) or pure AD (amyloid-? and tau aggregation) pathology do not represent most affected patients. Biologically and histopathologically, there is an overlap of these age-associated proteinopathies. They form a continuum with concomitant amyloid-?-, tau-, and ?-synuclein aggregation as well as microvascular changes. DLB and PDD are age-related neurodegenerative disorders sharing clinical and histopathologic aspects with both PD and AD. Hence, they can be seen as intermediate neurodegenerative disorders in a spectrum between pure PD and pure AD. Because the pattern of histopathology, neuronal network dysfunction, and associated clinical deficits is indeed continuous, the traditional view of distinct disease entities is increasingly being questioned. Temporal differences in the emergence of symptoms and clinical features warrant the continued clinical distinction between DLB and PDD. While DLB and PDD groups' neuropsychological profiles often differ from those in AD, the diagnostic sensitivity, specificity, and predictive values of these profiles remain largely unknown. PDD and DLB neuropsychological profiles share sufficient similarity to resist accurate and reliable differentiation. Although heterogeneous cognitive changes (predominantly in memory and executive function) may manifest earlier and more frequently than previously appreciated in PD, and executive deficits may be harbingers of dementia, the enthusiasm to uncritically extend the concept of mild cognitive impairment (MCI) to PD should be tempered. Instead, future research might strive to identify the precise neuropsychological characteristics of the prodromal stages of PD, PDD, and DLB which, in conjunction with other potential biomarkers, facilitate early and accurate diagnosis, and the definition of neuroprotective, neurorestorative, and symptomatic treatment endpoints. Biomarker-based approaches targeted to disentangle histopathology-clinical relationships within this spectrum may further help to guide classification of neurodegenerative disorders and treatment stratification. Imaging and fluid biomarker studies are available that support the notion of distinct disease entities, but research also supports the idea of a continuum of cerebral changes between the two extremes of pure AD and pure PD. The present paper will present the relevant evidence and argue in favour of the two distinct entities approach.

Special Issue on Controversies in Neurology. From the 10th World Congress on Controversies in Neurology (CONy), Lisbon, Portugal. 17–20 March 2016.

International Journal of Clinical Neurosciences and Mental Health 2016; 3(Suppl. 1):D34

Icon_pdf Download PDF

Debate


Amyotrophic laterial sclerosis (ALS) with frontotemporal deficits and FTD—a spectrum or separate entities - read full article

By: Lea T. Grinberg

Point of view: Spectrum Despite significant clinical overlapping, frontotemporal dementia with motor neuron disease and amyotrophic lateral sclerosis (ALS) have been historically considered as separate entities. In 2006, TAR DNA-binding protein 43 (TDP-43), encoded by the TARDBP gene, has been identified as the major pathological protein the so-called frontotemporal lobar degeneration (FTLD) with ubiquitin-immunoreactive (up-in) inclusions (FTLD-U) with or without motor neuron disease and amyotrophic lateral sclerosis (ALS). This finding created the basis for unifying the majority of FTLD-U and ALS as a spectrum of TDP-43 pathies. Interestingly, though, groups focusing on ALS and FTD are yet to integrate fully, either by structural reasons as these groups were historically allocated to different clinics or because it was unclear why some patients showing TDP-43 type B proteinopathy would not manifest motor neuron disease. The discovery of the C9orf72 mutation in 2011 shed light on this questions. Affected members of families with C9orf72 mutation, an autosomal dominant disease, express a broad range of clinical phenotypes from pure ALS to pure FTD, AD-type symptoms, and parkinsonism. Studies in C9orf72 families unravel that certain genetic variations including in the gene TMEM10b and ATAX2 may contribute to the phenotype variation. In summary, TDP-43 type B proteinopathy underlies the majority of ALS with frontotemporal deficits and FTD cases. Genetic variations may impact the clinical presentation and explain the broad spectrum of presentations seen in these patients sharing similar neuropathological features.

Special Issue on Controversies in Neurology. From the 10th World Congress on Controversies in Neurology (CONy), Lisbon, Portugal. 17–20 March 2016.

International Journal of Clinical Neurosciences and Mental Health 2016; 3(Suppl. 1):D35

Icon_pdf Download PDF

Debate


Mild cognitive impairment in Parkinson's disease - read full article

By: Amos D. Korczyn

Point of view: No
The mild cognitive impairment (MCI) concept was developed to identify the earliest stages of cognitive impairment. MCI and, more specifically, amnestic MCI were initially proposed as pathological transitional states that ultimately progress to full blown AD. However, it has been found that MCI subjects do not uniformly progress to dementia (either AD or another) and may revert back to normal cognitive state. The MCI is concept has been borrowed to other neurodegenerative diseases, particularly Parkinson's disease (PD). However the operational definition of MCI may not adequately convey the intended concept. Additional modifications to the concept and its operationalization are needed in order to better identify patients with incipient cognitive impairment and to guide clinical and research practices. Patients with PD have a very high likelihood of developing dementia, which develops insidiously. Cognitive impairment may start even before other symptoms, although this is not in accordance with Braak's sequence. There is no available data to support the concept that a certain constellation of cognitive symptoms in an otherwise healthy individual will herald development of PD or indeed will progress to dementia. Therefore, at present, identification of subtle cognitive dysfunction even in a person with diagnosed PD does not benefit the patient and should be avoided, except for research purposes.

Special Issue on Controversies in Neurology. From the 10th World Congress on Controversies in Neurology (CONy), Lisbon, Portugal. 17–20 March 2016.

International Journal of Clinical Neurosciences and Mental Health 2016; 3(Suppl. 1):D36

Icon_pdf Download PDF

Debate


Does traumatic chronic encephalopathy (CTE) exist? - read full article

By: Rudolph Castellani

Point of view: No
Accumulation of phosphorylated tau (p-tau) is accepted by many as a long-term consequence of repetitive mild neurotrauma based largely on brain findings in boxers (dementia pugilistica) and, more recently, former professional athletes, military service members, and others exposed to repetitive head trauma. The term “chronic traumatic encephalopathy” has been in the literature for decades, although the term has been applied more liberally to sporting activities since 2005. The most specific pathology according to a recent consensus group is the presence of phosphorylated tau in perivascular areas and in depths of sulci. Some caution before accepting chronic traumatic encephalopathy as an entity is warranted, however. Concussions and subconcussive head trauma exposure are poorly defined in available cases, the clinical features reported in chronic traumatic encephalopathy are not at present distinguishable from other disorders, and adequate control groups as well as prevalence data are virtually non-existent. Moreover, dementia pugilistica, which has widespread acceptance, has had autopsy correlation in a surprisingly small number of cases, which are further complicated by numerous co-morbidities, including substance abuse, vascular disease, infection, and genuine neurodegenerative disease. With respect to the modern iteration of chronic traumatic encephalopathy, the association of sparse immunohistochemical reactivity with psychiatric signs such as impulse control issues and suicide is also problematic. Predicting complex behaviors on the basis of such changes is beyond the reach of neuropathological interpretation. In general, because the definition of neurodegenerative disease requires a defined clinical phenotype, invariable disease progress, and a defined pathological phenotype, chronic traumatic encephalopathy falls short of neurodegenerative disease. Indeed, the clinical phenotype varies from normal to advanced dementia, disease progress is lacking in the majority of reported cases, and the pathological phenotype varies from absence of pathology to widespread pathology and co-morbitidies. As such, chronic traumatic encephalopathy is more a hypothetical construct or concept than a neurodegenerative disease entity.

Special Issue on Controversies in Neurology. From the 10th World Congress on Controversies in Neurology (CONy), Lisbon, Portugal. 17–20 March 2016.

International Journal of Clinical Neurosciences and Mental Health 2016; 3(Suppl. 1):D37

Icon_pdf Download PDF

Debate


Is NPH over-diagnosed? - read full article

By: Michael Geschwind

Point of view: Yes
Normal pressure hydrocephalus is characterized by the classic triad of cognitive dysfunction, gait disorder and urinary incontinence, sometimes colloquially referred to as the 3 Ws “woozy, wobbly and watery.” A well-published New York Times article claimed that a vast percentage of Alzheimer’s disease cases did not in fact have AD, but rather had NPH, which was treatable. This lay article among other lay literature has suggested that NPH is an underdiagnosed condition. As my university, the University of California San Francisco (UCSF) is a major neurology and neurosurgery tertiary referral center we have been referred many cases of suspected NPH, often for shunting, in whom we have determined patients do not have an NPH disorder. Part of the problem lies with NPH being a poorly defined entity both clinically and radiologically. Although the entity of NPH exists and some of the symptoms can be treatable and even reversible, it is imperative to avoid placing a shunt in a patient with a neurodegenerative disease that will result in progressive atrophy leading to shunt complications such as subdural hematomas.

Special Issue on Controversies in Neurology. From the 10th World Congress on Controversies in Neurology (CONy), Lisbon, Portugal. 17–20 March 2016.

International Journal of Clinical Neurosciences and Mental Health 2016; 3(Suppl. 1):D38

Icon_pdf Download PDF

Debate


Does corticobasal degeneration exist as a clinicopathological entity? - read full article

By: Lea T. Grinberg

Point of view: No
Corticobasal degeneration has been described in the late 1960's as "corticodentatonigral degeneration with neuronal achromasia" in three patients presenting parkinsonism and involuntary motor activity. All patients showed asymmetric degeneration of the perirolandic and parolfactory cortices, basal ganglia and substantia nigra. In most cases, the affected cortices featured gliosis and ballooned neurons. From this reports, other followed with alternative nomenclature, but similar clinicopathological features. By the late 1980's, when the term corticobasal degeneration (CBD) received almost universal acceptance, CDB was considered a unique clinicopathological entity, meaning an almost perfect correlation between the clinical features with a particular neuropathological entity. However, with the advent of immunohistochemistry for tau protein, it became evident that different pathological entities including Alzheimer's disease, frontotemporal lobar degeneration with tau inclusions of the Pick's or PSP-type could underly a "CBD" clinical presentation. Moving forward, the term corticobasal syndrome (CBS) replaced CBD as a clinical diagnosis and the term CBD was reserved to describe a distinctive 4-repeat tauopathy with an involvement of the gray and white matter. Recent clinicopathological series report that about 1/3 of patients developing CBS show CDB. The remaining present other entities, especially Alzheimer's diseases. Ongoing studies are focusing in refining CBS clinical classification to enable better antemortem prediction of the underlying pathology in these patients.

Special Issue on Controversies in Neurology. From the 10th World Congress on Controversies in Neurology (CONy), Lisbon, Portugal. 17–20 March 2016.

International Journal of Clinical Neurosciences and Mental Health 2016; 3(Suppl. 1):D39

Icon_pdf Download PDF

Debate


Behavioral therapy is necessary for the complete treatment of migraine and chronic migraine - read full article

By: Randall Weeks

Point of view: Yes
Attention to psychological and behavioral issues become even greater treatment considerations as the frequency of a patient’s migraine increases, there is increased disability secondary to headache, and/or there is inadequate response to usually effective treatment. As migraine becomes more chronic, headache-related disability increases, there are higher direct and indirect costs, and there are higher rates of co-morbid conditions, greater poly-pharmacy, and greater social impediments. Such findings highlight the complexity of such patients which necessitate a comprehensive, behavioral treatment strategy. Hence, behavioral therapy is necessary for the complete treatment of migraine and chronic migraine. It should be emphasized that behavioral and other non-pharmacological treatments are not anti-pharmacological. The combination of both pharmacological and non-pharmacological treatment has been shown to be superior to each individually and appear to maximize long-term therapeutic benefit. It is a mistake to view pharmacological vs. behavioral treatment strategies as adversarial, contradictory, or oppositional. In addition, effective non-pharmacological therapies help to ensure pharmacological treatment compliance which has been shown to be a significant problem with headache patients. Barriers to the use of abortive and preventive medications have been identified and have been found to be limiting factors in treatment efficacy. Modifying maladaptive behaviors which undermine adherence to pharmacological treatment is a critical component in the treatment of migraine and chronic migraine. This underscores the reality that pharmacological treatment involves a series of behaviors, and therefore, should be considered “behavior therapy” as well as a non-pharmacological treatment strategy. The American Academy of Neurology-U.S.Consortium noted a variety of reasons that cause migraine patients to seek behavioral and other non-pharmacological treatment for migraine headache. These include: 1. Patient preference; 2. Poor tolerance/poor response to preventive medications; 3. Medical contraindications to medications; 4. Pregnancy, planned pregnancy, or nursing; 5. History of overuse of acute-care medications; 6. Significant stress or deficient stress/pain coping strategies. More than 100 empirical studies have examined the efficacy of bio-behavioral therapies and headache. The American Academy of Neurology-U.S. Consortium published evidence-based guidelines for migraine headache treatment and concluded that relaxation training, thermal biofeedback combined with relaxation training, EMG biofeedback, and cognitive-behavioral therapy were effective treatment options for migraine. These results have been confirmed in other meta-analytic reviews. Research has identified a variety of “modifiable” risk factors (including medication overuse) that appear to be associated with the escalation of the frequency and severity of migraine headache and are amenable to behavioral treatment. These include attack frequency, obesity, medication overuse, stressful life events, caffeine overuse, and snoring/sleep apnea. These risk factors are amenable to behavioral treatment. The above behavioral treatments are critical in formulating a treatment strategy to address the modifiable risk factors noted above for the escalation of migraine. Effective treatment begins with a thorough diagnostic interview and the introduction of a headache diary as a tool for self-monitoring. Educating patients about headache mechanisms and the course of treatment allows a collaborative relationship between the patient and clinician. Patients must be “active participants” in the management of their headache issues. It is essential that clinicians monitor and be attentive to treatment adherence with respect to both pharmacological and non-pharmacological treatment strategies.

Special Issue on Controversies in Neurology. From the 10th World Congress on Controversies in Neurology (CONy), Lisbon, Portugal. 17–20 March 2016.

International Journal of Clinical Neurosciences and Mental Health 2016; 3(Suppl. 1):D40

Icon_pdf Download PDF

Debate


Behavioral therapy is necessary for the complete treatment of chronic migraine - read full article

By: Frank Andrasik

Point of view: No
All treatments for headache serve 1 or more of 3 functions. One is to abort an existing attack, another is to relieve pain when headache is present, and the other is to prevent occurrence of future headache attacks. This presentation reviews the evidence base for medication and psychological interventions for achieving each of these aims, paying special attention to the qualifiers “necessary” and “complete”. Numerous well-designed clinical trials support the utility of various medications, primarily triptans, for aborting migraine attacks. Only one psychophysiologically-based approach—blood volume biofeedback for constricting blood flow in the temporal artery—purports to serve abortive functions. Although developed and designed with this intent in mind, not a single investigation has attempted to examine if it indeed serves this purpose (or what is its exact mechanism of action). Evidence is similarly lacking to support the notion that psychological approaches alone have palliative effects for existing headaches, while evidence does support medication as lessening intensity of extant headaches. The major thrust of psychologically-based treatments for headache can thus be considered as focusing on prevention of future attacks. In this regard, both treatment approaches (medication and psychological) have been shown to be of value to chronic migraineurs. Again, numerous well controlled trials and qualitative and quantitative reviews (meta- analyses) support the efficacy of varied prophylactic pharmacological agents (anti- epileptics, beta-blockers, botulinum toxin, etc.) for reducing key headache parameters. With very few exceptions, the clinical trials examining psychological prophylaxis have been confounded by allowing patients to continue on their current medication regimes. Meta-analyses comparing medication and these “confounded” psychological treatments generally find similar outcomes, raising questions about the unique contributions of the psychological interventions. Only a few large-scale clinical trials have compared “unconfounded” psychological treatments to medication alone, with both forms of treatment being found to produce similar effects. The combination of the 2 different treatments in these limited trials has shown some additive effects. Having presented this brief review of the evidence, it is time to return to the central aspects of this debate—are both treatments necessary for complete treatment? The conclusion has to be a definitive no, for two main reasons. 1. Psychological treatments have yet to show any clinical utility for aborting or palliating existing headaches. For many patients, medications are not only sufficient, but they are the only approach with supportive evidence for these purposes. For many patients, medication alone provides the level of relief they are seeking (and thus may be considered complete). 2. As a substantial number of migraine patients respond well to prophylactic medications, one must ask what is the incremental utility of additionally pursing psychologically-based treatments, given they require special training that few providers have, are often effort-intensive, sometimes require specialized devices (in the case of biofeedback), are not widely available, have yet to be routinely imported into primary care and specialty settings where treatment is typically administered, and often are not covered by third party payers. It may turn out to be the case that a small percentage of migraineurs will find it necessary to pursue both treatment options (perhaps others as well), but the research existing at present provides very few insights into deciding which patients might in fact need or even want a combination of treatments, nor is there a solid basis for deciding what in fact constitutes complete treatment.

Special Issue on Controversies in Neurology. From the 10th World Congress on Controversies in Neurology (CONy), Lisbon, Portugal. 17–20 March 2016.

International Journal of Clinical Neurosciences and Mental Health 2016; 3(Suppl. 1):D41

Icon_pdf Download PDF

Debate


Computers can accurately diagnose primary headache disorders as well as most physicians - read full article

By: Robert Cowan

Point of view: Yes
2500 years ago, patients would queue in the town square and await their turn to see the traveling physician, hoping he would have the right diagnosis and treatment in his head. We have come a long way since then. Today, patients sit in waiting rooms, awaiting their turn to see the physician, hoping he or she would have the right diagnosis and treatment in his head. 2500 years ago, according to the best medical science, there were four diseases, corresponding to black bile, yellow bile, phlegm and blood. And there were four treatments: bleeding, vomiting, diarrhea, and expectoration. Most physicians could keep the diagnoses and treatments straight. But today, approximately 100,000 distinct disease states have been described, and most have multiple treatment options. To expect “most physicians” which means primary care doctors, to retain enough information to diagnose and properly treat 100,000 different diseases is a tall order. The challenge to a primary care doctor confronted with a patient presenting with headache is only slightly less daunting. Bearing in mind that headache makes up only a small percentage of the patient complaints seen in a typical primary care clinic, the primary care physician would need to know the diagnostic criteria for more than 150 primary headache disorders identified in the ICHD 3 (beta). And this number does not even include the many secondary headache disorders that could present in the out-patient setting. Admittedly, many of the 150 headache disorders identified in ICHD 3 (beta) are relatively uncommon, but even among the common primary headaches: Migraine with aura, Migraine without aura, Cluster, Tension-type headache, and chronic the chronic forms of each, the diagnostic criteria are quite specific, and it is the rare Neurologist, much less primary care physician that can accurately characterize each of these clinical entities. Indeed, even among headache specialists, careful review of documentation does not always support the clinical impression if one adheres strictly to ICHD 3 (beta) criteria. Thus, there is little evidence to suggest that primary care doctors do an adequate job of diagnosing the primary headaches. In fact, there is considerable evidence to the contrary. Is a computer any better? A computer program is only as good as the programmer makes it. If the program does not ask the right questions, the correct conclusions cannot be drawn. If the rule engine does not extract the correct data points or the correct data points are not available, then the program fails. Fortunately, when there are established criteria for diagnostic categories, as there are in the ICHD 3 (beta) it is a simple matter of reverse engineering to create questions that will identify data points to meet or exclude those criteria. Thus, a computer program cannot, by definition, draw a conclusion that is not supported by data. The variable, of course, is the quality of the data obtained. There is a variety of techniques to help ensure the reliability of the query. For example, the same data point can be approached several ways with different questions, or even the same question phrased several different ways. The consistency of the responses can then be valued with respect to reliability. For example: if we want to identify the migrainous feature of light sensitivity, the question could be “are you sensitive to light?” This question, standing alone could have several interpretations that may or may not be related to a diagnosis of migraine. The patient could have photophobia due to a concurrent condition such as retinitis pigmentosa, or light sensitivity of long-standing, not correlated with other migrainous features resulting from light eye color or even central sensitization due to another chronic primary headache condition. However, if the response to that question is combined with a question about light avoidance during a headache, and association with sound sensitivity (ICHD 3 (beta) requires BOTH photophobia and phonophobia), the reliability of the data point [+ photophobia] becomes more reliable. It is also possible to use decision-tree analysis (in which the response to one question prompts the next question), and machine learning to improve the quality of the data. These techniques when combined with clinical expertise from a panel of experts can reliably tie historical elements obtained in a web or app-based history to specific sets of diagnostic criteria. One might even argue, that a well-designed computer program is MORE reliable than an unstructured or semi-structured interview for reaching a diagnosis that meets specific criteria because it is not prey to the vagueries of memory or interviewer bias. Where then is the role of the clinician in the diagnosis of primary headache? The diagnostic algorithms of a computer-based tool is only as good as the data that is entered. There is no physical examination, no diagnostic testing. At best, the computer can make a diagnosis based on historical elements provided by the patient and the physician. If the physician can also enter findings on examination and testing, the diagnostic accuracy can be improved in so far as findings on examination and testing are requisite to the diagnosis. In the case of a patient presenting with a primary headache disorder, the consensus among headache specialists is that the vast majority of these headaches can be diagnosed based on history alone. This is not to say that examination and testing are irrelevant, only that these components of the medical encounter rarely change the diagnosis generated from the history in patients with primary headache. Given that the gold standard, at present, is a clearly articulated set of criteria for a large number of entities, the computer is ideally suited to correlate data points in the history with elements of diagnostic criteria, not prone to interviewer bias or knowledge deficits.

Special Issue on Controversies in Neurology. From the 10th World Congress on Controversies in Neurology (CONy), Lisbon, Portugal. 17–20 March 2016.

International Journal of Clinical Neurosciences and Mental Health 2016; 3(Suppl. 1):D42

Icon_pdf Download PDF

Debate


Computers can accurately diagnose primary headache disorders as well as most physicians - read full article

By: Dimos D. Mitsikostas

Point of view: No
Primary headache disorders are the most common brain conditions among general population with specific diagnostic criteria revised every five years (ICHD-IIIbeta). But headache is a symptom in the main rather a condition. Only when headache attacks fulfill those specific diagnostic criteria consistently does a primary headache disorder occur. In addition, ICHD-IIIbeta criteria demand a normal neurological examination for a primary headache disorder that only an experienced neurologist performs. In most cases headache is primary but secondary headache disorders may be related to life threatening conditions. They may respond to common analgesics and mimic primary ones a lot. Diagnostic tests are necessary therefore when the treating physician doubts for the primary origin of headache. Although there are official recommendations for these tests (EHF published recently a consensus on technical investigation for primary headache disorders), the clinical relevance and interpretation of the test findings remains extremely complex, that only an experienced physician performs, again. There is no doubt that computers offer tremendous assistance in searching and analyzing data; nevertheless this support stays poor in front of a person suffering from headache. Because headache is the commonest presenting symptom in people asking medical consultation, the above concerns (among many others) to use digital diagnostic procedures exclusively are principal in managing headache.

Special Issue on Controversies in Neurology. From the 10th World Congress on Controversies in Neurology (CONy), Lisbon, Portugal. 17–20 March 2016.

International Journal of Clinical Neurosciences and Mental Health 2016; 3(Suppl. 1):D43

Icon_pdf Download PDF

Debate


The use of placebo is essential in headache trials - read full article

By: Randall Weeks

Point of view: Yes
In 1962, the Congress of the United States passed the Kefauver-Harris Amendment that mandated that manufacturers provide evidence of drug effectiveness in addition to safety in order for the Food and Drug administration (FDA) to approve the agent for a specific clinical indication. The FDA in 1970 published guidelines describing what acceptable controls in a clinical trial were. The double-blind randomized clinical trial was established as the “gold standard” for the emerging pharmaceutical industry. In 2012, the International Headache Society (IHS) Clinical Trials Committee published “guidelines for controlled trials of drugs in migraine: Third Edition. A guide for investigators”. In that document, they noted placebo rates ranged from 6 to 47% in clinical trials for abortive agents with respect to migraine relief. Placebo rates in headache reduction in preventive trials ranged from 20 to 40% (or even higher). The committee recommended that in clinical trials “Drugs used for acute treatment of migraine should be compared with placebo”. With respect to preventive agents, “Drugs used for migraine prophylaxis should be compared with placebo. When two presumably active drugs are compared, placebo control should also be included in order to test the reactivity (assay sensitivity) of the trial which would allow greater generalizability of study results”. In 2002, the World Medical Association Declaration of Helsinki stated that when an effective treatment for a disease exists, it was unethical to assign patients in a research study to a treatment known to be less effective. Standards for the acceptable use a placebo in clinical trials have changed over time, and (with informed consent), it is now considered acceptable to use placebos in clinical trials in which withholding the best current treatment will result in only temporary discomfort and no serious adverse effects. The IHS guidelines (noted above) state that research protocols should allow the use of rescue medication any time after the first primary efficacy time point (typically, two hours after intake of study medication). This is necessary for the evaluation of “new treatments”. Demonstration of treatment efficacy demands that the target (active) agent must be shown to be statistically significantly superior to an inert substance (placebo) not believed to be a specific therapy for the target condition. As noted above, this is the “gold standard” in clinical research. Placebo rates (and factors that influence them) become increasingly important as potential methodological manipulations (e.g., “over-powering” clinical studies) may allow small differences between groups to reach statistical significance when, in fact, such differences may be clinically meaningless. Similarly, placebo rates have been shown to vary dramatically depending upon a variety of “non-specific” treatment factors (the type of treatment, degree of invasiveness, contextual factors in the research interactions, unbalanced randomization ratios, etc). Placebo-related variables are believed to contribute to treatment efficacy in clinical settings. While they create “noise” in the interpretation of research results, enhancing these variables is desirable in clinical settings. In sum, issues related to placebo are extremely important variables in both research and clinical and settings.

Special Issue on Controversies in Neurology. From the 10th World Congress on Controversies in Neurology (CONy), Lisbon, Portugal. 17–20 March 2016.

International Journal of Clinical Neurosciences and Mental Health 2016; 3(Suppl. 1):D44

Icon_pdf Download PDF

Debate


The use of placebo is essential in headache trials - read full article

By: Dimos D. Mitsikostas

Point of view: No
Medicine is based on placebo than millennia since man first became conscious of himself and this continues today. Because pain is not only a sensory but an emotional experience as well, brain modifies pain perception considerably. Thus, placebo effects for pain and headache appear maximal while placebo effects for outcomes like cancer survival appear to be minimal. In randomized controlled studies (RCTs) for headache prevention and acute treatment placebo effect reaches 30% approximately. Interestingly, the benefits of placebo persist even if placebo is honestly described indicating that whether treatment involves medication or placebo, the information provided to patients and the ritual of pill taking are important components of care (Kam-Hansen et al., 2014). Thus, placebo and medication effects can be modulated by expectancies. There is good evidence that several agents are superior to placebo for almost all primary headache disorders so far. Patients treated with placebo do experience adverse effects in addition (nocebo effect, Mitsikostas et al., 2015) demonstrating crucial ethical concerns. These observations indicate that the use of placebo in headache RCTs is not as much essential as we used to believe before, because the headache treatment itself includes the placebo already, as in clinical practice. In the contrary, head-to-head comparisons of drugs in RCTs remain indispensable and practical.

Special Issue on Controversies in Neurology. From the 10th World Congress on Controversies in Neurology (CONy), Lisbon, Portugal. 17–20 March 2016.

International Journal of Clinical Neurosciences and Mental Health 2016; 3(Suppl. 1):D45

Icon_pdf Download PDF

Debate


CGRP antibodies will become the treatment of choice for chronic migraine - read full article

By: Lars Edvinsson

Point of view: Yes
The management of patients with migraine is often unsatisfactory because available acute and preventive treatment is either ineffective or poorly tolerated. The peptide calcitonin gene-related peptide (CGRP) has been found to have a key role in migraine, supported by studies showing that CGRP is released in migraine attacks, and that different CGRP receptor antagonists (gepants) aborted the migraine pain and one study indicated a prophylactic effect. Recently, three different monoclonal antibodies targeting the CGRP ligand (LY2951742, ALD403 and TEV-48125) and one targeting the CGRP receptor (AMG334) have completed phase 2 trials in frequent episodic migraine and the results reported. These early trials revealed them all to be significantly more effective than placebo. TEV-48125 has also been studied in chronic migraine with a good outcome. The adverse effects in these trials were not different from placebo. In migraine prevention, these humanized antibodies against CGRP or the CGRP receptor are agents that represent a promising new approach in therapy and are currently in phase 3 studies.

Special Issue on Controversies in Neurology. From the 10th World Congress on Controversies in Neurology (CONy), Lisbon, Portugal. 17–20 March 2016.

International Journal of Clinical Neurosciences and Mental Health 2016; 3(Suppl. 1):D46

Icon_pdf Download PDF

Debate


CGRP antibodies will become the treatment of choice for chronic migraine - read full article

By: Jose Miguel Lainez

Point of view: No
The International Headache Society defines chronic migraine as more than fifteen headache days per month over a three month period of which more than eight are migrainous, in the absence of medication overuse. Episodic migraine is the other migraine sub-type, which is defined as less than 15 headache days per month We always start the preventive treatment in combination with a detoxification programme in the cases where the patient fulfils analgesic overuse criteria. Many different strategies and drugs have been proposed to treat this difficult condition (steroids, NSAIDs, different antidepressants, antiepileptic, ect., but only topiramate and onanobotulinumtoxinA have proved their efficacy in clinical trials. Other alternatives with less evidence could be valproic acid, propranolol or a combination of different therapeutic approaches. With this approach we obtain a very good response in 30-40% of patients and a good response in another 30-35%. The importance of Calcitonin gene-related peptide (CGRP) in the pathogenesis of migraine is well characterized. Several trials with different compounds have proved the efficacy of the migraine anti-CGRP antibodies in episodic migraine. A multicenter, randomized trial using two different doses of a humanized monoclonal antibody (TEV-41825) against placebo has been published. The patients included were allowed to use up to 2 different preventives in a stable dose. The trial was positive with a reduction in headache-hours of any severity, in the number of moderate or severe headache-days, and significant difference in number of days on which triptans were used between the placebo group and each of the TEV-48125 dose groups. The tolerability was good with no serious adverse events. But the percentage of reduction in these parameters were not superior to the actual treatments. Besides, around of 40% of patients were using at least one additional preventive. Bearing in mind these data and also the possible cost of these biological compounds, the anti-CGRP antibodies will be an alternative, but not the treatment of choice in the management of chronic migraine.

Special Issue on Controversies in Neurology. From the 10th World Congress on Controversies in Neurology (CONy), Lisbon, Portugal. 17–20 March 2016.

International Journal of Clinical Neurosciences and Mental Health 2016; 3(Suppl. 1):D47

Icon_pdf Download PDF

Debate


Medication over-use is the main causative factor in chronic migraine - read full article

By: Jose Miguel Lainez

Point of view: Yes
Chronic Migraine is a disabling condition for patients and severely affects the ability to lead a productive life. The prevalence is around 2% of general population and it is defined as headache lasting 15 or more days per month for more than 3 months in subjects with a history of migraine. Overuse of medication is very frequent and, in headache centres, more than 90% of patients with chronic migraine meet overuse criteria. According to the ICHD-III? Medication Overuse Headache is headache occurring on 15 or more days per month developing as a consequence of regular overuse of acute or symptomatic headache medication (on 10 or more, or 15 or more days per month, depending on the medication) for more than 3 months. It usually resolves after the overuse is stopped All he drugs used to treat migraine can produce MOH, although the drugs change over time and from region to region. Mechanisms may differ from one class of overused drug to another and these mechanisms may include a combination of pronociceptive pain facilitation with weakened descending pain inhibition. We will discuss these different mechanisms from the different compounds and their implication in the chronification of headache. Besides, more of the drugs used can produce dependence and the patients with MOH share many characteristics with patients with other drug dependence. In relation with the treatment, withdrawal of the overused medication is the treatment of choice. Withdrawal of the drug overused leads, in most cases, to an improvement of the headache and even can resolve the problem completely. For all these reasons medication over-use is the main causative factor in chronic migraine.

Special Issue on Controversies in Neurology. From the 10th World Congress on Controversies in Neurology (CONy), Lisbon, Portugal. 17–20 March 2016.

International Journal of Clinical Neurosciences and Mental Health 2016; 3(Suppl. 1):D48

Icon_pdf Download PDF

Debate


Medication over-use is the main causative factor in chronic migraine - read full article

By: Hayrunnisa Bolay

Point of view: No
Majority of patients referred to tertiary headache clinics suffer from chronic migraine and medication overuse headache that represents the most important challenge to the headache specialists. Chronic migraine is considered to evolve from episodic migraine headaches with an incidence rate of 2.5%. The transition of episodic form to more frequent attacks pattern that may require several months or years, and is influenced by lifestyle, life events, comorbid conditions and genetic background. More importantly this transition period is also frequently accompanied by overuse of abortive headache medication. There are many factors identified to play a role in the migraine chronification process. Risk factors such as older age, female sex, Caucasian race, low socioeconomic status with low education level and income, and genetic factors, family history of mood disorders and substance use disorders (alcohol, drugs) are unfortunately not modifiable. Those patients tend to have greater psychiatric disorders such as depression, anxiety, personality problems, impairment in occupational, social, and family functioning, medical comorbidities such as hypertension, diabetes, high cholesterol levels, obesity and chronic pain disorders. In addition, physical inactivity, smoking, medication overuse, caffeine /tein overuse, sleep disorders (e.g., insomnia, snoring), chronic musculoskeletal and gastrointestinal complaints are also implicated. Lack of awareness in avoiding trigger factors, irregular life-style rhythms, using ineffective drugs and/or dosages and late referral to headache centers also increase the risk of medication overuse in the chronification process of migraine. Medication overuse headache (MOH) is a common and debilitating secondary headache that may complicate every type of primary headache and all the drugs employed for abortive headache treatment can cause MOH. Withdrawal from medication overuse is an important step in the treatment, which reduce the attack frequency. However withdrawal of overusing abortive drugs per se does not revert the chronic migraine process. In conclusion, medication overuse is one of the significant contributors in the chronification process but NOT the main causative factor.

Special Issue on Controversies in Neurology. From the 10th World Congress on Controversies in Neurology (CONy), Lisbon, Portugal. 17–20 March 2016.

International Journal of Clinical Neurosciences and Mental Health 2016; 3(Suppl. 1):D49

Icon_pdf Download PDF

Debate


Migraine starts in the cortex - read full article

By: Hayrunnisa Bolay

Point of view: Yes
A cerebral cortical phenomenon known as cortical spreading depression (CSD) was linked to lateralized headache and shown to be able to activate peripheral trigeminal fibers and second order trigeminal neurons in the brainstem nucleus (TNC). CSD is implicated in releasing CGRP and nitric oxide from trigeminal nerve endings and leading to neurogenic inflammation in the dura mater. CSD is a key to understand familial hemiplegic migraine phenotype, critical involvement of glutamatergic synapse, female hormonal influence and the efficacy of preventive anti-migraine drugs. Animal studies investigating the mechanisms of migraine and CSD are commonly conducted under anesthesia, despite the fact that pain is a conscious experience. Anesthesia have profound effects on the mechanisms by which CSD is initiated and propagated, and clearly prevents observation of any associated behavioral response. Functional decortication of one hemisphere by CSD in lissencephalic brain would result in transient visual, somato-sensory & motor deficits. CSD in freely moving lissencephalic animals evoked reduced locomotor activity, freezing & grooming episodes and emitted pain calls (22-27 KHz) during freezing episodes. Activation of thalamic reticular nucleus was detected by CSD in only awake animals. Electrocorticographic recordings demonstrated the direct propagation of CSD waves in to thalamic reticular nucleus. Activation was unilateral and lateralized to the side that CSD occurred. It was also lateralized to the side that trigeminal pain nucleus is activated. It was dependent on full conscious experience as highly vulnerable to anesthetics. Blockade of TRN activation by valproate, triptans and CGRP antagonists implicated its relation to nociception. CSD selectively activated visual sector of TRN, though other six TRN sectors of auditory, gustatory, visceral, somatosensoriyal, motor and limbic TRN were not affected by CSD. TRN consists of GABAergic neurons that surround the thalamus. TRN projects to thalamic relay nuclei in an inhibitory manner and receives glutamatergic excitatory afferents from both cortex and thalamic relay nuclei. TRN mainly functions as a gatekeeper of sensory outflow to the cortex, which is involved in selective attention, lateral inhibition, and discrimination of sensory stimuli. Burst firing of TRN neurons inhibits thalamo-cortical transmission and are associated with sleep spindles or silent periods during wakefulness. Lack of bilateral activation in TRN is against non-specific attention or being awake. Thalamic burst firing occurs spontaneously in human neuropathic pain conditions and also following noxious stimulation. Fifty to 65% of neurons in somatosensoriel TRN are nociceptive. Cav3.1 & 3.2 (T-channel) knockout mice, exhibit increased threshold for somatic & visceral nociception, which are incapable of thalamic burst firing, and fewer bursts. Oscillations in the low-frequency spindle range observed during freezing periods following CSD is suggested to be associated with pain perception. Involvement of TRN as a subcortical thalamic structure by a cortical event is important to explain several clinical features of migraine such as 1) Dysfunction of the GABAergic neurons in TRN would result in enhanced transmission of sensory information to the visual cortex, 2) Photophobia and visual hallucinations of aura may reflect dysregulation of visual stimuli by the TRN, 3) TRN could play a role in either termination or initiation of an attack as sleep is closely related with migraine, attacks are often associated with the circadian cycle and are typically relieved by sleep, 4) an activation of an ipsilateral central route particularly in awake subjects could play also a role in activating ipsilateral brainstem pain structures secondary to cortical activation.

Special Issue on Controversies in Neurology. From the 10th World Congress on Controversies in Neurology (CONy), Lisbon, Portugal. 17–20 March 2016.

International Journal of Clinical Neurosciences and Mental Health 2016; 3(Suppl. 1):D50

Icon_pdf Download PDF

Debate


Cortical spreading depression is not the inducer of all migraine attacks - read full article

By: Lars Edvinsson

Point of view: No
Migraine is a complex disease surrounded by numerous hypotheses. No doubt there is a genetic background but only mechanistically shown for hemiplegic migraine with glutamate as a common trait: hyperexcitability and reduced threshold for induction. It is a challenge to investigate the early phase of migraine attacks for technical reasons. Olesen (1981) early described rCBF alterations following injection of the radioactive tracer 133Xenon and later confirmed by MRI (Hadjikhani 2001); there was first an initial hyperemia followed by oligemia that spread across the cortex anteriorly without respecting the vascular territories. In addition there was close correlation between rCBF changes and the observed neurology. Woods (1994) reported in a PET study bilateral spreading wave of cerebral hypoperfusion in spontaneous migraine attack, associated by headache but without clear aura. Hadjikhani described a spreading wave of rCBF reductions with MRI in one patient that induced a migraine aura during basketball training. The symptoms observed in these studies correlated with the neurology symptoms. Thus, evidence exists for association between the aura phase preceding pain in a migraine attack and association with reduction in rCBF. Numerous experimental studies have examined induced cortical spreading wave of depression (CSD) as a surrogate method to obtain and understand this early part of a migraine attack but only scant clinical data exist. CSD leads to dramatic alterations in cerebral hemodynamics, however, mechanisms involved in promoting and counteracting cerebral vasodilator responses are unclear (Busija 2008). Experimental data suggest that the hyperemia phase as seen in rodents does not appear in primates but the cortical depression can be induced (Lauritzen). Is the cortex involved in all migraine attacks and a starting point? Maniyar (2014/5) recently revealed subcortical activation in the premonitory phase (posterolateral hypothalamus, midbrain tegmental area, periaqueductal grey, dorsal pons) and in various cortical areas including occipital, temporal and prefrontal cortex in conjunction with glyceryl trinitrate-triggered migraine attacks. These brain activations can explain many of the premonitory symptoms. Despite demonstration of cortical participation in migraine aura, the contribution of other brain structures including subcortical nuclei may indicate that the aura phenomenon is present only in some patients; the sequence of neurobiological events during a migraine attack remains to be elucidated further.

Special Issue on Controversies in Neurology. From the 10th World Congress on Controversies in Neurology (CONy), Lisbon, Portugal. 17–20 March 2016.

International Journal of Clinical Neurosciences and Mental Health 2016; 3(Suppl. 1):D51

Icon_pdf Download PDF

Debate


Electrical stimulation will not replace medications for the treatment of Cluster Headache - read full article

By: José M. Pereira Monteiro

Point of view: No
By Electrical Stimulation or Neurostimulation or Neuromodulation for the treatment of Cluster Headache we mean the following procedures: 1. Hypothalamic deep brain stimulation (DBS); 2. Occipital nerve stimulation (ONS); 3. Sphenopalatine ganglion stimulation (SPGS); 4. vagal nerve stimulation (VNS) and 5) spinal cord stimulation (SCS). Regarding the following features: 1. Procedures characteristics: 1. Surgical procedures; 2. Invasive procedures; 2. The time elapse to start the effect with a highly variability; 3. A fast relapse after an interruption on stimulation; 4. Potential complications: Infectious, hemorrhagic, functional, mechanical and/or technical; 5. Effectiveness: A reduced number of randomized and controlled studies and degree of effectiveness: with a large variability in different series; 6. The cost/effectiveness profile unfavorable; 7. Its clinical applicability: 1. Reduced amount of patients: 2. Restricted use to: a. Chronic CH patients and b. Pharmacologic refractory CH patients. I should say that Electrical Stimulation will not replace medications for the treatment of Cluster Headache, at least in the near future and, without better evidence on efficacy, safety and cost effectiveness of the procedures nevertheless its great utility for Chronic Refractory Cluster Headache patients.

Special Issue on Controversies in Neurology. From the 10th World Congress on Controversies in Neurology (CONy), Lisbon, Portugal. 17–20 March 2016.

International Journal of Clinical Neurosciences and Mental Health 2016; 3(Suppl. 1):D52

Icon_pdf Download PDF

Debate


Should asymptomatic intracranial aneurysm always be treated? New treatment guidelines - read full article

By: Pedro Castro

Point of view: Yes
Unruptured intracranial aneurysms (UIA) are relatively common in the general population and can be found in percentage as high as 6%. UIA are not static vascular anomalies but grow over time and eventually rupture. The subarachnoid hemorrhage that results from this rupture can be a dramatic event causing high morbidity and even death. The impact of a ruptured UIA can be depicted in a Finnish study, where 178 UIAs who were hospitalized, and during a mean follow-up of 13 years, had a 50% excess mortality compared with the general population. In the United States, rates of in-hospital mortality in acute care have reached 6.3%. Therefore the decision whether to treat or not to treat an UIA must take into account the fact that this pathological finding is not benign, affect young individuals and causing significant clinical but social burden. For all the reasons pointed this far, we conclude that, in theory and with complications-free treatment, all UIA should be treated. In favor of this approach is the fact the rate of treatment complications have been reducing progressively in the last decades making endovascular and surgical treatment safer. Sometimes, a wrong decision to exclude a UIA from intervention is related to a falsely belief that small aneurysm are devoid of risk of rupture. This is based on the findings of older studies like the International Study of Unruptured Intracranial Aneurysms (ISUIA). In this study, patients with no history of subarachnoid hemorrhage and IUA <7 mm in diameter did not show ruptures in follow-up. However, ISUIA have been criticized for several reasons. First, the number of patients in certain categories is small, so some of the estimates of rupture risk in the strata shown in are imprecise. The study show some internal inconsistency because some predictors of rupture confirmed at first phase some were not present phase. Additionally, the proportion of patients undergoing an interventional procedure varied tremendously from center to center in this nonrandomized study, in general, the surgeon or radiologist evaluating the patient would only have conservatively managed those patients who were deemed to be at low risk of rupture, and therefore, selection biases could change the risk profile of included participants. Finally, differential follow-up and detection biases could alter apparent rates, and some outcome events may have been missed. In studies with very long follow-up, have found that the rate of rupture can be has high as 29% during their lifetime, and the annual rupture rate per patient was 1.6%. The real picture seems that a patient an IUA may have a more dynamic and serious course and if follow-up is stretched enough all UIA will rupture. The most recent meta-analysis of all studies combined show that studies vary dramatically in size and duration of follow-up, and they included both prospective and retrospective design. As suspected aneurysms <7 mm also showed rupture, at an annual rate of 0.4%. Curiously, family history and previous rupture from a different aneurysm were not identified as risk factors for rupture. This means that we cannot predict really “safer” IUA based on size or in clinical ground. In conclusion, because UIA can have such a catastrophic clinical outcome and treatments are increasingly safer, all UIA are potentially indicated for treatment.

Special Issue on Controversies in Neurology. From the 10th World Congress on Controversies in Neurology (CONy), Lisbon, Portugal. 17–20 March 2016.

International Journal of Clinical Neurosciences and Mental Health 2016; 3(Suppl. 1):D53

Icon_pdf Download PDF

Debate


Should asymptomatic intracranial aneurysm always be treated? New treatment guidelines - read full article

By: Daniel Bereczki

Point of view: No
Three to four percent of stroke cases are caused by subarachnoidal bleeding due to aneurysma rupture. Unruptured intracranial aneurysms (UIA) are:asymptomatic incidental aneurysms, symptomatic aneurysms, and multiple aneurysm cases in SAH patients. The rupture incidence of unruptured aneurysms in the general adult population should be at least 1% per year. Recently, well-designed prospective clinical studies, metaanalyses and guidelines have been published dealing with diagnosis and therapy of UIAs. The prevalence of unruptured intracranial aneurysm is different from population to population, more frequent findings among elderly, females and polycystic kidney patients. Unruptured familial intracranial aneurysm patients represent ca. 8-10% of cases. Because only a minority of UIA patients will present with SAH it would be important to identify those UIA patients who live in high risk for rupture. Hypertension, smoking, certain locations, growth, special morphology of UIA are associated with high risk for rupture. But it is unclear if the change of modifiable risk factors influences the outcome of previously asymptomatic UIAs. Patients with family history of aneurysm, cranial nerve symptoms or with a prior SAH live in higher risk and need individual consideration and close follow up. Patients with polycystic kidney disease and persons with a family history of aneurysms or SAH may benefit from screening but the cost-effectivness of screening in other groups is unclear. Patients with ?2 family members with IA or SAH should be offered aneurysmal screening by CTA or MRA. TOF MRA is preferred to CTA for repeated long-term follow-up. With increasing size over 7 mm, the risk of SAH increases. The internal carotid and basilar artery aneurysms were more likely to grow than in other regions. Cavernous carotid aneurysms have the lowest, anterior circulation aneurysms have intermediate rates of rupture while posterior circulation aneurysms have the highest rates of rupture. The ICA and basilar artery aneurysms were more likely to grow than in other regions. Unfortunately, both the interval between imaging studies and the mode of that remain unclear. Although DSA is the optimal method for decision on repair, but follow-up imaging should be performed by either CTA or MRA. The physician should consider patient age, location and size, comorbidities and the long term outcomes of his/her center. The microsurgical intervention is associated with higher morbidity, than endovascular repair therefore in elderly patients the benefit of coiling seems to be greater. The microsurgery could be preferred in the treatment of the majority of MCA aneurysms and the endovascular intervention in the treatment of most basilar apex and vertebrobasilar confluence aneurysms. The flow-diverting stents, and stent-assisted coiling procedures might be new treatment strategies in the future and can be also considered in carefully selected cases, but the long-term outcome is not yet determined. After microsurgery or endovascular intervention, repeated imaging and assessment of cognitive outcome is warranted. The assessment of the degree of aneurysm obliteration after surgical or endovascular intervention is also necessary to determine the frequency of follow-up. Long- term follow-up is particularly important for those aneurysms that are incompletely obliterated. Summary: (1) Numerous factors should be considered for determining the optimal outcome of a UIA (growth, size, location, morphology, age, prior SAH, family history, multiplicity): all these factors may predispose to a higher risk of rupture; (2) Although the surgery may be associated with longer lasting protection against aneurysm regrowth, but the endovascular intervention could be superior to surgery in other aspects (lower morbidity and mortality, shorter length of stay, costs), so it may be reasonable to choose this therapy in basilar apex UIA and in old patients; (3) Endovascular coiling is associated with a reduction in procedural morbidity and mortality over surgical clipping in selected cases but has an overall higher risk of recurrence; (4) If many risk factors exist in a patient with small asymptomatic UIA and low hemorrhage risk, observation is a reasonable alternative; and (5) Although the ESO guideline summarizes only general recommendation on the therapy of UIA, both guidelines (ESO and AHA/ASA) agree that individual decision is necessary before any therapeutic step.

Special Issue on Controversies in Neurology. From the 10th World Congress on Controversies in Neurology (CONy), Lisbon, Portugal. 17–20 March 2016.

International Journal of Clinical Neurosciences and Mental Health 2016; 3(Suppl. 1):D54

Icon_pdf Download PDF

Debate


Evidence-based medicine (EBM) vs. personalized medicine in stroke victims. EBM should be the basis for high quality care - read full article

By: António Vaz Carneiro

Point of view: EBM
The way doctors manage patients—and management is here used in the sense of diagnosing, treating and following up patients—is a central issue for modern health systems. In fact, when one looks at the new tendencies for health care policies—quality assurance systems, patient-centred care, rational practice implementation and outcome based financing (to name just a few)—the central role of the quality of care is obvious. And quality of care means above all clinical care, done by physicians. The central issue is then: which is the best information source for clinical care, science or experience? The classic definition of Evidence-Based Medicine (EBM) is from Dr. David Sackett (1996): …“the conscientious, explicit and judicious use of current best evidence in making decisions about the care of the individual patient. It means integrating individual clinical expertise with the best available external clinical evidence from systematic research.” EBM is the integration of three factors into the decision making process for patient care (Sackett D, 2002): research evidence (found in clinically relevant studies conducted using sound methodology), clinical expertise (clinician’s cumulated experience) and patient values (personal preferences and unique concerns and expectations). The practical steps of EBM include: 1) assess the patient, 2) ask the clinical question, 3) acquire the evidence, 4) critically appraise the evidence, 5) apply the results to the patient and 6) self-evaluate one’s practice. Despite the impressive foundations EBM has constructed to use research into practice, some clinicians still debate the role of clinical experience of the individual doctor as opposed to scientific data from high quality clinical studies in taking care of patients. Certainly, clinical experience is crucial for the quality of clinical care if for no other reason because it captures a reality that science hardly can. For example, the average elderly patient usually presents with three or four diseases and a couple of extra risk factors, and these type of patients is seldom studied in clinical research. The patients usually included in clinical study‘s samples are very homogeneous, possessing mostly the same level of baseline risk (or in subgroups well defined), have much less co-morbidities and therefore are less representative of the group of daily patients needing care. On the other hand, clinical experience alone is absolutely insufficient to give patients a high quality of care. One has to stay abreast of the scientific evolution of one’s field of clinical practice, so that patients have the full benefit of innovation of care happening every day. As a well-known saying goes: “…If the clinician does not continually learn the scientific basis of his/her trade, after a while the patient is not consulting with a doctor but with a museum…” The problem of combining one´s expertise with clinical data is not very problematic if these two types of knowledge are more or less overlapping. The problems arise when they are opposite. For example, for decades patients with serious head trauma (GCS <14) were treated with steroids to diminish cerebral edema (an intervention never tested in a proper fashion). The study CRASH (Lancet 2004; 364: 1321–28) showed that, when compared with placebo, there was no significant reduction in mortality with the use of methylprednisolone in the 2 weeks after head injury (21.1% vs 17.9%; relative risk 1.18 [95% CI 1.09–1.27]; p=0.0001). However, the risk of death at 6 months of follow-up (Lancet 2005; 365: 1957–59) was clearly higher in the corticosteroid group than in the placebo group (25.7% vs 22.3%, relative risk 1.15, 95% CI 1.07–1.24; p=0.0001), as was the risk of death or severe disability (38.1% vs 36.3% dead or severely disabled; 1.05, 0.99–1.10; p=0.079). This is an example in which clinical impressions were invalidated by sound scientific data originating in high quality studies. Confronted with these results, the clinician must decide the appropriate course for the individual patient, always justifying his/her specific choices. Concerning the scientific basis for medical decision support, two concepts are important (Horton R, 2007): 1. How good are the data in terms inherent quality? This is reliability. 2. How appropriate are those data to the individual patient’s problem? This relevance. If doctors want to use scientific data to manage patients, reliability and relevance are the most important questions to consider. What about patients with stroke? Given the fact that there is a lot of studies on stroke (a quick search of Medline looking for papers with the word “stroke” in the title gives back almost 70,000 articles…), the question should be how to select the reliable and relevant studies to support medical decision making in stroke patients. Specifically concerning therapy, we need to select clinical trials that are useful to guide us through interventions on stroke victims by providing data that correctly assesses the effects of treatments on major morbidity as well as mortality, on subgroups of patients presenting with different baseline risks. This is due to the well-known fact that some treatments for chronic diseases can produce large benefits but, given the fact that stroke is a heterogeneous condition (similar patients have different prognosis), the selection of individualized therapy should be based on clear and reproducible data. The scientific basis of clinical practice demands that, once the best evidence is selected, every study should be appraised in terms of its internal validity (how rigorous is the design of the study to answer the clinical question it posed), the importance of its results (clinical, not statistical significance) and its external validity (the degree of generalizability of its results). For example, to minimise biases and random errors in clinical trials one should guarantee proper randomization, intention-to-treat analysis, rigorous blinding and accounting of patients (to name only a few factors). Clinicians are used to treat individual patients and therefore may feel that clinical trials do not give individual information for optimal care. However, clinicians that feel this way should bear in mind that all the diagnostic or therapeutic techniques available for them were developed in groups of patients similar to the ones they wish to manage, as one of the reasons to do these type of studies is that the individual variability of prognostic factors can only be identified through sufficiently large randomized groups of patients compared among them. Concerning therapy for acute stroke, the external validity of clinical trials results is paramount, since it allows using the data generated in these studies. But its limitations should also be understood: among the most important are the setting of the trial, the specific characteristics of trial patients, outcome measures, difference between trial protocols and clinical practice and the difference in the rate of adverse effects of treatment. Once careful analysis is done, the practitioner can then apply (or not) the interventions provided by the studies.

Special Issue on Controversies in Neurology. From the 10th World Congress on Controversies in Neurology (CONy), Lisbon, Portugal. 17–20 March 2016.

International Journal of Clinical Neurosciences and Mental Health 2016; 3(Suppl. 1):D55

Icon_pdf Download PDF

Debate


Genetic testing for stroke will soon be clinically relevant - read full article

By: Hugh Markus

Point of view: No 
There are a number of rare causes of stroke resulting from single gene disorders. The most common of these is Cerebral Autosomal Dominant Arteriopathy with Subcortical Infarcts and Leukoencephalopathy (CADASIL). In such cases a diagnosis can be made reliably from genetic testing, and most individuals with a NOTCH3 mutation causing, for example, will develop features of the disease during their lifetime. In such cases genetic testing is very important both to make a diagnosis, and also to offer presymptomatic testing to family members. This may be particularly relevant if family members are planning to have children and would like to consider prenatal testing. However these causes are rare and genetic factors are much more important, on a population basis, for multifactorial stroke. Epidemiological studies, and more recently techniques estimating heritability from genome-wide association study (GWAS) data, have shown that genetic factors are important in common stroke. GWAS analyses have identified a number of genetic associations for stroke and strikingly almost all of these are associated with specific stroke subtypes (i.e. for ischaemic stroke, large artery disease or cadioembolic stroke). It has been suggested that genotyping for these variants could be useful in predicting stroke risk in individuals. Indeed a few years ago some commercial companies were offering risk prediction using genotyping for patients with a variety of complex diseases including cardiovascular disease. However currently this is not useful to the individual patient, and indeed this led to the FDA stopping companies from advertising these services. The reason it is not useful is that each genetic variant accounts for only a small amount of increased risk. The odds ratios are usually between 1.1 and 1.2, i.e. they cause an extra 10% or 20% increase in risk. By studying sibling relative risk (an epidemiological measure of how genetic stroke is) one can work out how many variants with an odds ratio of about 1.1 to 1.2 account for the observed heritability of stroke. This comes to about 100-200. Currently we have only described only about 8 risk variants for ischaemic stroke. This means that even if we genotype these 8 variants we are only accounting for a very small proportion of overall stroke risk. Essentially the amount we can account for is so small that it does not serve any useful predictive use. Indeed it could be misleading in giving patients a full sense of reassurance. There are other issues which include whether patients would really want this information, and whether giving patients this information would have a useful effect on lifestyle measures to reduce stroke risk.

Special Issue on Controversies in Neurology. From the 10th World Congress on Controversies in Neurology (CONy), Lisbon, Portugal. 17–20 March 2016.

International Journal of Clinical Neurosciences and Mental Health 2016; 3(Suppl. 1):D56

Icon_pdf Download PDF

Debate


Carotid Dissection: should anticoagulants be used? - read full article

By: Hugh Markus

Point of view: Aspirin is all that is necessary
Carotid dissection is an important cause of stroke in younger individuals. It has been estimated it may account for as many as 25% of stroke in patients under 50. It is associated with an increased risk of early recurrent stroke. It is believed this is primarily due to thromboembolism from the site of the dissection and this has led to clinicians giving antithrombotic treatment to try to reduce this risk of recurrent stroke. It has been suggested that anticoagulants may be more effective because there is thrombus at the site of dissection. However there are also potential disadvantages of anticoagulants in that they could lead to further bleeding within the vessel wall and extension of the dissection and vessel occlusion. Furthermore many clinicians used to give anticoagulants for tight carotid stenosis but data subsequently showed that antiplatelet agents are more effective. Embolism from the stenosis is also thought to be the main cause of recurrent stroke in carotid stenosis. The CADISS trial recently reported the first randomised comparison of anticoagulants versus antiplatelet agents in patients with recent carotid and vertebral dissection. The striking finding was that there were very few recurrent events in this patient group. There was no difference between recurrent events in patients taking aspirin or anticoagulants. The trial only included 250 patients but provides the most robust data on which to base our clinical management of this patient group. On the basis of the low recurrent stroke risk and the lack of any difference between anticoagulants and antiplatelet agents, antiplatelet agent therapy alone is sufficient in patients with recent carotid dissection.

Special Issue on Controversies in Neurology. From the 10th World Congress on Controversies in Neurology (CONy), Lisbon, Portugal. 17–20 March 2016.

International Journal of Clinical Neurosciences and Mental Health 2016; 3(Suppl. 1):D57

Icon_pdf Download PDF

Debate


Carotid dissection: should anticoagulants be used? - read full article

By: José M. Ferro

Point of view: Yes
Carotid dissection is a frequent cause of stroke in the young adult, often producing devastating deficits. After the acute phase, recurrence of dissection and of stroke is rare. Anticoagulants, antiplatelet drugs and less often endovascular interventions or vascular surgery are used to reduce the risk of recurrence. Until recently, anticoagulation was the most used preventive treatment. Two dangers of anticoagulation are often feared: enlargement of the intramural hematoma and severe intracranial or systemic bleeding. There is no evidence from serial imaging and clinical studies that anticoagulation causes increase in size of the intramural hematoma. Two systematic reviews did not find any difference on the comparative efficacy of anticoagulants and antiplatelets to prevent recurrent strokes. A recent RCT—CADISS—found no difference in efficacy of antiplatelet and anticoagulant drugs at preventing stroke and death in patients with symptomatic carotid and vertebral artery dissection but stroke was rare in both groups, and much rarer than reported in some observational studies. The study has however several methodological limitations, including being a feasibility trial not reaching the target no of inclusions, having a lower than expected no of endpoints, the diagnosis of dissection was not confirmed after review in many cases and several non-included patients meet inclusion criteria for randomization. The risk of bleeding with anticoagulants is overestimated in patients with dissection. Patient with dissection are younger and healthier and the period of anticoagulation is shorter than in elderly patients with AF.

Special Issue on Controversies in Neurology. From the 10th World Congress on Controversies in Neurology (CONy), Lisbon, Portugal. 17–20 March 2016.

International Journal of Clinical Neurosciences and Mental Health 2016; 3(Suppl. 1):D58

Icon_pdf Download PDF

Debate


Is the ABCD2 grading useful for clinical management of TIA patients? - read full article

By: Jonathan Streifler

Point of view: Yes
Transient ischemic attacks (TIA’s) are very important in identifying stroke risk; it is reported to be 3.1% in 2 days and 5.2% in 7 days! While this was the average risk, there are high-risk's TIA patients which carry even higher early risk of stroke. This was reported clearly in the past 10 years and it was shown that those with the high early stroke risk can be identified by clinical and investigational means. Clinical scores such as ABCD2, ABCD3 were developed for TIA patients and most studies reported their usefulness in identifying those high-risk patients. As specific etiologies such as high grade carotid stenosis along with positive brain imaging were also found to be associated with higher risks, the ABCD3-I score was developed; it includes brain and cervical imaging and its usage was claimed to carry even a higher predicting value. These high-risk patients need urgent therapeutic approach, as effective stroke prevention measures are available and invaluable; by appropriate immediate approach, the stroke risk was reduced by up to 80% in one study! Other studies showed similar results. These good results can be achieved only by utilizing facilities to identify urgently TIA patients- i.e. 24h TIA clinics such as the SOS TIA clinic in Paris, which also reported favorable results. Specific measures to reduce stroke risks (such as carotid endarterectomy or stenting) are available yet it is impractical to wait for such intervention without introducing immediate medical treatment in the interim and, likewise, in cases where potential interventions are not identified. TIA’s, in most cases, stem from the arterial tree due to embolic particles originating at unstable atherosclerotic plaques where thrombotic & thromboembolic processes occur; by antithrombotic treatment we can slow the coagulation cascade at the site of unstable plaques. Of all antithrombotic agents, antiplatelets (AP) were proven to be the most effective in preventing or reducing these processes (besides statins). Recommended AP agents for secondary stroke prevention include aspirin alone, clopidogrel alone and the combination of dipyridamole with low dose aspirin. Its relative stroke risk reductions range from 22 to 37%, yet these results are based on studies which emphasize long term treatment. The key issue nowadays, as TIA treatment should be urgent, is how early these agents exert their protective effects. Clopidogrel is a pro-drug and its effectiveness can be hastened by the administration of a loading dose (300-600 mg). Its combination with aspirin was found useful in several clinical vascular situations (such as unstable angina and stent implantation). Yet, similar studies in secondary stroke prevention- the MATCH and SPS3 studies- found no beneficial effect throughout the studies' periods (1.5 & 3.4 years respectively), mainly due to bleeding side effects. Therefore this combination is consider risky and is not recommended for secondary stroke prevention. Both studies, however, did not aim for the very early post TIA/ stroke period- the period when the risk is the highest! Small studies comparing this combination early on in patients with symptomatic carotid disease (CARESS, CLAIR) demonstrated a significant reduction in emboli production and subsequent meta-analyses of outcome data from these studies along with data taken from larger studies (for those patients recruited very early) as well as from newer, relatively small, studies (FASTER, EARLY), as well as a large Chinese study (CHANCE) have shown beneficial effect for dual AP regimen in reducing risks of stroke and death early on. Therefore it seems that we have a powerful AP treatment which could be used for our high-risk TIA patients. It's worth the risk, at least for this subgroup (by using the ABCD grading scores). Another issue is how early should the investigation be done? the ABCD2 score (and alike) is useful for this decision; a recent NICE guideline suggest a cutoff of 4 points to splint patients into 2 or 7 days of investigation completion schedule. Thus the ABCD2 grading score is useful in the management of TIA patients. These points will be further elaborated in this debate.

Special Issue on Controversies in Neurology. From the 10th World Congress on Controversies in Neurology (CONy), Lisbon, Portugal. 17–20 March 2016.

International Journal of Clinical Neurosciences and Mental Health 2016; 3(Suppl. 1):D59

Icon_pdf Download PDF

Debate


Starting anticoagulants in post-stroke AF patients: how soon? - read full article

By: Isabel Amorim, Sofia Proença, Carolina Falcão, and Daniela Pinto

Point of view: No
It is an unusual opportunity to be tasked with the request to take the negative position on time in of starting anticoagulants in post-stroke atrial fibrillation patients. I usually begin the anticoagulant program earlier than later. I have two hedge my comments based on the assumption of the stroke type; its location, size, isolated event, or the most recent of several events; coexisting brain lesions contraindicating anticoagulation, and systemic factors that may influence anticoagulation safety. Most atrial-fibrillation-related strokes are infarct in type, the most common path up the internal carotid to the circle of Willis; from there to the middle cerebral artery stem and assuming a typical bifurcation, passing into the lower division; the final lodgment occurring in the posterior sylvian region and posterior temporal lob. The most common syndrome is a Wernicke type aphasia in the dominant hemisphere, and behavior disturbance with hemineglect in the nondominant. The severity of the syndrome reflects the degree to which one or more of the usual three branches of the lower division are affected, and whether collateral from the posterior cerebral artery minimizes the extent of temporal, parietal, and lateral occipital infarction. Assuming the infarct is confined to the posterior portion of the sylvian fissure with good collateral, there should be no hesitation in starting anticoagulants as soon as the syndrome is clinically evident and the extent of the injury documented by imaging. Relying on the syndrome alone was the classical approach before imaging. I have several painful examples of patients with primary hematoma or major hemorrhagic infarction, neither the diagnosis or stroke severity obvious on initial clinical examination alone. In other territories, early trials with thrombolytics demonstrated even hemorrhagic conversion for infarcts of one gyrus size seemed well-tolerated and were not unduly made worse by early anticoagulation. Obstructions in the distal intracranial internal carotid or major circle of Willis vessels have so often been followed by hemorrhagic changes in the lenticulostriates that those in our group have been reluctant to recommend early anticoagulation for fear of exaggerating the already major hemorrhagic conversion. Few would argue against withholding anticoagulants when major intracranial hemorrhagic disease coexists. In many the first imaging ever performed on the patient was after a stroke, because anticoagulants were instituted when atrial fibrillation was discovered without brain imaging beforehand. The tolerance of the brain for simultaneous anticoagulation, with intracranial aneurysms, arteriovenous malformations, or even amyloid angiopathy seems quite remarkable. The per-day recurrent embolic risk in a setting of atrial fibrillation is static and low. Early institution of anticoagulants is not required in the initial days after a stroke event. However, a prothrombotic state justifies early intervention. The common practice of delaying anticoagulants for a week or more seems outmoded, now that the features of the stroke can be well-characterized by modern imaging. Our practice is to use a flat dosing program (no loading dose) if warfarin is the choice. Aspirin is given daily during the running phase can be discontinued when the INR appears in a therapeutic range. Recalling how long it takes the intravascular coagulation status to be reflected by the INR means that most cases are likely not to be fully anticoagulated even when the clinicians take the INR at face value. The introduction of oral thrombin inhibitors are changing the anticoagulant management program and when successful could mean early therapeutic anticoagulant values will become common and allow the testing of whether hemorrhagic conversion will prove more or less common compared with the traditional oral warfarin programs. Aspirin or other antiplatelet agents were initially assumed to be safe with these new oral thrombin inhibitors, but less so at present.

Special Issue on Controversies in Neurology. From the 10th World Congress on Controversies in Neurology (CONy), Lisbon, Portugal. 17–20 March 2016.

International Journal of Clinical Neurosciences and Mental Health 2016; 3(Suppl. 1):D60

Icon_pdf Download PDF

Debate


Endovascular therapy in acute stroke: Start with IV tPA or go directly to the catheter lab? - read full article

By: László Csiba

Point of view: Start with IV tPA
Large vessel occlusions represent ca.10-15% of all ischemic stroke. There is strong evidence for efficacy for thrombectomy in adjunct to i.v. fibrinolysis, when compared with i.v. fibrinolysis alone. Recently, 5 multicenter, prospective studies have confirmed the benefit of mechanical thrombectomy (met). The results of recent studies comparing the efficacy of combined intervention (intravenous + endovascular therapy versus intravenous only) are as follow (we focus only on those studies that included 100% iv. Thrombolysis patients as control group): the IMS-III included patients with intravenous t-pa and additional endovascular therapy or intravenous t-pa alone, in a 2:1 ratio. The primary outcome measure was a modified rankin scale score of 2 or less. Unfortunately, the ims trial had inhomogenous met group using four endovascular interventions: intraarterial t-PA (51 patients), microsonic sv infusion system with intraarterial t-pa (14 patients), merci retriever (77 patients), penumbra system (39 patients), and solitaire fr revascularization device (4 patients). There was no significant difference between the endovascular-therapy and intravenous t-pa groups in the overall proportion of participants with a modified rankin score of 2 or less (40.8% and 38.7%, respectively. The trial showed similar safety outcomes and no significant difference in functional independence with endovascular therapy after intravenous t-PA, as compared with intravenous t-pa alone. Extend-IA investigators applied 0.9 mg/kg of t-pa in less than 4.5 hours after the onset of ischemic stroke either to undergo endovascular thrombectomy with the solitaire fr or to continue receiving alteplase alone. All the patients had occlusion of the internal carotid or middle Cerebral artery and evidence of salvageable brain tissue and ischemic core of less than 70 ml on computed tomographic (CT) perfusion imaging. All patients received alteplase at a dose of 0.9 mg per kilogram as standard care. Endovascular therapy improved the functional outcome at 90 days, with more patients achieving functional independence (score of 0 to 2 on the modified rankin scale, 71% vs. 40%; p=0.01). There were no significant differences in rates of death or symptomatic intracerebral hemorrhage. The swift prime investigators assigned stroke patients to t-pa alone (control group) or to undergo endovascular thrombectomy with the use of a stent retriever within 6 hours after symptom onset. Patients had confirmed occlusions in the proximal anterior intracranial circulation and an absence of large ischemic-core lesions. The rate of functional independence (modified rankin scale score, 0 to 2) was higher in the intervention group than in the control group (60% vs. 35%, p<0.001). There were no significant between-group differences in 90-day mortality (9% vs. 12%, p=0.50) or symptomatic intracranial hemorrhage (0% vs. 3%, p=0.12). The other studies (McClean, REVASCAT, Escape etc.) have also confirmed the beneficial effect of mechanical intervention. The recent positive RCTs share same common features: patients with a high NIHSS and aspect score of 8–10 were included, and most commonly in the control group there was proof of vessel occlusion required. In general the time to endovascular treatment was below 4.5h and cotreatment with rtpa occurred in more than 90% of all cases. The recently published karolinska guideline summarizes: “mechanical thrombectomy, in addition to intravenous thrombolysis within 4.5 h when eligible, is recommended to treat acute stroke patients with large artery occlusions in the anterior circulation up to 6 h after symptom onset (grade A, level 1A, KSU grade A). Mechanical thrombectomy should not prevent the initiation of intravenous thrombolysis where this is indicated, and intravenous thrombolysis should not delay mechanical thrombectomy (grade A, level 1A, KSU grade A). Similar statement has been formulated in the American guideline: “patients eligible for intravenous r-tPA should receive intravenous r-tPA even if endovascular treatments are being considered (class I; level of evidence A). But recently Kass-Hout t et al. Analysed patients with acute large artery occlusion. Forty-two received endovascular therapy in combination with iv thrombolysis (bridging group), and 62 received endovascular therapy only. The favorable outcome (mrankin <2 at 90 days), did not differ between the bridging group and the endovascular-only group (37.5% and 32.76%; p=0.643). There was no difference in mortality rate (19.04% and 29.03%; p=0.5618) and sICH rate (11.9% and 9.68%; p=0.734). A significant difference was found in mean time from symptom onset to treatment in the bridging group and the endovascular-only group (227±88 min vs. 125±40 min; p<0.0001). They concluded, that combining iv thrombolysis with endovascular therapy resulted in similar outcome, revascularization, sICH, and mortality rates compared with endovascular therapy alone. So, the iv. Part could be omitted and the patients should go directly to the catheter lab. But the final answer could be given by a prospective, randomized, multicenter trial with the following criteria: 1. Acute ischemic stroke patients 4,5 hours after stroke; 2. All patients should undergo CT or MR angiography; 3. Only patients with large vessel occlusion (ICA, MCA occlusion) should be randomized; 4. One group of patients should be treated only with mechanical thrombectomy as soon as possible; 5. The other group of patients should receive first iv. thrombolysis with additional mechanical thrombectomy; and 6. mRankin scale after 3 months and complications should be compared. This study will finally answer the question if a large vessel occlusion patient should be transferred directly to the catheter lab or start first with iv. thrombolysis.

Special Issue on Controversies in Neurology. From the 10th World Congress on Controversies in Neurology (CONy), Lisbon, Portugal. 17–20 March 2016.

International Journal of Clinical Neurosciences and Mental Health 2016; 3(Suppl. 1):D61

Icon_pdf Download PDF

Debate


Endovascular therapy: Start with IV tPA or go directly to the catheter lab? - read full article

By: João Sargento-Freitas

Point of view: Straight to the catheter lab
The recent compelling evidence of intra-arterial therapies in acute ischemic stroke have urged the revision of local algorithms in stroke units across the globe. In fact, in the presence of a proximal intracranial occlusion endovascular treatments reached unprecedented hemodynamic and functional efficacy in an otherwise problematic clinical scenario. Up until recently, the attempt to reperfuse the symptomatic area was limited to the “old” intravenous infusion of alteplase (IVtPA). Albeit its merits, the clinical impact caused is significantly impaired due to its narrow therapeutic window, extensive list of contra-indications and limited efficacy in large vessel occlusions. In acute ischemic stroke with salvageable cerebral tissue a simplistic and pragmatic approach could define three main clinical scenarios: patients with contra-indication to IVtPA, patients with and those without large-vessel occlusions. For the first clinical scenario the answer is straightforward: to the catheter lab in all those with proximal occlusions. The answer is more troublesome in the advent of a large vessel occlusion without contra-indication to IVtPA. In this setting IVtPA has a reported recanalization rate of 10-20% with very limited clinical impact. On the other hand, it is not without side effects in the ischemic area, in remote cerebral areas as well as other organs susceptible to bleeding, not rarely in uncompressible locations. Ultimately, it may represent exposing the patient to potentially severe risks for minimal impact in the ischemic brain. For patients without proximal intracranial occlusions IVtPA is highly efficacious, rendering intra-arterial therapies as unnecessary. In conclusion, IVtPA will remain the mainstay of acute stroke treatment for all those with clear clinical indications. However, the advent of intra-arterial therapies has had a dramatic impact on stroke algorithms worldwide. Particularly, in the subset of patients with large vessel occlusions the option of going straight to the catheter laboratory is appealing as it would prevent the use of a marginally effective therapy with rare but potentially severe complications, promoting the need for urgent intra-arterial recanalization.

Special Issue on Controversies in Neurology. From the 10th World Congress on Controversies in Neurology (CONy), Lisbon, Portugal. 17–20 March 2016.

International Journal of Clinical Neurosciences and Mental Health 2016; 3(Suppl. 1):D62

Icon_pdf Download PDF

Debate


Testing for thrombophilia in cryptogenic stroke in the young: is it useful? - read full article

By: José M. Ferro

Point of view: No
The epidemiological evidence linking protrombothic states to arterial stroke is much weaker than that with venous stroke. Despite that evidence, screening for acquired and genetic thrombophilia is performed in young stroke patients in many stroke centers. This means searching for protein C and S and antithrombin deficiencies, factor V Leiden and prothrombin G20210A mutations and homocysteine plasma levels and for lupus anticoagulant and autoantibodies (anticardiolipin and anti-beta2 glycoprotein) linked to the antiphospholipid syndrome. This screening must also take in consideration the effect of acute stroke phase inflammatory reaction, the influence of anticoagulants, the need for repeated testing and in some instances the need for additional genetic or familiar studies. All these evaluations take time and lead to incremental costs in the standard work up package of “young stroke”. With the exception of hyper-homocysteine plasma and antiphospholipid syndrome all the other prothrombotic condition are very rare. Therefore systematic screening for thrombophilia in young stroke victims has a low yield. Basing screening on clinical hints such as recurrent stroke, strong family history, combination of venous and arterial thromboembolic events or on clinical features suggesting antiphospholipid syndrome, such as recurrent thrombotic events or unfavorable pregnancy outcomes, in particular miscarriage, increases the efficiency of the screening. The therapeutic consequence of editing a prothrombotic state is in general lifetime anticoagulation. However the evidence supporting long term anticoagulation after stroke in patients with a prothrombotic condition is weak and it is unknown if long term anticoagulation improves the outcome and Quality of Life of young stroke patients. Therefore systematic testing for thrombophilia is unlikely to improve the outcome and to be cost-effective in young stroke patients.

Special Issue on Controversies in Neurology. From the 10th World Congress on Controversies in Neurology (CONy), Lisbon, Portugal. 17–20 March 2016.

International Journal of Clinical Neurosciences and Mental Health 2016; 3(Suppl. 1):D63

Icon_pdf Download PDF

Debate


Post-stroke neurorehabilitation: compensation vs. restoration - read full article

By: John Krakauer

Point of view: Restoration
Early rehabilitation needs to be focused on restitution not compensation Data will be presented from both humans and animal models that show there is a unique time limited period early after stroke in which motor recovery at the level of impairment occurs. Rehabilitation techniques need to be developed that maximally- exploit this window of spontaneous biological recovery and enhanced responsiveness to training. Compensatory training should be avoided in this period and can be postponed until after the window has closed.

Special Issue on Controversies in Neurology. From the 10th World Congress on Controversies in Neurology (CONy), Lisbon, Portugal. 17–20 March 2016.

International Journal of Clinical Neurosciences and Mental Health 2016; 3(Suppl. 1):D64

Icon_pdf Download PDF

Debate


Is the improvement of MAO-B-I clinically relevant? - read full article

By: László Vécsei

Point of view: Yes
Selegiline is a selective, irreversible MAO-B inhibitor at therapeutic dose of 10 mg/day, but loses its selectivity at greated dosage. The potential of selegiline to modify disease progression in PD was proposed when it was shown to prevent MPTP-induced parkinsonism in monkeys. There is no conclusive evidence from clinical trials to prove that selegiline has „disease-modification” effects. Long term clinical trials of selegiline have shown improved motor outcome and reduced levodopa requirement. Whether these findings were attributed to the symptomatic benefits of the disease-modification property of selegiline remain debate. Unlike rasagiline in which delayed-start design trials were carried out in an attempt to separate confounding symptomatic effects from disease-modifying effects, there are none for selegiline. Rasagiline is a second generation propalgylamine-based selective, irreversible MAO-B inhibitors. It was reported to have potent anti-apoptotic effects independent of MAO inhibition in in vitro and in vivo experimental parkinsonian models. Unlike selegiline, rasagiline is not metabolized to L-amphetamine-like metabolites which may cause appetite suppression and insomnia. In the PRESTO study the Clinical Global Impression (CGI) and the UPDRS ADL scores during „off” time showed improvement as secondary end points, with both doses of rasagiline, but not with PD Quality of Life summary score. In the LARGO study, patients who had received rasagiline had statistically significant reduction of mean daily „off” time. Recent study supports the efficacy and safety of safinamide (oral aminoamide derivative with broad mechanism of action such as reversible MAO-B inhibition, blockage of voltage-dependent sodium channels, modulation of calcium channels and of glutamate release) as an adjunct to levodopa in PD patients with motor fluctuations. In earlier clinical studies, it was shown to improve motor control in patients with PD who received it as an add-on to dopamine agonist or as an adjunct to levodopa. The dual mechanism (reversible MAO-B inhibition and glutamate release inhibition) is belived responsible for the alleviation of motor symptoms of PD.

Special Issue on Controversies in Neurology. From the 10th World Congress on Controversies in Neurology (CONy), Lisbon, Portugal. 17–20 March 2016.

International Journal of Clinical Neurosciences and Mental Health 2016; 3(Suppl. 1):D65

Icon_pdf Download PDF

Debate


Therapies targeting alpha-synuclein will be the treatment of choice in PD - read full article

By: Dieter H. Meier

Point of view: Yes
To develop a truly disease-modifying therapeutic, it will be necessary to stop the progression of the underlying pathophysiology. A tremendous amount of research has been devoted to understanding the role of misfolding and aggregation of the synaptic protein alpha-synuclein (ASYN). Both human genetic studies and experiments in animals provide compelling links between the dysregulation of ASYN and PD. The neuropathological hallmark of PD and other synucleinopathies is the accumulation of alpha-synuclein (ASYN) containing cytosolic inclusions, called Lewy-bodies. As with other misfolded proteins, it is likely that in PD the microscopically detectable Lewy bodies containing ASYN polymers are final deposits while earlier stages of aggregates are involved in the pathogenic process. Recent studies further suggest that membrane-embedded oligomers of ASYN may be a particularly toxic form of ASYN, resulting in disruption of synaptic function, loss of cell membrane integrity and ultimately, in neuronal degeneration. Treatments that prevent the formation and accumulation of these toxic membrane-embedded oligomeric aggregates of ASYN may prevent further decay or even restore synaptic function in impaired systems and slow the rate of degeneration, thus providing a therapeutic benefit for patients. Treatment approaches that target the misfolding and aggregation process are currently being explored in early clinical studies with antibodies, vaccination and small molecules. Another, therapeutic principle is to enhance the clearance of these protein aggregates by rectifying defects in a dysregulated clearance mechanism . Approaches aimed at enhancing clearance are still at the animal-testing stage but hold out promise because they may prove to be effective even after the disease has progressed to its later stages. We have developed molecules based on both approaches—inhibition of aggregation and enhancement of clearance— with convincing effects on alpha-synuclein reduction and in the ‘clinical’ assessments in these animal models. In summary, while the physiological role of ASYN is currently not fully understood, it is clear that the accumulation of misfolded forms of ASYN contributes to the pathology of PD and that preventing the formation of toxic oligomers and/or enhancing cellular clearance mechanisms may be viable therapeutic approaches to halt or slow disease progression.

Special Issue on Controversies in Neurology. From the 10th World Congress on Controversies in Neurology (CONy), Lisbon, Portugal. 17–20 March 2016.

International Journal of Clinical Neurosciences and Mental Health 2016; 3(Suppl. 1):D66

Icon_pdf Download PDF

Debate


Therapies targeting alpha-synuclein will be the treatment of choice in PD - read full article

By: Ruggero G. Fariello

Point of view: No
Alpha-Synuclein (alpha-syn) and its aggregation tendency plays a pivotal role in the pathogenesis of LBD ,PD and MSA. Less clear is the pathogenic role of alpha-syn in Hallervorden Spatz Disease. Particularly in LBD there is general agreement that dissolving alpha-syn aggregates would take care of the most important pathogenic process leading to dementia. True, in AD all the attempt to obtain symptomatic benefits by dissolving beta-amyloid (amy) aggregates have miserably failed. However, beta-amy aggregation is only one pathogenic factor in AD. Thus, clearance of beta-amyloid from brains cannot be expected to have the same beneficial results of clearing alpha-syn in the synucleopathies. Said this, the very high risk of successfully translating benefits obtained in animal models of neurodegenerative diseases to the clinical setting still remains. At present no molecule in development impedes both the antifibrillogenic and the anti-oligomerization of the protein which may key to the pathogenic process. Several compounds, are in various phase of development, at least two are mab and claim "vaccination" potential. The certainty that encephalitic processes will result from prolonged treatment has not been reached yet. Also the consequences of blocking alpha-syn throughout the brain (and in other parts of the bodies) have not been fully explored. The field of a disease modifying treatment addressing alpha-syn aggregation in PD may move forward more expeditely using small molecules or peptides.

Special Issue on Controversies in Neurology. From the 10th World Congress on Controversies in Neurology (CONy), Lisbon, Portugal. 17–20 March 2016.

International Journal of Clinical Neurosciences and Mental Health 2016; 3(Suppl. 1):D67

Icon_pdf Download PDF

Debate


Do COMT Inhibitors have a future? - read full article

By: Joaquim Ferreira

Point of view: Yes
COMT inhibitors are an important pharmacological class for the treatment of motor fluctuations in Parkinson's disease (PD). However, issues such as the magnitude of the effect, relevancy of the benefit, safety and best time for their use are still matters of discussion. Best data available comparing entacapone with placebo concludes on a reduction of 41 minutes of daily OFF time and the clinical relevancy of such an effect may be questioned. On the other hand, although there is a consensus regarding the higher potency of tolcapone, its utilisation is limited due to safety concerns on liver toxicity. Conversely, other antiparkinsonian drugs like the dopamine agonists and the MAO-B inhibitors have also demonstrated efficacy for the treatment of wearing-off and these questions the best strategy for the sequential use of the different alternatives in the management of the disease. Considering all these factors, the future of COMT-I for the management of PD is dependent on having new drugs which are more potent, safer or easier to use and which additional benefits they add to the currently available armamentarium. The recently available data from a new COMT inhibitor, opicapone, currently under evaluation by the European Medicines Agency, argues in favour of the possibility to have new drugs which add potency compared with the old COMT-I, with a simpler mode of administration which may add a benefit for the use of this pharmacological class.

Special Issue on Controversies in Neurology. From the 10th World Congress on Controversies in Neurology (CONy), Lisbon, Portugal. 17–20 March 2016.

International Journal of Clinical Neurosciences and Mental Health 2016; 3(Suppl. 1):D68

Icon_pdf Download PDF

Debate


High Intensity Focal Ultrasound (HIFU) is a newly developed technique intending - read full article

By: Jose Obeso

Point of view: Yes
Pallidotomy and thalamotomy began in the 1950s and electrolytic thalamotomy with electrophysiological intraoperative assessment became established for the treatment of tremor in the 1960s. This procedure waned for over 2 decades with pharmacological developments(i.e. levodopa and other drugs). Surgery for movement disorders regained prominence when pallidotomy first and deep brain stimulation (DBS) son after were applied to the treatment of Parkinson’s disease (PD) and dystonia in the 1990s. Lesion of the subthalamic nucleus (STN) have been less popular because of the fear to cause hemiballism, but actually employed in many countrie,s particularly because of the high cost and technological demands of DBS, without major complications. Clinical trials have investigated the safety and efficacy of thermal lesions created by transcranial, HIFU, which now offers the possibility of using more frequently focal ablative treatment for movement disorders. The outcomes of HIFU treatment is highly predictable as essentially should be the same than well-established for thalamotomy, pallidotomy and subthalamotomy. The potentials side effects are also the same without the risk of intracranial surgery. Recent, still preliminary data, indicates that HIFU can indeed be used with marked efficacy for the treatment of essential tremor and other disorders with tremor predominant manifestation, including Parkinson’s disease. The reduced invasiveness and excellent benefit to risk profile allows to use it to treat patients that otherwise could not benefit from surgical procedures. This is a welcome addition to the therapeutic armamentarium of movement disorders.

Special Issue on Controversies in Neurology. From the 10th World Congress on Controversies in Neurology (CONy), Lisbon, Portugal. 17–20 March 2016.

International Journal of Clinical Neurosciences and Mental Health 2016; 3(Suppl. 1):D69

Icon_pdf Download PDF

Poster


The role of rehabilitation in multiple sclerosis—is it worth it? - read full article

By: Isabel Amorim, Sofia Proença, Carolina Falcão, and Daniela Pinto

Introduction: Multiple Sclerosis is a complex immune-mediated disease that causes demyelination and degeneration within the brain and spinal cord. This may result in muscle global weakness, abnormal tone, visual disturbances, decreased sensation, tremor/ataxia, bladder, bowel and sexual dysfunction, fatigue and impaired ambulation. Those symptoms cause disability and have a huge impact on quality of life (QOL). Methods: Literature review about the evidence assessing the rehabilitation interventions for maintaining functional capacity and reducing risk for losing important abilities and independence. Databases of Cochrane Library/Pubmed/Medline were search from 2005-2016. Results: Physical exercise is safe and should be encouraged. Even though rehabilitation has no direct influence on disease progression, studies have shown that this intervention reduce the limitations in order to maintain quality of life. Timing and setting of rehabilitation interventions should be selected individually. Benefits are generally higher in earlier phases of MS. A multidisciplinary approach, constitutes the basic concept of rehabilitation. The main symptoms that need to be specifically attended are spasticity, cognitive impairment, motor, sensory and visual disturbance, fatigue and bladder dysfunction. Deficits in ambulation should be addressed to improve energy efficiency and reduce falls. Compensation through appropriate prescription of assistive devices, bracing, and wheelchairs will help improve safety. Cognitive training can improve memory span, working memory, and immediate visual memory. New promising rehabilitation techniques may also be useful: impairment-oriented training, CIMT, electromyogram-triggered neuromuscular stimulation, and robotic interactive therapies. Conclusion: Rehabilitation can have significant impact on achieving and maintaining QOL improving independence in patients with MS.

Special Issue on Controversies in Neurology. From the 10th World Congress on Controversies in Neurology (CONy), Lisbon, Portugal. 17–20 March 2016.

International Journal of Clinical Neurosciences and Mental Health 2016; 3(Suppl. 1):P1

Icon_pdf Download PDF

Poster


A diagnostic dilemma: acute disseminated encephalomyelitis following herpetic encephalitis or multiple sclerosis (MS)? - read full article

By: Cristina Baetu, I. Buraga, G. Mihailescu, and A.M. Enachi

By definition both ADEM and MS cases must manifest disseminated disease of central nervous system. AADEM is an uncommon monophasic idiopathic inflammatory demyelinating disease; it usually develops after an acute viral infection, vaccination or organ transplantation. We present the case of a female patient , age 50 who was admitted in our hospital with abrupt onset of fever ,confusion and aphasia. Initial lab tests revealed increased levels of herpes virus (IgM and IgG). Serological tests for other common neurotropic viruses and parasites were negative. Magnetic resonance imaging showed multifocal changes in the brain parenchima mainly in the white matter so she started treatment with high doses of methilprednisolone. The CSF IgG index and oligoclonal bands were positive; Electroencephalogram revealed epileptiform activity. Is it ADEM following acute viral infection or is it atypically multiple sclerosis ? Did the herpes virus triggered ADEM or MS? We will present the differential diagnosis with the final results and outcome of our case.

Special Issue on Controversies in Neurology. From the 10th World Congress on Controversies in Neurology (CONy), Lisbon, Portugal. 17–20 March 2016.

International Journal of Clinical Neurosciences and Mental Health 2016; 3(Suppl. 1):P2

Icon_pdf Download PDF

Poster


Fampridine in multiple sclerosis: beyond walking - read full article

By: J. Beato-Coelho, M. Pereira, I. Correia, J. Marçal, I. Ribeiro, A. Melo, C. Nunes, L. Sousa, J. Campelo, S. Batista, and C. Macário

Introduction: Fampridine is indicated in patients with multiple sclerosis (MS) with walking disability (EDSS 4-7). It has been reported that 40% of these patients present an improvement on walking speed (WS) of at least 20%. Data regarding fampridine impact on other symptoms of MS are scarce. Objectives: To evaluate the effect of fampridine on WS, cognition and manual dexterity (MD) in MS patients. Methods: We included all MS patients who started fampridine from March to November 2015. Our evaluation protocol included Timed 25-Foot-Walk (T25-FW) to measure WS, Symbol Digit Modality Test (SDMT) for cognition and 9-Hole Peg Test for MD. Patients were evaluated at baseline and after 2 weeks of fampridine 10mg twice daily. We defined as responders those who had a faster WS of at least 20%. Results: Thirty patients were included, 73.3% females, with a mean age of 51.4 years old, and a median EDSS of 5.5. The responders were 19 (63.3%). After 2 weeks of fampridine there was a significant improvement in the WS (31.36 vs 30.66 p0.001) and MD (32.53 vs 30.66 p=0.005). For cognition, as measured by SDMT, we found no difference (32.13 vs 32.87 p=0.165). Considering only the responders population, there was a trend towards improvement in SDMT yet not significant (30.1 vs 31.9 p=0.055). Conclusion: In this population fampridine improved not only the WS but also manual dexterity. We did not confirm benefits in cognition

Special Issue on Controversies in Neurology. From the 10th World Congress on Controversies in Neurology (CONy), Lisbon, Portugal. 17–20 March 2016.

International Journal of Clinical Neurosciences and Mental Health 2016; 3(Suppl. 1):P3

Icon_pdf Download PDF

Poster


Unusual expression of multiple sclerosis (case report) - read full article

By: M. Beridze, G. Chakhava, L. Shanidze, and E. Devidze

Methods: We investigated a 44 year-old male patient diagnosed with Multiple Sclerosis (MS), who in two years developed typical clinical signs of parkinsonism. Patient investigated neurologically, Brain contrast MRI (1.5 Tesla) was made two times after diagnostics with 1 year interval. Cerebrospinal Fluid (CSF) was researched for oligoclonal bands. CSF and blood were researched by ELISA method to detect IgM and IgG against Chlamydia pneumonie, Mycoplasma pneumonie, Borrelia burgdorferi, Herpes simplex 1/2, Cytomegalovirus. Results: Clinically patient expressed amiostatic face, oligobradikinesia, extrapyramidal spasticity in all limbs, resting tremor in upper limb fingers, horizontal nystagmus. Brain MRI showed multiple gadolinium enhanced demyelinization lesions in periventricular and subcortical white matter. CSF oligoclonal bands were positive without dysfunction of blood-brain barrier. Particularly, IgG C SF-Serum ratio was 4.6kA, Albumine CSF/Serum ratio -6.2kA, Tibbling CSF ratio-0.75 kA, Local IgG synthesis (Reiber)-1.3kA, Range Albumin CSF-Serum ratio-7.0kA. CSF and blood IgM, IgG were negative against Chlamydia pneumonie, Mycoplasma pneumonie, cytomegalovirus, Herpes simplex ½, while the blood IgG was strongly positive against Borrelia Burgdorferi, confirmed by following Western blot test. CSF conventional PCR (target ospA gene) showed positive result for Borrelia Burgdorferi. Patient was treated by puls-therapy with 1gr/intravenous Solumedrol (5 days) along with Rocephin treatment (2gr /iv) for 21 days followed by Antiparkin (Carbidopa 250mg, Levodopa 25mg). Conclusion: MS and even Parkinsonism should be differentiated from chronic neuroboreliosis.

Special Issue on Controversies in Neurology. From the 10th World Congress on Controversies in Neurology (CONy), Lisbon, Portugal. 17–20 March 2016.

International Journal of Clinical Neurosciences and Mental Health 2016; 3(Suppl. 1):P4

Icon_pdf Download PDF

Poster


Adiponectin and its fractions in newly diagnosed, treatment-naïve multiple sclerosis patients - read full article

By: Wojciech Bik, A. Baranowska- Bik, D. Uchman, J. Tomalka-Kochanowska, A. Litwiniuk, M. Kalisz, L. Martynska, B. Baranowska, and J. Kochanowski

Background: Multiple sclerosis (MS) is a chronic autoimmune, inflammatory disease of the central nervous system with exact etiology being still unclarified. MS results in neurodegeneration and demyelination. Adipose tissue is able to produce active molecules, adipokines. Adiponectin belongs to a group of anti-inflammatory adipokines. Plasma adiponectin circulates in three major forms: trimer (low molecular weight, LMW), hexamer (medium molecular weight, MMW), and high molecular weight (HMW) multimer, and additionally in proteolytically cleaved form, globular adiponectin. Different adiponectin fractions have been shown to exert distinct biological activity. Aim: We aimed to assess adiponectin and its fractions in newly diagnosed, treatment-naïve MS patients. Material and methods: The study group comprised of 32 patients (24 women/8 men) with the first time episode of MS (mean age 34.9±8.3yrs.; BMI 24.4±4.8 kg/m2). The controls included 40 individuals (34 females/6 men; mean age 32.3±8.1yrs.; BMI 24.3±4.6 kg/m2). Fasting plasma adiponectin and its fractions were evaluated with ELISA. Statistical analyses were performed. Results: Comparison between results of MS group and the controls revealed no significant differences in concentrations of all evaluated parameters. When data were adjusted to BMI we found that total adiponectin and HMW values were markedly lower in MS group (both p0.01), MMW adiponectin concentration was increased in MS subjects (p0.001) while LMW adiponectin levels remained comparable between the groups. Conclusions: Alterations of adiponectin levels, independent of BMI, in newly diagnosed MS patients may be related to autoimmune neurodegeneration and demyelination.

Special Issue on Controversies in Neurology. From the 10th World Congress on Controversies in Neurology (CONy), Lisbon, Portugal. 17–20 March 2016.

International Journal of Clinical Neurosciences and Mental Health 2016; 3(Suppl. 1):P5

Icon_pdf Download PDF

Poster


Biological-based complementary and alternative medicine use in multiple sclerosis patients - read full article

By: Merisanda Casar Rovazdi, V. Vidovic, S. Rendulic Slivar, and O. Kraml

Introduction and aim: People with multiple sclerosis (MS) often seek complementary and alternative medicine (CAM) to manage their disease. The aim of the study was to determine the frequency and modality of the biological-based CAM use among MS patients. Patients and methods: The study included 70 MS patients that underwent inpatient rehabilitation at the Lipik Hospital. A semi-structured questionnaire on the current usage of biological-based CAM was applied. Results: Fifty-two (74.3%) respondents reported that they were currently using biological-based CAM. Respondents most commonly used D vitamin (n=37; 52.9%), followed by vitamin B complex (n=26; 37.1%), magnesium (n=16; 22.9%), calcium (n=13; 18.6%), multivitamins/minerals (n=7; 10%), omega-3 fatty acids (n=7; 10%), hemp products (n=5; 7.1%), vitamin C (n=4; 5.7%), and Swank`s diet (n=4, 5.7%). Other types of biological-based CAM were taken by less than 5% of respondents. In the group of users there were a statistically significant higher proportion of patients with lower level of disability (p=0.047), relapsing-remitting disease course (p=0.011) and shorter duration of disease (p= 0.004) compared with the group of non-users. There were no statistically significant between-group differences according to sex (p=0.142) and age (p=0.110). Conclusion: Study results demonstrated frequent use of biological-based CAM among MS patients, despite the lack of evidence about the effectiveness of most of these therapies. There is a need for additional researches on the efficacy and safety of CAM therapies.

Special Issue on Controversies in Neurology. From the 10th World Congress on Controversies in Neurology (CONy), Lisbon, Portugal. 17–20 March 2016.

International Journal of Clinical Neurosciences and Mental Health 2016; 3(Suppl. 1):P6

Icon_pdf Download PDF

Poster


Efficacy of teriflunomide in achieving no evidence of disease activity from 6 months to 2 years in the TEMSO study - read full article

By: A. Chan, J. de Seze, P. Truffinet, K. Thangavelu, P. Rufi, and M. Comabella

Background: Attainment of no evidence of disease activity (NEDA) has been proposed as a therapeutic goal in MS. Treatment with teriflunomide 14mg increased the likelihood of patients achieving NEDA over a 2-year period in TEMSO (NCT00134563). Residual disease activity may occur while full therapeutic efficacy of teriflunomide becomes established. This post hoc analysis of TEMSO evaluated impact of teriflunomide on NEDA using 6 months from treatment initiation as baseline. Methods: Patients with relapsing forms of MS (N=1086) were randomized to receive teriflunomide 14mg, 7mg, or placebo for 108 weeks. We evaluated achievement of NEDA (no gadolinium-enhancing T1 lesions, no new/enlarging T2 lesions [MRI activity], no relapse, and no 12-week sustained disability progression [clinical disease activity; CDA]) and proportions free from CDA or MRI activity, from 6 months to 2 years. Results: From 6 months to 2 years, a significantly greater proportion of teriflunomide-treated patients (14mg, 28.1%, P0.0001; 7mg, 21.5%, P=0.0180) achieved NEDA vs placebo-treated patients (14.3%). The proportion CDA-free was significantly higher in the 14-mg group (61.3%, P=0.0022) vs placebo (49.2%). The proportion free of MRI activity was significantly higher with teriflunomide 14mg (45.1%, P0.0001) and 7mg (35.4%, P=0.0029) vs placebo (24.6%), with 14mg exhibiting superiority over 7mg (P=0.0141). Conclusions: Teriflunomide is associated with a significant dose-dependent increase vs placebo in proportion of patients achieving NEDA from 6 months to 2 years in the TEMSO study, providing further evidence for efficacy on key measures of CDA and MRI activity.

Special Issue on Controversies in Neurology. From the 10th World Congress on Controversies in Neurology (CONy), Lisbon, Portugal. 17–20 March 2016.

International Journal of Clinical Neurosciences and Mental Health 2016; 3(Suppl. 1):P7

Icon_pdf Download PDF

Poster


The relationship between the BICAMS battery, disease disability, duration and relapse rate in Lithuanian MS patients - read full article

By: Natasa Giedraitiene, R. Kizlaitiene, and G. Kaubrys

Background: Cognitive impairment (CI) occurs frequently in multiple sclerosis (MS). It can present in patients at any time regardless of the disease severity. Recently the Brief International Cognitive Assessment for Multiple Sclerosis (BICAMS) has been created as a brief, simple, and specific instrument for the evaluation of CI in MS patients. However, it is unknown whether the BICAMS battery has the relation with the disease disability, disease duration and relapse rate. Objectives: The purpose of the study was to assess the cognitive status of MS patients by the Lithuanian version of BICAMS and to evaluate the impact of CI on the disability, duration and relapse rate of the disease. Methods: 50 MS patients and 50 cognitively normal control subjects, matched on age, gender, and the level of education were enrolled. Cognitive functions have been assessed by the BICAMS tests. Results: MS patients performed significantly worse than controls on the three neuropsychological tests of BICAMS (p0.001). The younger and working intellectually persons performed on these tests significantly better than older persons, manual workers or unemployed persons (p0.05). MS patients with higher disability score, were tended to perform the tests worse (p0.05), but the relationships between the BICAMS tests and the duration of the disease or relapse rate were not found (p0.05). Test - retest reliability was excellent for all the three subtests (r0.8, p0.05). Conclusions: Better performance of the BICAMS tests was associated with lower severity of the disability, however the relations between BICAMS tests, disease duration and relapse rate weren’t found.

Special Issue on Controversies in Neurology. From the 10th World Congress on Controversies in Neurology (CONy), Lisbon, Portugal. 17–20 March 2016.

International Journal of Clinical Neurosciences and Mental Health 2016; 3(Suppl. 1):P8

Icon_pdf Download PDF

Poster


Alemtuzumab demonstrates persistent clinical efficacy outcomes over 5 years in patients with active relapsing-remitting multiple sclerosis, with most not receiving retreatment: CARE-MS I and II extension studies - read full article

By: Eva Havrdova, Douglas L. Arnold, D. Alastair S. Compston, Hans-Peter Hartung, Krzysztof W. Selmaj, Linda Kasten, and David H. Margolin on behalf of the CARE-MS I and CARE-MS II Investigators

Background: Patients with active relapsing-remitting multiple sclerosis (RRMS) who were treatment-naive (CARE-MS I; NCT00530348) or with inadequate response (?1 relapse) to prior therapy (CARE-MS II; NCT00548405) had improved outcomes with alemtuzumab versus SC IFNB-1a over 2 years. Objective: To examine alemtuzumab’s efficacy and safety over 5 years in CARE-MS patients. Methods: Patients received 2 courses of alemtuzumab 12 mg (Months 0 and 12), with as-needed retreatment for disease activity, or another disease-modifying therapy (DMT). Annualised relapse rate (ARR), 6-month confirmed disability progression (?1-point Expanded Disability Status Scale [EDSS] increase [?1.5-point if baseline EDSS=0]), and 6-month sustained reduction in pre-existing disability (SRD; ?1-point EDSS decrease [baseline ?2.0]) were assessed. Results: 349 (95%) and 393 (93%) CARE-MS I and II patients entered extension (NCT00930553), respectively; 68% and 60% received no alemtuzumab since initial 2 courses; 98% and 92% received no other DMT. ARRs remained low from Year 3 (0.19 and 0.22) to Year 5 (0. 15 and 0.18). Through Years 0–5, 80% and 75% were free from 6-month confirmed disability progression, and 33% and 43% achieved 6-month SRD. Infusion-associated reactions and infections were reduced versus core studies, and serious adverse events (AE) were low. Thyroid AEs peaked at Year 3, then declined. Conclusions: Alemtuzumab improved relapse and disability outcomes over 5 years despite most patients not receiving retreatment. Based on these findings, for the majority of RRMS patients, alemtuzumab may provide an innovative treatment approach with efficacy persisting through 5 years in the absence of continued treatment and associated treatment burden.

Special Issue on Controversies in Neurology. From the 10th World Congress on Controversies in Neurology (CONy), Lisbon, Portugal. 17–20 March 2016.

International Journal of Clinical Neurosciences and Mental Health 2016; 3(Suppl. 1):P9

Icon_pdf Download PDF

Poster


Multiple sclerosis and involuntary movements - read full article

By: Gabriela Mihailescu, C. Baetu, S.M. Nica, A.M. Vladila, D.A. Mitrea, G. Socoliuc, A.D. Boangiu, and I. Buraga

Introduction: Movement disorders were considered uncommon in multiple sclerosis (MS), but tremor (action, postural) can be a highly disabling symptom (transient or persistent), as well as other involuntary movements. Methods: We studied 130 patients (80 male and 50 female) with multiple sclerosis. 115 with relapsing remitting (RR-MS), 5 secondary progressive (SPMS) and 10 clinical isolated syndrome (CIS) treated and monitorised in the Neurology Department of the Colentina Clinical Hospital. 76% aged 19-39 years, 84% having EDSS score 1- 4, 16% EDSS 4.5 - 6.5. 25 patients were treated with Interferon beta-1a intramuscularly, 27 with Interferon beta-1 a subcutaneously, 18 with Interferon beta-1b, 51 with glatiramer acetate and 9 with natalizumab. We performed a clinical examination, including finger to nose testing, drinking from a cup, 9 Hole–Peg test, writing/drawing, a questionnaire regarding concomitant treatments, comorbidities and movement disorders, Brain tremor severity scale and FAMS (Functional assessment of MS scale) Results: The prevalence of tremor in our group was 31,53 %, especially for action tremor of the upper limbs. 2,3 % seemed to be linked to the specific immunomodulatory treatment. Other involuntary movements present were: Restless leg syndrome 3,84%, facial hemispasm 2,3%, ballism 0,76%, tics 3.07%, myoclonus 3, 84%. Conclusions: Movement disorders are not very rare in MS patients. The pathophysiology is various and so the treatments. Comorbidities and concomitant therapies precipitated involuntary movements, which were more frequent in women, 30-39 years of age, transient or permanent and correlated to the EDSS score. They disabling, causing psychological, social and economic problems.

Special Issue on Controversies in Neurology. From the 10th World Congress on Controversies in Neurology (CONy), Lisbon, Portugal. 17–20 March 2016.

International Journal of Clinical Neurosciences and Mental Health 2016; 3(Suppl. 1):P10

Icon_pdf Download PDF

Poster


Teriflunomide slows down brain volume loss in relapsing MS: a SIENA analysis of the TEMSO MRI dataset - read full article

By: E. W. Radue, T. Sprenger, L. Gaetano, N. Mueller-Lenke, J. Wuerfel, K. Thangavelu, and S. Cavalier

Background/Objectives: Two phase 3 studies, TEMSO (NCT00134563) and TOWER (NCT00751881), showed significant effects of teriflunomide on slowing disability progression in patients with relapsing MS (RMS). In TEMSO, teriflunomide significantly reduced lesional MRI disease markers, but no significant attenuation of brain volume loss (BVL) (measured by brain parenchymal fraction) was observed. Given associations of BVL and long-term disability, blinded independent analysis of the TEMSO MRI dataset was warranted using a validated alternative methodology, SIENA (structural image evaluation using normalization of atrophy), to assess effects of teriflunomide on BVL. Methods: Median annualized percentage change in brain volume from baseline was calculated (SIENA). Treatment groups were compared by rank ANCOVA, adjusted for region, age, Expanded Disability Status Scale strata, and normalized brain volume (SIENAX) at baseline. Results: 969 patients were included. Median percentage reduction from baseline in brain volume at Months 12 and 24 for placebo was 0.61 and 1.29. For teriflunomide 14mg and 7mg these reductions were 0.39 and 0.90, and 0.40 and 0.94. BVL was lower for both teriflunomide groups vs placebo at Months 12 and 24: 14mg (36.9%, P=0.0001); 7mg (34.4%, P=0.0011); and 30.6% (P=0.0001) for 14mg; 27.6% (P=0.0019) for 7mg. Conclusions: Teriflunomide was associated with significant reductions in BVL vs placebo over 2 years. These findings, using SIENA, an established measure of brain tissue loss, are consistent with effects of teriflunomide on delaying disability progression observed across studies in patients with RMS.

Special Issue on Controversies in Neurology. From the 10th World Congress on Controversies in Neurology (CONy), Lisbon, Portugal. 17–20 March 2016.

International Journal of Clinical Neurosciences and Mental Health 2016; 3(Suppl. 1):P11

Icon_pdf Download PDF

Poster


The prevalence of cognitive impairment among Hungarian patients with relapsing-remitting multiple sclerosis and clinically isolated syndrome - read full article

By: Daniel Sandi, T. Biernacki, D. Szekeres, J. Fuvesi, Zs. T. Kincses, Cs. Rózsa, K. Mátyás, K. Kása, J. Matolcsi, D. Zboznovits, A. Pyreschitz, É. Langane, L. Vécsei, and K. Bencsik

Introduction: Cognitive impairment (CIm) is a frequent symptom of multiple sclerosis (MS); its prevalence is reported to be 43-70%. The cognitive decline is not global: information processing speed, visual and verbal memory are the most frequently affected domains. We aimed to determine the prevalence of CIm among the relapsing-remitting MS (RRMS) and clinically isolated syndrome (CIS) patients in Hungary and to assess the differences between genders and patients with different educational levels. Patients and methods: Five-hundred and fifty-four CIS and RRMS patients were enrolled to our study, 405 was treated at the Department of Neurology of the University of Szeged; 111 at the Jahn Ferenc Dél-Pest Hospital in Budapest and 38 at the Markhot Ferenc Hospital in Eger. We used the BICAMS battery to assess their cognitive state. For statistical analysis we used Chi square and Fisher exact tests. Results: Three-hundred and eighteen (57.2%) patients had CIm. CIm was significantly (p=0.001) more frequent among men (70.1%) than women (51.6%). While among men, there was no difference between patients with different educational levels, the prevalence of CIm among women with higher education was significantly (p=0.001) less common (42.5%) than women with lower education (62.5%). Discussion: Our prevalence data is similar to those reported in the literature (43-70%). We found that men are more vulnerable to CIm than women in MS, as was reported by a recent study. We are the first to report, that the higher cognitive reserve is only a protective factor among female patients.

Special Issue on Controversies in Neurology. From the 10th World Congress on Controversies in Neurology (CONy), Lisbon, Portugal. 17–20 March 2016.

International Journal of Clinical Neurosciences and Mental Health 2016; 3(Suppl. 1):P12

Icon_pdf Download PDF

Poster


Alemtuzumab-treated patients with active relapsing-remitting multiple sclerosis demonstrated slowing of brain volume loss over 5 years, with most patients not receiving retreatment for 4 years - read full article

By: Krzysztof W. Selmaj, D. Alastair S. Compston, Massimo Filippi, Gavin Giovannoni, Hans-Peter Hartung, Eva Havrdova, Sven Schippling, David H. Margolin, Karthinathan Thangavelu, and Douglas L. Arnold on behalf of the CARE-MS I and CARE-MS II Investigators

Background: Patients with active relapsing-remitting multiple sclerosis (RRMS) who were treatment-naive (CARE-MS I; NCT00530348) or who had inadequate response (?1 relapse) to prior therapy at baseline (CARE-MS II; NCT00548405) demonstrated significant slowing of brain volume (BV) loss over 2 years with alemtuzumab versus SC IFNB-1a. Slowing persisted through 4 years, despite most patients not receiving retreatment. Objective: To examine alemtuzumab’s effect on BV over 5 years in patients in the CARE-MS extension (NCT00930553). Methods: Patients were randomised to 2 annual alemtuzumab courses (Months 0 and 12), with as-needed retreatment for relapse and/or magnetic resonance imaging disease activity, or another disease-modifying therapy (DMT). BV loss was measured annually by brain parenchymal fraction change. Results: 349 (95%) CARE-MS I and 393 (93%) CARE-MS II alemtuzumab patients entered the extension; 68% in CARE-MS I and 60% in CARE-MS II received no alemtuzumab treatment since Month 12, and 98% and 92% received no other DMT. Over 4 years, median annual rate of BV loss was reduced and remained low in CARE-MS I (Years 1–5: –0.59%, –0.25%, –0.19%, –0.15%, and –0.20%, respectively) and CARE-MS II (Years 1–5: –0.48%, –0.22%, – 0.10%, –0.19%, and –0.07%). Conclusions: Slowing of BV loss with alemtuzumab was maintained over 5 years in patients with RRMS, despite most not receiving additional treatment beyond 12 months. Based on these findings, for the majority of RRMS patients, alemtuzumab may provide an innovative treatment approach with efficacy persisting through 5 years in the absence of continued treatment and associated treatment burden.

Special Issue on Controversies in Neurology. From the 10th World Congress on Controversies in Neurology (CONy), Lisbon, Portugal. 17–20 March 2016.

International Journal of Clinical Neurosciences and Mental Health 2016; 3(Suppl. 1):P13

Icon_pdf Download PDF

Poster


Major depression in patients with multiple sclerosis - read full article

By: Viktor Vidovic, M. Casar Rovazdi, O. Kraml, and S. Rendulic Slivar

Introduction and aim: Depression is frequently underdiagnosed and undertreated in patients with multiple sclerosis (MS). The aim of the study was to determine the prevalence of major depression in MS patients and analyze the frequency of antidepressants intake among patients with major depression. Methods: The study was conducted on 73 MS patients that underwent inpatient rehabilitation at the Lipik Hospital. The diagnosis was made by use of the Patient Health Questionnaire-nine (PHQ-9) screening test, where a sum of ?10 denoted positive finding. Study patients were divided into two groups, according to the presence or absence of major depression. Results: Sixteen respondents (21.9%) met the criteria for the diagnosis of major depression. Of these 16 patients, 7 (43.8%) were taking antidepressants. We found that 12 (75%) of respondents with positive PHQ-9 criteria did not inform neurologist on the presence of mood disorder. There were no statistically significant between-group differences according to age (p=0.814), sex (p=0.167), EDDS score (p=0.710), disease duration (p=0.213) and disease course (p=0.876). Conclusion: Based on screening test results, substantial proportion of MS patients suffer from major depression. The fact that a significant proportion of patients did not inform neurologist on their mood disturbance, and low frequency of antidepressants intake among MS patients with depression, call for an active approach to diagnosis and treatment of depression.

Special Issue on Controversies in Neurology. From the 10th World Congress on Controversies in Neurology (CONy), Lisbon, Portugal. 17–20 March 2016.

International Journal of Clinical Neurosciences and Mental Health 2016; 3(Suppl. 1):P14

Icon_pdf Download PDF

Poster


Acute demyelination in childhood associated with TNF alpha-inhibitor therapy - read full article

By: Sara Vila-Bedmar, E. Waubant, and J. Graves

Introduction: Tumor necrosis factor-alpha inhibitors (TNFi) have revolutionized the treatment of rheumatological autoimmune disorders. We report a rare, although serious concern with TNFi usage, demyelination of the central nervous system. Material and methods: Case report. Results: A 15-year old woman with history of polyarticular juvenile idiopathic arthritis stable on methotrexate and infliximab developed blurred vision and retro-orbital pain in her right eye. She had no preceding illness or fever and her arthritis was well controlled. Her examination confirmed right optic neuritis with severely impaired visual acuity (20/200), dyschromatopsia and right afferent pupillary defect. Blood test results were within normal range, extensive infectious work-up and aquaporin-4 antibody were negative. A brain MRI performed one week after the onset of symptoms revealed asymmetric T2-hyperintensity and enlargement of the right prechiasmatic optic nerve, compatible with optic neuritis without abnormal enhancement, and the brain parenchyma appeared unremarkable. She declined to have a lumbar puncture, which had been proposed for routine studies, IgG index and oligoclonal bands. She was treated with pulse high-dose steroids and experienced rapid improvement. Infliximab was discontinued and methotrexate was increased to 25 mg weekly. After 3 years of follow-up her central acuity is 20/20 in the right eye. She has had no clinical or MRI evidence of additional demyelinating lesions. Conclusions: TNFi medications can be associated with demyelination in the central and peripheral nervous system even in childhood. Close follow-up of these patients is mandatory to determine whether they have a monophasic or recurrent CNS disorder.

Special Issue on Controversies in Neurology. From the 10th World Congress on Controversies in Neurology (CONy), Lisbon, Portugal. 17–20 March 2016.

International Journal of Clinical Neurosciences and Mental Health 2016; 3(Suppl. 1):P15

Icon_pdf Download PDF

Poster


ABCD2 score: help or hindrance? - read full article

By: Nuno Ribeiro and N. Beaman

Introduction: ABCD2 score is the tool used in the initial assessment of patients presenting with transient neurological symptoms of vascular origin, to determine their probability of going on to develop a stroke. It is used primarily by General Practitioners and Emergency Department staff to refer into specialist TIA clinics. Scores greater than or equal to 4 should be assessed in 24 hours, those with scores less than 4 in 7 days. Method: We reviewed the ABCD2 score for patients seen in the TIA clinic between July and November 2015. The total number of patients reviewed was 153. Patients were divided into two groups; high risk with ABCD2 score ? 4 (61) and low risk 4 (92). The diagnoses were recorded for all patients. Aids used to come to diagnosis included CT brain, MRI brain and Carotid Doppler ultrasound. Results: Of the 153 patients referred, 50 were clinically diagnosed as "definite TIA", 15 as "probable TIA" and 19 as "possible TIA" (54.9%). The remaining 69 were diagnosed with conditions unrelated to transient ischaemia. Of those with a TIA diagnosis, 44 had an ABCD2 score ? 4 and 40 an ABCD2 score 4. Conclusion: Diagnosing TIA is a complex and demanding task. ABCD2 score can be a useful aid to categorise urgency of referral. However, it is apparent when used incorrectly, it leads to inappropriate referral to TIA clinics. In our case 69 referrals based on ABCD2 score were not related to TIAs.

Special Issue on Controversies in Neurology. From the 10th World Congress on Controversies in Neurology (CONy), Lisbon, Portugal. 17–20 March 2016.

International Journal of Clinical Neurosciences and Mental Health 2016; 3(Suppl. 1):P16

Icon_pdf Download PDF

Poster


Unilateral intracranial arteriopathy in young adults: an etiologic and therapeutic challenge - read full article

By: F. Bernardo and P. Pita Lobo

Introduction: Arterial ischemic stroke (AIS) in young adults is uncommon. Intracranial stenosis is a possible cause of AIS and has several etiologies such as non-atherosclerotic vasculopathies and premature atherosclerosis. There is little evidence regarding AIS treatment in young adults, particularly concerning arteriopathies. Case Presentation: A 39-year-old woman, with past history of idiopathic cerebral palsy and auriculoventricular block, was admitted after onset of right facial palsy and right upper limb motor and sensory deficits associated with neck pain. Head CT scan suggested a left MCA deep infarct. Additional testing revealed left carotid siphon critical stenosis on conventional angiography without specific etiologic features. The patient was discharged with aspirin 250mg/daily. She maintained clinical fluctuation during outpatient period. SPECT scan revealed left hemisphere hypoperfusion that improved after adenosine administration. Seven months later the patient maintains clinical fluctuation with mild improvement, despite having significant better cortical perfusion on the re-evaluation SPECT scan, without additional therapy. Are we facing a pre-existing blood vessel abnormality associated with a de novo static vasculopathy (dissection) or is it a progressive arteriopathy (atherosclerotic, Moyamoya disease)? Conclusion: What should be done towards critical intracranial stenosis without an established etiology, cerebral hypoperfusion and clinical fluctuation? We must repeat intracranial vascular imaging in order to differentiate nonprogressive from progressive arteriopathies and try to establish a definitive cause. Since the later have a higher risk of stroke recurrence should we optimize medical treatment by improving hypoperfusion or avoiding stenosis progression? Could endovascular treatment and surgery play a role in selected cases?

Special Issue on Controversies in Neurology. From the 10th World Congress on Controversies in Neurology (CONy), Lisbon, Portugal. 17–20 March 2016.

International Journal of Clinical Neurosciences and Mental Health 2016; 3(Suppl. 1):P17

Icon_pdf Download PDF

Poster


Pseudoathetosis associated with loss of proprioception after acute ischemic stroke - read full article

By: Kyung-Hee Cho and Young-Min Park

Background & Significance: A profound loss of proprioception leads to the pseudoathetosis resulting from the failure of proper integration of cortical sensory function. However, pseudoathetosis has rarely reported in patients with acute ischaemic stroke. We describe a patient who exhibited abrupt loss of proprioception and combined pseudoathetosis following acute cerebral infarct that involved in the postcentral gyrus. Case: A 72-year-old female was brought to the emergency department 1 hour after she suddenly had the tingling sense and involuntary movements of the left arm. She had atrial fibrillation with dual anti-platelet medications. Neurological examination shows the loss of position sense and limb-kinetic movement in the distal part of the left arm. The most remarkable sign was a dystonic posturing and pseudoathetosis of the left arm and leg, which was only reveal when the patient outstretched her extremities with the eyes closed. Diffusion-weighted MRI showed acute infarcted lesion involving right parietal cortex. There was total occlusion of the right proximal internal carotid artery and inferior branch of the right middle cerebral artery in MR angiography. Nerve conduction studies were normal. Conclusions or Comments: The proprioceptive sensory loss without overt damage to the motor system can lead to pseudoathetosis, which rarely occurs following acute ischaemic stroke on the parietal cortex lesion. Postulated that the loss of proprioception causes alterations in the cortical sensory inputs to the striatum and, finally, variable mixtures of involuntary movements. However, why only a small proportion of patients with proprioceptive sensory loss develop involuntary movements is unknown.

Special Issue on Controversies in Neurology. From the 10th World Congress on Controversies in Neurology (CONy), Lisbon, Portugal. 17–20 March 2016.

International Journal of Clinical Neurosciences and Mental Health 2016; 3(Suppl. 1):P18

Icon_pdf Download PDF

Poster


Neurosonology in central retinal artery occlusion—does spot sign have a prognostic value? - read full article

By: I. Correia, A.I. Martins, C. Durque, J.J. Ribeiro, J. Sargento-Freitas, G. Santo, F. Silva, and L. Cunha

Introduction: Central Retinal Artery Occlusion (CRAO), the occlusion of the central retinal artery (CRA), result in retina infarction and vision loss, generally related to cardiac or arterio-arterial embolization. Neurosonology studies are important for etiologic and diagnostic work-up. Recently, a hyperechoic signal was reported within the distal portion of the CRA – “spot sign”. Some authors consider it to be an important predictive prognostic marker for persistent loss of vision since it may indicate calcified or cholesterol emboli and explain the low therapeutic success rate to thrombolysis. Clinical Case: We report a 68-year-old female patient, with known arterial hypertension and diabetes mellitus type 2, who complained of acute, persistent, painless loss of vision in her right eye, except for the superior temporal visual field where figures could be noted. Ophthalmologic examination of right retina revealed a “cherry-red spot”. Carotid and intracranial color-coded sonography showed heterogeneous carotid plaques with irregular surface without hemodynamic significance. Ocular color-coded sonography identified sub-occlusive flow in ipsilateral CRA and “spot sign”. Thoracic angio-CT showed irregular and calcified atheromatous plaques in the ascending aorta and beginning of braquicephalic trunk. She was started on secondary vascular prevention. In clinical follow-up evaluation, two months later, no new vascular episode or visual improvement was seen. Conclusions: In this report we present a CRAO case, in which neurosonology evaluation identified a ‘‘spot sign’’ in the CRA. We hypothesise that this finding may have prognostic value and therefore, neurosonology studies should be used in CRAO evaluation.

Special Issue on Controversies in Neurology. From the 10th World Congress on Controversies in Neurology (CONy), Lisbon, Portugal. 17–20 March 2016.

International Journal of Clinical Neurosciences and Mental Health 2016; 3(Suppl. 1):P19

Icon_pdf Download PDF

Poster


Mild stroke with a proximal occlusion—too good to treat? - read full article

By: Francisca Costa, R. Reis, F. Gomes, L. Fonseca, T. Parreira, M. Silva, and E. Azevedo

Introduction: Mechanical thrombectomy is a recognized effective treatment of acute intracranial proximal occlusions. However, as NIHSS cut-off is a debatable issue, when should we consider an acute stroke severe enough to treat? Our aim is to discuss this issue with an illustrative case. Clinical Case: 58 year-old female, previous mRankin 0, smoker with an history of ductal breast carcinoma submitted to chemotherapy, is admitted mid-afternoon due to a inferior facial paralysis and dysartria noticed at wake-up (NIHSS 2). Brain CT revealed a spontaneous hyperdensity of proximal left M1 segment and a small caudate-capsular-lenticular acute ischemic infarct. Duplex ultrasound revealed a distal ICA occlusion. Echocardiography showed severe depression of left ventricular ejection fraction (20%). Considering the evolution time window and the mild neurologic deficits, a decision to withhold endovascular treatment was made and the patient was admitted to our stroke unit. On the third day, there was neurologic deterioration (NIHSS 14). At this time, brain CT maintained the described infarct area but had a large perfusion deficit in MCA territory, compatible with a significant perfusion mismatch. Angio-CT confirmed ICA distal occlusion. After multidisciplinary discussion, mechanical thrombectomy was performed, 53 hours after symptom onset, successfully (TICI 3). The patient was discharged with anticoagulation (heart failure), with NIHSS 2. Discussion: The decision to intervene in acute stroke events is not taken lightly, as the dynamic nature of these events is not always predictable. Hence, a multidisciplinary and individual approach of these patients might be warranted.

Special Issue on Controversies in Neurology. From the 10th World Congress on Controversies in Neurology (CONy), Lisbon, Portugal. 17–20 March 2016.

International Journal of Clinical Neurosciences and Mental Health 2016; 3(Suppl. 1):P20

Icon_pdf Download PDF

Poster


The outcome in patients with acute ischemic stroke associated with nonvalvular atrial fibrillation—previously on oat or without - read full article

By: Radmila Amanovic Curuvija, Dragana Kosevic, Irena Grkic, Sanja Atic, and Vesna Miletic

Background: Management of non-valvular atrial fibrillation (NVAF) focuses on the use of anticoagulation to decrease the risk of acute ischemic stroke (AIS). Until recently, vitamin K antagonist (VKA) treatment was considered the standard of care, with the emergence of non-VKA oral anticoagulants (NOACs) shifting treatment practice. The question is: what is happening in everyday practice? Methods: To assess the impact of the oral anticoagulant therapy (OAT) to stroke prevention in NVAF,we identified prospectively for six month period in 2015 year, all patients with NVAF and AIS who was previously on OAT or without. The previous clinical studies included in the systematic review of AIS risk factors identified history of AIS, increasing age, hypertension and structural heart disease to be good predictors of AIS risk in NVAF patients. Results: In our data, 199 patients was referred to our Institution due to AIS associated with NVAF, and among them were 115(57,7%) female and 84 (42,3%) male. Mean age was 77,2 years (44-102 years). Among them 49 (24,6%) patients was previously on OAT. In the group of patients who was on OAT, died 14 (7.03%) patients, and in other group-without OAT, died 36 (18.09%) patients. In group with OAT 18 patients had previously AIS. Conclusion: In everyday practice OAT prescription for NVAF in prevention of AIS is extremely low and cannot be scientifically explained in light of well known guidliness. In our data, we proved benefit with OAT in prevention AIS in patients with NVAF.

Special Issue on Controversies in Neurology. From the 10th World Congress on Controversies in Neurology (CONy), Lisbon, Portugal. 17–20 March 2016.

International Journal of Clinical Neurosciences and Mental Health 2016; 3(Suppl. 1):P21

Icon_pdf Download PDF

Poster


Bilateral cerebral hemorrhages: not always portentous - read full article

By: B. Das, D. Khurana, S. Mehta, V.Y. Vishnu, S.R. Bhatkar, V. Lal, and N. Khandelwal

Background: Bilateral intracerebral hemorrhages (BICH) are unusual and limited to case reports. Their presence has long been considered to be associated with worse prognosis. However with availability of newer management strategies for ICH, they may not portend a bad outcome. Observation and results: We looked for cerebral double hemorrhage (CDH) in all acute hemorrhagic stroke patients presented in the emergency department of our tertiary care centre, from January 2013 to June 2015. Six patients of cerebral double hemorrhage (CDH), associated with hypertension were noted. Four patients were over 50 years of age while two were young strokes (43 and 17 years of age) and one was female. Three patients had bilateral basal-ganglia bleed (BBB), one had bilateral thalamic bleed (BTB) while two had dual pathology. All but one was known hypertensive with poor drug compliance. Patients were managed with intensive blood pressure control. All but one patient had significant improvement in sensorium at discharge. Average hospital stay was one week. Conclusion: CDH in contrast to previous belief, may be associated with better outcomes if managed as per current ICH treatment guidelines.

Special Issue on Controversies in Neurology. From the 10th World Congress on Controversies in Neurology (CONy), Lisbon, Portugal. 17–20 March 2016.

International Journal of Clinical Neurosciences and Mental Health 2016; 3(Suppl. 1):P22

Icon_pdf Download PDF

Poster


Nonaneurysmal sulcal subarachnoid haemorrhage in a patient with atherosclerotic intracranial stenosis - read full article

By: A. Gouveia, A. Martins, J. Sargento-Freitas, L. Almendra, F. Silva, B. Rodrigues, C. Machado, G. Cordeiro, and L. Cunha

Background: Nonaneurysmal sulcal subarachnoid haemorrhage (sSAH) is a rare cause of cerebrovascular disease and represents a small proportion of nontraumatic SAH. A few cases of sSAH in patients with extracranial atherosclerotic disease have been reported. However, the association of sSAH with intracranial atherosclerotic stenosis is exceptional. Clinical case: A 54-year-old male patient, with active smoking, hypertension and dyslipidaemia, presents with abrupt severe headache, followed two days later by right visual field defect and fluctuating dysphasia. The initial head CT revealed left peri-rolandic sSHA and, at the fourth day, two new hypodense lesions (left cortical parieto-occipital and left subcortical parietal). Repeated transcranial color coded Doppler (TCCD) evaluations, performed in the first 10 days, found a persistent focal acceleration in distal M1 segment of middle cerebral artery (MCA) with downstream flow attenuation. The digital subtraction cerebral angiography excluded the presence of aneuryms and arteriovenous malformations and showed a severe focal stenosis in distal M1 segment of MCA, with a typical atherosclerotic morphology. Six months later, the patient remains with right inferior homonynous quadrantanopia. In TCCD evaluation there is still evidence of severe MCA stenosis and there has been complete SAH reabsortion in the CT. Conclusion: We report a patient with spontaneous sSAH and ipsilateral severe MCA atherosclerotic stenosis. We propose a causal relationship between them, and discuss its pathophysiological mechanisms.

Special Issue on Controversies in Neurology. From the 10th World Congress on Controversies in Neurology (CONy), Lisbon, Portugal. 17–20 March 2016.

International Journal of Clinical Neurosciences and Mental Health 2016; 3(Suppl. 1):P23

Icon_pdf Download PDF

Poster


Predictors of ischemic infarction in patients with isolated vertigo - read full article

By: Byung Kun Kim

Background and Objectives: Although isolated vertigo is common problems in emergency room (ER), the initial distinction between central and peripheral vertigo in isolated vertigo is not easy. This study aims to evaluate the predictors of ischemic infarction in patients with isolated vertigo. Materials and Methods: The definition of isolated vertigo is vertigo without focal neurologic deficit except nystagmus and postural instability with unknown etiology. Diffusion weighted images were obtained 171 isolated vertigo patients. Results: Among 170 patients, 25 patients had acute lesions on DWI. Twelve out of 25 patients with stroke were impossible of standing without assistance including 5 patients of lateropulsion. Ocular lateropulsion in 2 patients with stroke and gaze evoked nystagmus in two were observed. Central vertigo mimicking peripheral vertigo were 13 out of 25 patients and 4 of them had a catch-up saccade on head thrust test. Nine central vertigo patients had a spontaneous unidirectional horizontal nystagmus. Seventy-six out of 145 patients without stroke had a spontaneous horizontal nystagmus and 53 patients had a catch-up saccade. Three peripheral vertigo patients had GEN and 26 patients were impossible of standing including 5 lateropulsion. Lateropulsion (p=0.014), head thrust test (p=0.039) and inability to stand (p=0.005) were significantly related with differentiation between central and peripheral vertigo. Conclusions: Although lateropulsion, inability to stand and head thrust test is important differential points between central and peripheral vertigo, differential diagnosis of isolated vertigo at emergency room is not always easy.

Special Issue on Controversies in Neurology. From the 10th World Congress on Controversies in Neurology (CONy), Lisbon, Portugal. 17–20 March 2016.

International Journal of Clinical Neurosciences and Mental Health 2016; 3(Suppl. 1):P24

Icon_pdf Download PDF

Poster


Carotid stenosis secondary to head and neck radiation therapy: a case report - read full article

By: Ermal Kurmaku, Erion Dushi, and Jera Kruja

Background: Carotid stenosis secondary to head and neck radiation therapy is becoming increasingly recognized as a cause of stroke in cancer survivors. Although knowledge of its pathology, natural history, and medical, endovascular and surgical therapy has grown proper guidelines are lacking. Case description: We describe a case of a 63 year old man who underwent regular follow up after receiving radiotherapy for a parotid gland cancer. He was never checked for a possible carotid disease until he developed fluctuating neurological signs. At this time the disease became rampant and led to a severe watershed stroke despite medical therapy. Conclusion: It is an emergency for the oncological and stroke societies to bring in new guidelines for the vascular screening of head and neck cancer patients treated with radiotherapy.

Special Issue on Controversies in Neurology. From the 10th World Congress on Controversies in Neurology (CONy), Lisbon, Portugal. 17–20 March 2016.

International Journal of Clinical Neurosciences and Mental Health 2016; 3(Suppl. 1):P25

Icon_pdf Download PDF

Poster


The role of non-invasive treatment in dural arteriovenous fistulas - read full article

By: Célia Machado, J. Araújo, J. Alves, J. Rocha, J. Pinho, and C. Ferreira

Background: Dural arteriovenous fistulas (DAVF) of the cavernous sinus are acquired arteriovenous shunts between dural branches of the internal and/or external carotid arteries and the cavernous sinus. Case Report: An 82 year-old woman was admitted for left eye pain, eyelid edema and conjunctival hemorrhage which developed during the previous 15 days. She presented left periorbital ecchymosis, nonpulsatile exophthalmos, chemosis, conjunctival injection and left external ophthalmoplegia. Ophthalmological evaluation revealed elevated left intraocular pressure (32 mmHg) and normal visual acuity. Cerebral angiography confirmed a DAVF of the left cavernous sinus (Borden classification type I; Barrow classification type D) with no evidence of cortical venous drainage. Non-invasive treatment with left carotid and left eye compression and acetazolamide was decided. Transient clinical improvement of local signs after compression periods, slight improvement of eye movements and reduction of intraocular pressure (24mmHg) occurred. On day 5 of treatment, she developed a mild and transient right motor deficit and compression maneuvers were stopped. Neuroimaging revealed no new lesions. Elevation of intraocular pressure persisted and endovascular treatment was proposed. Discussion: Manual external carotid-jugular compression is an accepted treatment for DAVF of the cavernous sinus except in cases with cortical venous drainage and progressive visual decline. A 30% cure rate with this technique has been reported, with a mean time to closure of 41-123 days. Predictors of compression treatment success include short symptom onset-treatment interval and venous drainage without involvement of the inferior petrosal sinus. We discuss benefits and risks of non-invasive treatment and timing for endovascular approach.

Special Issue on Controversies in Neurology. From the 10th World Congress on Controversies in Neurology (CONy), Lisbon, Portugal. 17–20 March 2016.

International Journal of Clinical Neurosciences and Mental Health 2016; 3(Suppl. 1):P26

Icon_pdf Download PDF

Poster


Neurosonology: a potential diagnostic tool in central retinal vein occlusion - read full article

By: Ana Martins, J. Sargento-Freitas, F. Silva, J. Beato-Coelho, G. Cordeiro, C. Farinha, J. Figueira, and L. Cunha

Introduction: Central retinal vein occlusion (CRVO) is a common vascular retinal pathology. It produces a subacute monocular severe visual loss, usually painless. Retinal and iris neovascularization can result in vitreous hemorrhages, neovascular glaucoma and tractional retinal detachment. The diagnosis is clinical-based, through fundoscopic exam, and supported by fluorescein angiography, an invasive technic requiring intravenous contrast administration. The diagnosis becomes harder in the presence of local complications preventing ocular fundus observation, as hemovitreous, sometimes requiring clarifying surgical intervention. Neurossonology, a non-invasive and safe technic, has not yet been pointed out as a definite diagnostic tool in CRVO. Clinical Case: Female, 82 years old, with known and poorly controlled essential hypertension and type 2 diabetes mellitus, developed a subacute visual acuity impairment in her left eye, allowing solely hand movements visualization. Ophthalmoscopy reveled a total hemovitreous of the left eye. Ocular echography did not show any other lesions. Differential diagnosis stood between CRVO and ocular arterial ischemic syndrome. Transorbital colour coded Doppler identified a preserved left ophthalmic artery and a reverberant flow in the central retinal vein, suggesting CRVO. The patient underwent pars plana vitrectomy associated to endolaser as management of this secondary complication of CVRO. Conclusions: The present clinical case underlines a potential new neurossonologic application, as a diagnostic tool in CVRO, particularly useful when ocular fundus cannot be properly visualized.

Special Issue on Controversies in Neurology. From the 10th World Congress on Controversies in Neurology (CONy), Lisbon, Portugal. 17–20 March 2016.

International Journal of Clinical Neurosciences and Mental Health 2016; 3(Suppl. 1):P27

Icon_pdf Download PDF

Poster


Carotid ultrasound and intraluminal mobile echoes: differential diagnosis - read full article

By: Irene Mendes, Vanda Pos-de-Mina, and Mateus Sónia

Introduction: Mobile intraluminal non-artifactual echoes in the carotid artery are rare findings. The differentiation between flapping atheromatous plaque, flapping thrombus, free-floatand even a combination of these with ultrasound is potentially difficult, in part due to the lack of precise description in the literature. It`s potential embolic risk makes the diagnosis an important and urgent issue. Methods: Retrospective and descriptive study including all patients referred to our Lab (LUSCAN) to perform carotid ultrasound, since 2007 to 2015. From the 7500 exams performed we selected the reports with mobile intraluminal non-artifactual echoes in the carotid artery and reviewed image`s characteristics. Results: We found five cases – two arterial wall adherent thrombus; a `flap` associated with plaque rupture; and two thrombus adherent to atheromatous plaque. In all cases the diagnosis was made by carotid ultrasound. There was one female patient, ages between 35 and 88 years, one patient was asymptomatic. The symptoms were homolateral to carotid lesion. The two arterial wall adherent thrombus were associated with prothrombotic conditions: pregnancy and lung carcinoma. From the five patients, four had a different therapeutic approach due to ultrasound findings – were anticoagulated. We describe the five patients and compare our findings with the literature data. Conclusion: Although rare, differential diagnosis of mobile intraluminal non-artifactual echoes in the carotid artery is crucial due to the need of further investigation of inherent causes and different therapeutic approaches.

Special Issue on Controversies in Neurology. From the 10th World Congress on Controversies in Neurology (CONy), Lisbon, Portugal. 17–20 March 2016.

International Journal of Clinical Neurosciences and Mental Health 2016; 3(Suppl. 1):P28

Icon_pdf Download PDF

Poster


Mechanical thrombectomy in acute stroke - read full article

By: Valentina Mileusnic, Slobodan Culafic, Aleksandra Zecevic, Irena Grkic, and Vesna Miletic

Background: Thrombectomy is a method of recanalization of occluded large cerebral arteries of the head and neck in acute stroke in a specified time window. This study included 17 patients who were treated at the Special Hospital for Cerebrovascular Diseases ‘St. Sava’ in the period March 2014 - December 2015. It involved monitoring patients until they were discharged from the hospital. All were divided into 2 groups: A group - 3 patients received the thrombolytic therapy (Aktiliza faktor), after which was performed thrombectomy; B group - 14 patients who were outside of the time window for thrombolytic therapy or did not meet the criteria. Therefore, only the thrombectomy was performed. Methods: All the patients undergone CT and CTA of endocrnium, laboratory testing, and X-Ray of lungs, and were scored by NIHSS and Rankin Scale. Mechanical thrombectomy was performed by Solitaire™ stent device. Results: (After the thrombectomy), without a deficit and smaller deficits (Rankin 0-1) – group A-5 patients, group B-1 patient; Severe disability (Rankin 5) – group A-3 patients, group B-1 patient ; Exitus letalis (Rankin 6) – group A-6 patients, group B-1 patient. Conclusion: The questions remains for the next Controversy: first thrombolysis and then thrombectomy, or just thrombectomy of occluded large cerebral arteries of the head and/or neck in acute stroke.

Special Issue on Controversies in Neurology. From the 10th World Congress on Controversies in Neurology (CONy), Lisbon, Portugal. 17–20 March 2016.

International Journal of Clinical Neurosciences and Mental Health 2016; 3(Suppl. 1):P29

Icon_pdf Download PDF

Poster


Thalamomesenteric infarction presenting as vertical one-and-a-half syndrome with contralesional horizontal gaze palsy - read full article

By: B. Na, H. Rhee, Y. Kwon, and S. Yoon

Vertical one-and-a-half syndrome consists of a bilateral conjugate upgaze palsy and a unilateral downward palsy or a bilateral conjugate downward palsy and a monocular upgaze palsy. We describe concurent vertical one-and-a-half syndrome and contralesional horizontal gaze palsy in a patient with acute ischemic stroke limited to unilateral paramedian thalamus and upper midbrain. A 75-year-old man admitted to our hospital for an abrupt onset of diplopia and ptosis. on admission, neurological examination revealed bilateral ptosis, conjugate upgaze palsy, downward gaze palsy of the right eye, and conjugate gaze limitation to the left side. two hours after the onset, the patient developed the left facial palsy and mild left-sided limb weakness (MRC grade 4). The diffusion-weighted MRI of the brain showed a focal high signal intensity in the right paramedian thalamus and upper midbrain. In this case, complex combinations of vertical and horizontal ocular motor disturbances was caused by an unilateral ischemic lesion of the meso-diencephalon. The patient showed vertical one-and-a-half syndrome with bilateral ptosis, contralesional conjugate gaze palsy, and hemiparesis. The impairment of upward ocular movements can be explained by a lesion affecting the riMLF or posterior commissure. It is suggested that the horizontal gaze palsy was caused by the involvement of the descending fibres from the frontal eye fields of the cerebral cortex before decussation at the midbrain level.

Special Issue on Controversies in Neurology. From the 10th World Congress on Controversies in Neurology (CONy), Lisbon, Portugal. 17–20 March 2016.

International Journal of Clinical Neurosciences and Mental Health 2016; 3(Suppl. 1):P30

Icon_pdf Download PDF

Poster


Comparison of frequency of death in patients with ischemic stroke and with/without diabetes mellitus - read full article

By: V. Miletic, Katarina Savic Vujovic, V. Golubovic, I. Grkic, M. Stojanovic, A. Zecevic, V. Mileusnic, R. Curuvija, V. Petrovic, and A. Vujovic

Diabetes mellitus is a strong risk factor for atherosclerosis and cerebral ischemia. Hyperglycemia often meet with non-diabetic patients, as a reflex mechanism, or the stress response to ischemic trauma. It was found that hyperglycemia associated with stroke, had a poor outcome. It is believed that this phenomenon is due to increased permeability of the blood-brain barrier, which occurs due to anaerobic glycolysis and increase acidity in the brain tissue.There is no solid evidence that good glucose levels reduces the risk of stroke in diabetics. The aim of this study was to compare the incidence of mortality in patients with ischemic stroke and diabetes mellitus compared to mortality in patients with ischemic stroke but without diabetes mellitus. 84 patients were hospitalized with acute ischemic stroke (November, 2015. There were 45 women (53.6%) and 39 men (46.4%). Twenty patients (23.8) with CVI had diabetes mellitus. 17 patients used oral antidiabetics and 3 an insulin. Mortality rate for this period was 27 patients (32%). In diabetic patients lethal outcome occurred in 5 cases (25%), while in the group of patients who did not have diabetes mellitus exitus occurred in 22 patients (34.3%). There was no statistically significant difference in mortality between the groups with acute ischemic stroke and diabetes and those with acute stroke without diabetes, but prevention of stroke in patients with diabetes is the correction of risk factors for the development of macrovascular complications.

Special Issue on Controversies in Neurology. From the 10th World Congress on Controversies in Neurology (CONy), Lisbon, Portugal. 17–20 March 2016.

International Journal of Clinical Neurosciences and Mental Health 2016; 3(Suppl. 1):P31

Icon_pdf Download PDF

Poster


Laterality of deep intracerebral haemorrhage and clinical outcome - read full article

By: R. Diaconescu, C.C. Stancu, M.F. Coteanu, M. Paunescu, D.L. Gavrila, and I.E. Plesea

Background: Intracerebral haemorrhage (ICH) is a devastating form of stroke, representing one of the main cause of death nowadays. Despite the fact that the percentage of the hospitalized patients with ICH has increased lately, the mortality rate has not declined. Purpose: To investigate the relationship between hemispheric laterality of acute deep ICH and clinical outcomes. Methods: We analyzed 469 patients with brain CT scan proven deep ICH of ?30 ml volume, presenting within 6 hours of symptoms onset. Baseline and 5 days Glasgow Coma Scale and National Institutes of Health Stroke Scale scores, 30 days modified Rankin Scores and mortality data were recorded. For morphological analysis, information was obtained from brain CT scans (baseline, and at 5 days) and autopsy reports. Hematoma volume was determined by the ABC / 2 method. Hematoma expansion was defined as an increase in ICH volume ? 33% of baseline. Results: The deep ICH we analyzed showed laterality that slightly favored left side (54%). 30-day mortality was higher among patients with left side deep ICH (33%). There were no differences between right and left side deep ICH regarding the major disability. Hematoma expansion was the strongest predictor of 30-day mortality and disability for all locations of deep ICH. Conclusions: Left side deep ICH proved to be more aggressive, associated with a higher risk of death.

Special Issue on Controversies in Neurology. From the 10th World Congress on Controversies in Neurology (CONy), Lisbon, Portugal. 17–20 March 2016.

International Journal of Clinical Neurosciences and Mental Health 2016; 3(Suppl. 1):P32

Icon_pdf Download PDF

Poster


Substance abuse as a cause for intracerebral hemorrhage - read full article

By: Mirjana Stojanovic, I. Grkic, V. Miletic, and B. Solunac

A right-handed thirty-six year old male presented with an acute loss of function in left limbs and profound sleepiness. Cranial CT showed findings suggestive of intracranial haemorrhage in the right fronto-temporal subcortical area (dimensions 66x36x63mm) with mild perifocal oedema and mass effect; bleeding extended into the lateral ventricle. On the left side, in the fronto-temporal subcortical area a smaller intracranial bleed was noted. CT angiography did not show signs of arterio-venous malformations nor aneurysms. Past medical history was unremarkable and there were no known drug allergies. Further history revealed that the patient took amphetamine with diazepam and high energy drinks immediately before the onset of his symptoms. No other known causes of intracranial bleeding were identified. We have shown that drug abuse can be a cause for intracranial bleed, especially amongst the younger population. It should therefore be considered especially when other causes are excluded.

Special Issue on Controversies in Neurology. From the 10th World Congress on Controversies in Neurology (CONy), Lisbon, Portugal. 17–20 March 2016.

International Journal of Clinical Neurosciences and Mental Health 2016; 3(Suppl. 1):P33

Icon_pdf Download PDF

Poster


Hyperventilation induced hypocapnia should be avoided in cases of cerebral hypoperfursion - read full article

By: K.J. Szabó, B. Rosengarten, L. Csiba, and L. Oláh

Introduction: Previous studies proved that hypercapnia induced vasodilation does not inhibit the visually evoked flow velocity changes in the posterior cerebral arteries. Our aim was to determine whether vasoconstriction induced by hypocapnia affects the neurovascular coupling. Methods: By using visual cortex stimulation paradigm, visually evoked flow velocity changes were detected by TCD in both PCAs of young healthy adults. The control measurement was followed by the examination under hyperventilation (HV). Visual-evoked-potentials were also recorded. Results: Comparing control and HV phases, the breathing frequency significantly increased (16±2 vs. 37±3/min), resulting in significant decrease of the end-tidal CO2 (37±3 vs. 25±3 mmHg) and decrease of resting peak systolic flow velocity (58±11 vs. 48±11 cm/s). To allow comparisons between volunteers, relative flow velocity was calculated in relation to baseline. Repeated measures analysis of variance revealed significant difference between the relative flow velocity time courses during hyper- and normoventilation (p0.001). The maximum changes of visually evoked relative flow velocities were 26±7% and 12±5% during normoventilation and HV (p0.01), respectively. VEPs did not differ during control and HV phases. Conclusions: The significantly lower visually evoked flow velocity changes but preserved VEP during HV suggested that hypocapnia induced vasoconstriction significantly inhibited the neuronal activity evoked flow response. Potential vascular effects of HV should not be ignored in patients with advanced steno-occlusive lesions of the brain supplying arteries, because decreased CBF, impaired vasodilation of resistance vessels, and attenuated cortical activity induced flow response, caused by HV, may increase the risk of cerebral ischemia in hemodynamically compromised patients.

Special Issue on Controversies in Neurology. From the 10th World Congress on Controversies in Neurology (CONy), Lisbon, Portugal. 17–20 March 2016.

International Journal of Clinical Neurosciences and Mental Health 2016; 3(Suppl. 1):P34

Icon_pdf Download PDF

Poster


Blood pressure management in acute ischemic stroke—the lower the better? - read full article

By: Ricardo Varela, A. Martins, J. Sargento-Freitas, F. Silva, J. Ribeiro, I. Correia, J. Gomes, M. Gonçalves, L. Cardoso, C. Machado, B. Rodrigues, G. Santo, and L. Cunha

Historical stroke cohorts reported a curvilinear relationship between blood pressure (BP) and clinical outcome. However, those studies were made disregarding recanalization state and predated current revascularization strategies. We aimed to investigate the relationship between BP in the in the first 24 hours after ischemic stroke and clinical outcome in patients submitted to intravenous and/or intra-arterial recanalization treatments. Consecutive acute stroke patients treated with intra-venous thrombolysis and/or intra-arterial therapies were enrolled in a retrospective cohort study. BP measurements were performed on regular intervals during the first 24 hours after stroke onset. The mean systolic BP (SBP) and diastolic BP (DBP) during the first 24 hours post-stroke were calculated. Recanalization was assessed at 6 hours by transcranial color coded Doppler, angiography or angio-CT. Functional outcome was assessed at 3 months by modified Rankin scale. Linear and quadratic multivariate regression models were performed to determine associations between BP and functional outcome. We included 674 patients, mean age 73.28 (SD: 11.50) years, 363 (53.90%) male. Arterial recanalization was documented in 355 (52.70%) patients. In multivariate analyses SBP and DBP in the first 24 hours post-stroke show a “J”-shaped relationship with functional outcome in the whole population and in the non-recanalyzed patients. Recanalyzed patients show a linear association with functional outcome. Previous concepts remained true regarding non-recanalyzed patients, however in recanalyzed patients lower systemic BP was associated with better outcome raising questions about features of this population, if there’s any room for active treatment and if so, how low should we go.

Special Issue on Controversies in Neurology. From the 10th World Congress on Controversies in Neurology (CONy), Lisbon, Portugal. 17–20 March 2016.

International Journal of Clinical Neurosciences and Mental Health 2016; 3(Suppl. 1):P35

Icon_pdf Download PDF

Poster


Non stenosing floating thrombus in carotid artery—case series - read full article

By: Joanna Wojczal, P. Luchowski, K. Rejdak, and Z. Stelmasiak

Non stenosing floating thrombus (FT) in carotid artery is a rare condition causing TIA or ischemic stroke (IS). The true incidence, precipitating condition and treatment is unknown. We found 5 patients with non stenosing FT in carotid artery from about 2500 routine duplex ultrasound examinations performed in acute ischemic stroke/TIA setting in 2,5 years period (incidence about 0.2%). All the patients presented clinically as TIA and in 4 of them minor infarcts were found on brain MRI. The mean age of the patient was 42 years. In all patients no obvious cause of thrombus formation was found by transthoracic and transesophageal echocardiography, holter ECG and hypercoagulable state examinations, and atheromatous plaques were absent as well. Two patients underwent upper respiratory tract infections two weeks before TIA. The patients were treated with therapeutic doses of LMWH and all of FT were dissolved within 7 days, as diagnosed by repeated ultrasound examinations. No complication was observed. FT can be a direct cause of TIA/minor stroke in young patients, however the precipitating condition of the thrombus formation is difficult to establish. The FT in carotid artery with clinically TIA and minor infarct on brain MRI can be treated successfully by LMWH, however the true value of the treatment must be confirmed in a larger study.

Special Issue on Controversies in Neurology. From the 10th World Congress on Controversies in Neurology (CONy), Lisbon, Portugal. 17–20 March 2016.

International Journal of Clinical Neurosciences and Mental Health 2016; 3(Suppl. 1):P36

Icon_pdf Download PDF

Poster


MoCA vs MMSE in post stroke patients - read full article

By: Sokrat Xhaxho, Jora Xhaxho, Joana Hankollari, Brunilda Xhaxho, and Jera Kruja

Introduction: Both the MMSE and the MoCA are routine cognitive screening tests rated on a 30-point scale. Neither test is very detail oriented and both would likely be used only for initial screening. The MoCA discriminates very well between normal cognition and mild impairment or dementia, but it’s too difficult for moderate to severe conditions, while the MMSE is likely a better test for more severe conditions. Aim: To evaluate the cognition in post stroke patients. To see if there is any difference between MoCA and MMSE tests and determine which one is the best to use in order to better evaluate the cognition in those patients. Methods: We included in this study 100 patients 24-48 h post stroke that were hospitalized in Clinic of Neurology, in University Hospital Centre “Mother Teresa”, Tirana. We evaluated each of them with MoCA and MMSE test one after the other. At the end we compared the mean of the points for each test. Results: We have a mean of 21.6 points for MoCA test and 23.75 points for MMSE test (normal 26 points for MoCA test and 27 points for MMSE test). There is a difference of 2.15 points between the tests. P=0.00766 that means that the difference is statistically significant. Conclusions: Cognition is an affected function in 24-48 h post stroke patients. The best way to evaluate this is MoCA test.

Special Issue on Controversies in Neurology. From the 10th World Congress on Controversies in Neurology (CONy), Lisbon, Portugal. 17–20 March 2016.

International Journal of Clinical Neurosciences and Mental Health 2016; 3(Suppl. 1):P37

Icon_pdf Download PDF

Poster


Cerebral and systemic endothelial functions in leukoaraiosis - read full article

By: Marjan Zaletel, Matija Zupan, Janja Pretnar-Oblak, Katarina Surlan, and Bojana Zvan

Background: Clinical relevance of leukoaraiosis (LA), its pathophysiology is still unclear. In the present work, we are focused on answering the question whether LA patients have cerebral and/or systemic endothelial dysfunction and whether this is solely a consequence of vascular risk factors (VRF). Subjects and Methods: Thirty patients with LA (58 ± 7 years) and 30 sex- and age-matched controls without LA (55 ± 6 years) were recruited with identical VRF. The cerebral endothelial function was determined by cerebrovascular reactivity to L-arginine (CVR) using TCD measurements of mean arterial velocity in both middle cerebral arteries before and after intravenous L-arginine infusion. The systemic endothelial function was determined by flow-mediated dilatation (FMD). All participants underwent a brain magnetic resonance imaging to search for radiological signs of LA that was classified according to the Fazekas score. Results: We found a significant decrease in both CVR (9.6 ± 3.2% vs. 15.8 ± 6.1%, p0.001) and FMD (4.8 ± 3.1% vs. 7.4 ± 3.8%, p=0.004) in patients with LA compared to controls. Both CVR (7.4 ± 3.1% vs. 12.2 ± 2.6%, p=0.001) and FMD (3.0 ± 2.2% vs. 6.4 ± 3.1%, p=0.011) were significantly decreased in LA subgroup Fazekas 3 compared to the subgroup Fazekas 1. The CVR and FMD significantly positively correlated in patients with LA (b=0.192, 95% CI=0.031-0.354, p=0.02). Conclusions: The results suggest that patients with LA have a significant impairment of both cerebral and systemic endothelial function, that is larger than could be expected, based on present VRF.

Special Issue on Controversies in Neurology. From the 10th World Congress on Controversies in Neurology (CONy), Lisbon, Portugal. 17–20 March 2016.

International Journal of Clinical Neurosciences and Mental Health 2016; 3(Suppl. 1):P38

Icon_pdf Download PDF

Poster


A new simple score for assessing behavioral and psychological symptoms of dementia (Abe’s BPSD SCORE=ABS) - read full article

By: Koji Abe, T. Yamashita, Y. Nakano, R. Morihara, Y. Ohta, and N. Hishikawa

In addition to cognitive impairment, behavioral and psychological symptoms of dementia (BPSD) are another important aspect of most dementia patients including post-stroke dementia. We attempted to create a new BPSD score for dementia with 10 BPSD items. This new simple BPSD score was compared to a standard-detailed BPSD score neuropsychiatric inventory (NPI) for a possible correlation (n=792) and a time to complete (n=136). Based on the clinical survey for local caregivers, a new BPSD score for dementia (ABS, Abe`s BPSD score) was newly created, in which each BPSD item was allotted by an already-weighted score (maximum 1–9) based on the frequency and severity, and was finalized with taking temporal occurrences into account. ABS was filled by the main caregiver with a full score of 44, was well correlated with NPI (r = 0.716, **p 0.01) in 792 AD patients (age 78.6 ± 7.0 years, MMSE 19.0 ± 5.9), and took a shorter time as only 56.8 ± 38.8 s (**p 0.01) than NPI score (132.7 ± 94.0 s) with 136 AD patients. A high inter-rater reliability was obtained (r = 0.964, **p 0.01) with a little smaller score (0.877 time) of ABS in secondary than the main caregivers. Thus ABS provides a new simple and quick test for BPSD assessment, with a good correlation to NPI but a shorter time, and with a high inter-rater reliability (Abe K et al.: J. Neurol. Sci. 2015; 350: 14-17).

Special Issue on Controversies in Neurology. From the 10th World Congress on Controversies in Neurology (CONy), Lisbon, Portugal. 17–20 March 2016.

International Journal of Clinical Neurosciences and Mental Health 2016; 3(Suppl. 1):P39

Icon_pdf Download PDF

Poster


Synaptic proteins predict cognitive decline in Alzheimer's disease and Lewy body dementia - read full article

By: Erika Bereczki, P. Francis, J. B. Pereira, A. Bogstedt, J. H. Baek, C. Ballard, and D. Aarsland

Background: Initial work suggests that the loss of synapses is more robustly correlated with cognitive decline than the traditional markers of Alzheimer`s disease (AD) pathology, Our objective was to compare the levels of three synaptic proteins involved in different steps of the synaptic transmission: Rab3A, SNAP25 and neurogranin, in three common forms of dementia: AD, dementia with Lewy bodies (DLB) and Parkinson’s disease dementia (PDD). Methods: 129 post-mortem human brain tissues from PD, DLB, AD and non-demented controls were analyzed using ELISA and Western blots in brain regional specific manner exploring their associations with morphological changes and cognitive decline. Results: We have observed robust changes reflecting synaptic dysfunction in all studied dementia groups. Decreased Rab3A and SNAP25 levels correlated with increased rate of cognitive decline in DLB and AD as well as with neuropathological markers. Discussion: Our results suggest that stabilization of synaptic protein levels such as Rab3A may represent an important treatment strategy in DLB patients, while SNAP25 could be a new marker in the progression of AD. These findings indicate that the proposition that synaptic markers can predict cognitive decline in AD, should be extended to Lewy body diseases.

Special Issue on Controversies in Neurology. From the 10th World Congress on Controversies in Neurology (CONy), Lisbon, Portugal. 17–20 March 2016.

International Journal of Clinical Neurosciences and Mental Health 2016; 3(Suppl. 1):P40

Icon_pdf Download PDF

Poster


Expression of regulatory proteins in choroid plexus changes in early stages of Alzheimer’s disease - read full article

By: A. Krzyzanowska, I. García-Consuegra, C. Pascual, D. Antequera, I. Ferrer, and Eva Carro

The role of choroid plexus in Alzheimer’s disease (AD) is being increasingly recognized. Recent studies suggest that the choroid plexus has a more important role in physiological and pathological brain functions than previously appreciated. To obtain additional insight on choroid plexus function, we performed a proteomic analysis of choroid plexus samples from AD stages I-II (n = 16), III–IV (n = 16), and V–VI (n = 11), and 7 age-matched control subjects. We used differential 2D electrophoresis (2-D DIGE) coupled with mass spectrometry to generate a complete picture of changes in choroid plexus protein expression occurring in AD patients. We identified 6 proteins: 14-3-3 ?/?, 14-3-3 ?, moesin, proteasome activator complex subunit 1 (PSME1), annexin V, and aldehyde dehydrogenase (ALDH), which are significantly regulated in AD pathology (p0.05, 1.5-fold variation in expression comparing with control samples), with central physiological functions, including mitochondrial dysfunction and apoptosis regulation, and able to model key pathological events. The data presented here contribute additional significance to the emerging importance of molecular and functional changes of choroid plexus function in the development of AD pathology.

Special Issue on Controversies in Neurology. From the 10th World Congress on Controversies in Neurology (CONy), Lisbon, Portugal. 17–20 March 2016.

International Journal of Clinical Neurosciences and Mental Health 2016; 3(Suppl. 1):P41

Icon_pdf Download PDF

Poster


Neuropsychological domains sensitive to conversion of dementia in non-demented patients with Parkinson’s disease - read full article

By: Sang-Myung Cheon, Su-Yun Lee, Jae Woo Kim, and Hye-Mi Jeong

Backgrounds and objectives: Dementia is one of the most disabling symptoms in patients with Parkinson’s disease (PD). The aims of this study were to investigate the neuropsychological and mild cognitive impairment (MCI) subtypes related to conversion of dementia in non-demented PD and PD-MCI patients. Methods: PD patients taken comprehensive neuropsychological test were recruited from outpatient clinic of referral hospital. PD with dementia (PDD) was defined according to the DSM-4 and PD-MCI by impaired performance on at least one of five cognitive domains. Five tests (forward digit span, Boston Naming Test, Rey Complex Figure, Seoul Verbal Learning Test and phonemic word test) were chosen as a baseline assessment to represent five cognitive domains; attention, language, visuospatial, memory and frontal/executive functions. Those tests were compared between PDD converters and non-converts in non-demented and PD-MCI patients. Results: Total 476 patients were recruited. Among them, 41 patients had become PDD converters and they showed older age at onset, lower education level and MMSE score, and higher MCI frequency. Dysfunction in the domains of language, visuospatial and memory were more prevalent in PDD converters at baseline. Among 205 PD-MCI patients, 27 PD-MCI patients converted to PDD, and they showed poor performance in visuospatial function. Conclusions: Visuospatial function was found to be a most sensitive domain to PDD conversion in non-demented patients with PD. This finding suggests that the performance of posterior cortical function would be more related to conversion of dementia in patients with PD.

Special Issue on Controversies in Neurology. From the 10th World Congress on Controversies in Neurology (CONy), Lisbon, Portugal. 17–20 March 2016.

International Journal of Clinical Neurosciences and Mental Health 2016; 3(Suppl. 1):P42

Icon_pdf Download PDF

Poster


Clinical diagnosis and biomarker constellation in AD in a clinical setting: how congruent are the biomarker findings - read full article

By: Hermann-Josef Gertz, David Weise, Solveig Tiepolt, Karl-Titus Hoffmann, Donald Lobsien, Thorsten Kaiser, Henryk Barthel, and Osama Sabri

Objectives: In clinical practice biomarkers are thought to confirm or exclude the diagnosis of AD. Methods: Cross-sectional observational study with 54 patients with mild cognitive impairment or dementia due to AD or not due to AD. Biomarkers of neuronal injury were medial temporal lobe atrophy (MTA) on magnetic resonance imaging (MRI) and tau concentration in the cerebrospinal fluid (CSF). CSF A? 1-42 and amyloid-targeting positron emission tomography (PET) were considered as biomarkers of amyloid pathology. Results: Forty cases were diagnosed as AD, 14 cases as non-AD based on clinical, neuropsychological and routine MRI assessment. In the AD group completely consistent pathological biomarkers were found in 32.5%. In 62.5% the findings were inconsistent. Congruence of biomarkers was 67.5% for neuronal injury and 75% for amyloid dysfunction. In two patients clinical diagnosis switched to non-AD due to completely consistent non-pathological biomarker findings. The criteria of the international working group (IWG-2, Dubois et al. 2014) were met in 75.0% of the clinically diagnosed AD cases. Conclusions: Different explanations of incongruent biomarker results need to be considered, including technical inaccuracies and too rigid cut off points. The different biomarker constellations represent distinct types or stages of AD.

Special Issue on Controversies in Neurology. From the 10th World Congress on Controversies in Neurology (CONy), Lisbon, Portugal. 17–20 March 2016.

International Journal of Clinical Neurosciences and Mental Health 2016; 3(Suppl. 1):P43

Icon_pdf Download PDF

Poster


The cholesterol oxidation products may underlie alpha-synuclein accumulation in Alzheimer’s disease and Parkinson’s disease - read full article

By: Othman Ghribi

Accumulation of alpha-synuclein (alpha-Syn) is a common hallmark of a group of brain disorders collectively known as synucleinopathies. These disorders include Parkinson`s disease (PD), the most common movement disorder; dementia with Lewy bodies (DLB), the second most common form of dementia; multiple system atrophy (MSA), a neurodegenerative disease leading to severe physical impairment; and Alzheimer’s disease (AD), the most common form of dementia. The role of alpha-Syn in the pathogenesis of synucleinopathies is not understood, but experimental studies point to a potential neurotoxic role of high levels of this protein in its soluble or aggregated forms. We found that the oxysterol 27-hydroxycholesterol (27-OHC), the major cholesterol oxidation metabolite in human plasma, causes both AD-like pathology and PD-like pathology in human neuroblastoma cells and in organotypic slices. We found that 27-OHC increases alpha-Syn transcription through activation of liver X receptors (LXR). Furthermore, we demonstrate that while activation of LXR with specific agonists increases, inhibition of LXR with specific antagonists reduces alpha-Syn accumulation. Such results suggest a possible role of oxysterols and LXR signaling in synucleinopathies. Oxysterol levels are elevated in the circulation in hypercholesterolemic individuals. Interestingly, oxidative stress can also increase conversion of cholesterol to oxysterols. Our data are significant to identifying factors that may contribute to the pathogenesis of synucleinopathies and to the underlying cellular mechanisms. Identification of such factors and signaling pathways is paramount to understanding the pathophysiology of synucleinopathies including AD.

Special Issue on Controversies in Neurology. From the 10th World Congress on Controversies in Neurology (CONy), Lisbon, Portugal. 17–20 March 2016.

International Journal of Clinical Neurosciences and Mental Health 2016; 3(Suppl. 1):P44

Icon_pdf Download PDF

Poster


Evidence of progressive pathogenesis in the brains of comparative normative control samples in an Alzheimer’s disease study - read full article

By: Brian Jeynes and J. Provias

Tissue samples from aging normative brains are rarely Alzheimer’s disease (AD) lesion burden free. In this study we investigate the AD lesion burden within comparative normative (NM) brain samples used in a study investigating the pathogenesis of AD. Quantitative data which included counts of NFTS, SPs, and capillaries immuno-stained for VEGF, eNOS, LRP, RAGE and P-gp from comparable and 10 randomly selected superior temporal site samples in each of 14 normative brains. The samples were taken from 8 female and 6 male brains aged 63 to 80 years. For the purposes of this study the brains were divided into two groups: those with less than 2 NFTs and / or 4 SPs (low lesion); and those with more of either lesion (high lesion). Our results demonstrate that there is a significant difference between the two groups and that the high lesion group results were quantitatively higher in every observation category (p=0.01 or less). Both LRP and P-gp expression levels were significantly negatively correlated to both NFT and SP burdens (p=0.05 or less). These results point towards underlying pathogenic blood-brain barrier microvascular alterations and dysfunction in normative brains and, further, are supportive evidence for progressive AD lesion pathogenesis in aging normative brains.

Special Issue on Controversies in Neurology. From the 10th World Congress on Controversies in Neurology (CONy), Lisbon, Portugal. 17–20 March 2016.

International Journal of Clinical Neurosciences and Mental Health 2016; 3(Suppl. 1):P45

Icon_pdf Download PDF

Poster


Huge intracranial tumors mimicking Alzheimer’s disease - read full article

By: S. Jung, Y.K. Minn, and S.H. Hwang

Abstract: Background & Significance: Whereas Alzheimer`s disease (AD) is degenerative disease and its clinical symptoms present with insidious onset and slow deterioration, symptomatic secondary dementia can also present slow progression of clinical symptoms mimicking AD. Case: A 73-year-old female presented with memory impairment for 2-3 years. Her symptoms progressed slowly and she could not maintain her daily routine activities by herself. Neurologic examination revealed no focal deficits, but extensive neuropsychology evaluation showed decreased attention, language, visuospatial, memory and executive functions as seen in patients with AD. Brain MRI revealed a huge meningioma compressing bilateral mesial frontal lobes and a bone tumor (cavernous hemangioma) on right anterior cranial fossa. She was referred to a neurosurgeon for surgical removal. Comments: We report a case of slowly progressing memory impairment mimicking AD caused by huge intracranial tumors.

Special Issue on Controversies in Neurology. From the 10th World Congress on Controversies in Neurology (CONy), Lisbon, Portugal. 17–20 March 2016.

International Journal of Clinical Neurosciences and Mental Health 2016; 3(Suppl. 1):P46

Icon_pdf Download PDF

Poster


Oxidative stress in Alzheimer's disease patients—study using d-ROM and BAP test - read full article

By: Kiyoshi Kanaya, Shine Abe, Hiroko Fujii, and Haruo Hanyu

Purpose: The oxidative stress and biological antioxidant potential of Alzheimer`s disease ( AD ) patients were measured using a free radical elective evaluator (FREE). Subjects and methods: The subjects consisted of 48 untreated AD patients examined at the Department of Geriatric Medicine of the Hachioji Medical Center. All subjects underwent an Alzheimer`s Disease Assessment Scale-cognitive component-Japanese version (ADAS-Jcog), oxidative stress was assessed by measuring serum dROM levels , BAP (biological antioxidant potential) and BAP/dROM ratio using FREE, and correlations between ADAS scores and oxidative stress indicators were tested. Degree of dementia was determined by using ADAS scores to categorize the subjects into three groups consisting of a mild (ADAS score: 0-9 ), moderate ( Score: 10-19 ) and advanced group (Score: 20 or higher) , and analyzing variance for dROM levels, BAP and BAP/d-ROM ratio among each group. Results: The average ADAS-Jcog score was 15.1. The average values for d-ROM levels, BAP and BAP/d-ROM ratio were 441.8, 2497.1 and 6.06, and when compared with each of their reference values, d-ROM levels indicated severe oxidative stress while BAP values indicated appropriate biological antioxidant potential. There was a negative correlation between ADAS scores and BAP values (r=0.313, P=0.03). An analysis of variance among the three groups yielded a relationship such that BAP/d-ROM ratio was significantly higher in the advanced group in a comparison between the mild group and advanced group (P=0.048). Conclusion: Elevated d-ROM levels and normal BAP values suggest an increase in oxidative stress accompanying chronic inflammation.

Special Issue on Controversies in Neurology. From the 10th World Congress on Controversies in Neurology (CONy), Lisbon, Portugal. 17–20 March 2016.

International Journal of Clinical Neurosciences and Mental Health 2016; 3(Suppl. 1):P47

Icon_pdf Download PDF

Poster


Effect of Edirex-Sanovel (pioglitazone) medication on the incidence of dementia - read full article

By: Vera Kapetivadze, R. Tabukashvili, N. Gegeshidze, Kh. Tchaava, T. Lazashvili, Z. Magapheridze, and Z. Grigorashvili

Objective: Peroxisome proliferator activated receptor ?-activating drugs show various salutary effects in preclinical models of neurodegenerative disease. The decade-long clinical usage of these drugs as antidiabetics now allows for evaluation of patient-oriented data sources. Methods: Using observational data from 2012-2015, we analyzed the association of Edirex-Sanovel (pioglitazone) and incidence of dementia in a prospective cohort study of 45 subjects aged ?60 years who, at baseline, were free of dementia and insulin-dependent diabetes mellitus. We distinguished between nondiabetics, diabetics without Edirex-Sanovel, diabetics with prescriptions of 6 calendar quarters of Edirex-Sanovel, and diabetics with ?6 quarters. Cox proportional hazard models explored the relative risk (RR) of dementia incidence dependent on edirex-sanovel use adjusted for sex, age, use of rosiglitazone or metformin, and cardiovascular comorbidities. Results: Long-term use of pioglitazone was associated with a lower dementia incidence. Relative to nondiabetics, the cumulative long-term use of Edirex-Sanovel reduced the dementia risk by 49% (RR = 0.50, p = 0.027). If diabetes patients used Edirex-Sanovel 6 quarters, the dementia risk was comparable to those of nondiabetics (RR = 1.20, p = 0.36), and diabetes patients without a Edirex-Sanovel treatment had a 25% increase in dementia risk (RR = 1.27, p 0.001). We did not find evidence for age effects, nor for selection into Edirex-Sanovel treatment due to obesity. Interpretation: These findings indicate that Edirex-Sanovel treatment is associated with a reduced dementia risk in initially non-insulin-dependent diabetes mellitus patients. Prospective clinical trials are needed to evaluate a possible neuroprotective effect in these patients in an ageing population.

Special Issue on Controversies in Neurology. From the 10th World Congress on Controversies in Neurology (CONy), Lisbon, Portugal. 17–20 March 2016.

International Journal of Clinical Neurosciences and Mental Health 2016; 3(Suppl. 1):P48

Icon_pdf Download PDF

Poster


Interaction of thymoquinone with alpha 7 nicotinic acetylcholine receptor in LPS-induced neuroinflammatory model - read full article

By: O.A. Heikal, Lobna Kassem, Maha Zekri, Islam Diasty, and Esraa Osama

Alzheimer’s disease (AD) is neurodegenerative disorder resulting from loss of cholinergic neurons in brain especially acetylcholine. It has been reported that alpha-7 nicotinic acetylcholine receptors (alpha-7 nAchRs) play an important role in cognitive function and can be target therapy for treating cognitive deficits. alpha-7 nAchR agonists cause memory enhancement through phosphorylation of cAMP response element binding protein (CREB). Thymoquinone (TQ) was recently considered as acetylcholine esterase inhibitor and increased alpha-7 nAchR expression in brain. However, the effect of TQ as alpha-7 agonist has not been investigated. Our aim was to investigate the mechanism of action of TQ on alpha-7 nAchR. Neuroinflammatory AD rat model was developed by injecting LPS i.p (0.8 mg/kg) once. A specific alpha-7 agonist and alpha-7 positive allosteric modulator were used. Rats were injected with TQ (10 mg/kg) i.p for 5 consecutive days with or without alpha-7 positive allosteric and another qroup with alpha-7 agonist + alpha-7 positive allosteric modulator. After one week, rat brains were subjected to immunohistochemical studies. Molecular docking studies were done in which TQ was docked on chimeric acetylcholine binding protein. Results indicate significant decrease in amyloid plaques with significant increase in p-CREB expression in TQ treated groups especially the group treated with TQ and allosteric modulator. Docking results show hydrophobic interactions of TQ similar to ligand interactions in complex with the receptors. This indicates the possible direct agonistic effect of TQ on alpha-7 nAchR and its role in modulating cognitive defects. TQ can be promising therapeutic module for treatment of AD.

Special Issue on Controversies in Neurology. From the 10th World Congress on Controversies in Neurology (CONy), Lisbon, Portugal. 17–20 March 2016.

International Journal of Clinical Neurosciences and Mental Health 2016; 3(Suppl. 1):P49

Icon_pdf Download PDF

Poster


Association of cerebrovascular disease with peripheral artery disease in older adults - read full article

By: Yong Soo Shim, San Jung, Bora Yoon, and Dong Won Yang

Background: Vascular disease is prevalent in older adults. Cognitive impairment and dementia may result from cerebrovascular disease. Transcranial Doppler (TCD) is a noninvasive technique for evaluating cerebral hemodynamics. Also, the ankle-brachial pressure index (ABI) and pulse wave velocity (PWV), markers of peripheral arterial disease, are known to be associated with cognitive impairment. We evaluated the association of TCD parameters, markers of cerebral microvasculopathy, with peripheral artery disease, as indicated by ABI and brachial-ankle PWV (baPWV). Methods: A total of 184 participants were included: 49 controls, 72 patients with mild cognitive impairment (MCI), and 63 patients with Alzheimer’s disease (AD). Demographic characteristics, mini-mental state examination (MMSE), and clinical dementia rating_sum of boxes (CDR_SOB) were assessed. Using TCD, cerebrovascular reactivity (CVR) was evaluated, in addition to the mean blood flow velocity (MFV), pulsatility index (PI), and resistance index (RI) of the middle cerebral artery. We also assessed baPWV and ABI. Results: The mean age of participants was different among 3 groups: controls; 66.45±6.53, MCI; 69.25±8.32, and AD; 74.56±6.07 (p=0.001). Additionally, markers of cerebral and peripheral artery disease are all different among 3 groups (all, p=0.05). After adjusting for age, ABI was associated with MFV (right; r=-0.225, p=0.005 and left; r=-0.169, p=0.035) and MMSE score (right; r=0.203, p=0.007 and left; r=0.159, p=0.048). Conclusion: There was an association of a marker of peripheral artery disease (ABI) with the impaired function of cerebral microvessels (MFV) and cognitive impairment. Management of peripheral vascular disease may help prevent the progression of cerebrovascular disease or cognitive decline.

Special Issue on Controversies in Neurology. From the 10th World Congress on Controversies in Neurology (CONy), Lisbon, Portugal. 17–20 March 2016.

International Journal of Clinical Neurosciences and Mental Health 2016; 3(Suppl. 1):P50

Icon_pdf Download PDF

Poster


Validation of olfactory deficit as a biomarker of Alzheimer’s disease - read full article

By: Kinga Szigeti, Muhammad Ubaid Hafeez, Matthew Woodward, Jesper Hagemeier, Ralph Benedict, and Li Yan

With increased longevity the prevalence of AD in the elderly represents a major public health problem. Olfactory identification deficit (OID) may represent a parallel neurodegenerative process preceding the AD disease trajectory. Clinical study with three components was performed: i) cross-sectional case-control study to evaluate the sensitivity and specificity of OID in differentiation normal aging from an amnestic disorder; ii) an exploratory longitudinal study of aMCI subjects (mean follow-up 477.6 ±223.3 days) to evaluate the utility of OID in predicting conversion from aMCI to AD; iii) a structural MRI subset (27 NC, 15 aMCI and 37 AD) to correlate OID with regional brain volumes. Correlation trend test between odor identification and disease status was significant after correcting for age, sex, and ApoE in the model (p=1.52x10-59). ROC/AUC was similar for the 40 item UPSIT and the top 10 smells. Smeller/non-smeller based on the 10 item subset with a cutoff of 7 ( = 7, non-smeller; 7, smeller) had a sensitivity and specificity of 88% and 71% for identifying AD. Conversion rates in the aMCI group were 36.4% in non-smellers and 17.3% in smellers (p=0.03). Volumetric analysis revealed differences in right hippocampal volumes between smellers and non-smellers in the aMCI stage. OID in the context of an episodic memory impairment reflects early right hippocampal involvement suggesting a central mechanism. Longitudinal studies exploring the time relationship between the trajectory of decline in olfactory identification and the development of an amnestic disorder are needed to further characterize the relationship.

Special Issue on Controversies in Neurology. From the 10th World Congress on Controversies in Neurology (CONy), Lisbon, Portugal. 17–20 March 2016.

International Journal of Clinical Neurosciences and Mental Health 2016; 3(Suppl. 1):P51

Icon_pdf Download PDF

Poster


Chronic obstructive pulmonary disease as a risk factor for dementia - read full article

By: Saule Turuspekova, D. Mitrokhin, A. Zhanayev, A. Ablayeva, G. Zhilkibayeva, and A. Umarbayeva

Relevance: Chronic obstructive pulmonary disease (COPD) remains a major public health problem. According to data released by the World Bank and the World Health Organization (WHO), it is expected that in 2020 it will be on the 5th place on the damage caused by diseases globally. It is now known that pulmonary pathology leads to disruption of cerebral blood flow. Insufficient oxygen supply to the brain at bronchial obstruction, which negatively affects the brain functions such as memory, attention, thinking. Purpose: To identify the state of the higher brain functions in patients with chronic obstructive pulmonary disease. Materials and methods: There are were studied 40 patients aged 26 to 87 years (including 28 men, 12 women) with COPD III and IV . Determined by pulse oximetry oxygen saturation of the blood. The study was conducted using the Montreal Cognitive Assessment Scale Results: The study showed a significant reduction of memory, attention, thought in 14 patients (35% -19 points), moderate decline of higher brain functions in 14 patients (35% -20 and 23 points ), a slight decrease in 8 patients (20% -25 points), and the norm in 4 patients (10%). At the same time found a direct correlation between cognitive impairment and peripheral oxygen saturation: the saturation 95% were identified cognitive impairment, with 85% dementia. Conclusion: The present study indicates a significant impact of COPD on the higher brain functions of humans.

Special Issue on Controversies in Neurology. From the 10th World Congress on Controversies in Neurology (CONy), Lisbon, Portugal. 17–20 March 2016.

International Journal of Clinical Neurosciences and Mental Health 2016; 3(Suppl. 1):P52

Icon_pdf Download PDF

Poster


Entorhinal cortical volume, a sensitive imaging biomarker in subjective memory impairment - read full article

By: Dong Won Yang, E. Lim, J. Cho, Y. Shim, B. Yoon, and Y. Hong

Introduction: Subjective memory impairment (SMI) has been considered as a transitional state between normal and MCI and with higher conversion risk to dementia. The aim of this study was to investigate the diagnostic sensitivity of entorhinal cortical volume, hippocampal volume and fractional anisotropy (FA) in SMI. Methods: We recruited 25 controls and 23 SMI. 3D T1 SPGR MRI and diffusion tensor image were obtained for the image analysis. Entorhinal cortical volume and hippocampal volume were measured by manual segmentation with Analyzer program. Entorhinal and hippocampal volume were divided by total intra cranial volume to correct size variation of brain. FA value was measured with ROI method at the head of hippocampus with Volume One program. Results: Age, gender, education were not different between groups (p=0.05). Mini-Mental State Examination score was lower in SMI group (28.3 vs. 26.0, p=0.05). Entorhinal cortical volume and FA value of hippocampus were lower in SMI group (p=0.001). Hippocampal volume ratio was not different between groups (0.151% VS 0.148%, p=0.44). Diagnostic accuracy of each of markers was evaluated with receiver operating characteristic curve. Area under the curve (AUC) value was highest in entorhinal cortical volume (AUC=0.939). AUC of the FA value of hippocampus were lower (AUC=0.867) and hippocampal volume had the lowest AUC value (AUC=0.533). Diagnostic accuracy of MMSE was higher than the hippocampal volume (AUC=0.769). Conclusions: Structural changes start earlier in the entorhinal cortex than in the hippocampus of SMI. Measurement of entorhinal cortical volume may be a sensitive imaging biomarker for the early detection of SMI.

Special Issue on Controversies in Neurology. From the 10th World Congress on Controversies in Neurology (CONy), Lisbon, Portugal. 17–20 March 2016.

International Journal of Clinical Neurosciences and Mental Health 2016; 3(Suppl. 1):P53

Icon_pdf Download PDF

Poster


Awareness and its relation to psychiatric symptoms in early-onset Alzheimer’s disease - read full article

By: Bora Yoon, Dong Won Yang, Seong Hye Choi, Yong S. Shim, and San Jung

Background: Anosognosia in patients with Alzheimer’s disease (AD) appears differently by various conditions such as disease severity or neuropsychiatric symptoms (NPS). However, it remains uncertain how anosognosia is related to disease severity or NPS in early-onset (EO) AD. We investigated the incidence of anosognosia and associating factors especially NPS by disease severity. Methods: We recruited 616 EOAD patients. We subdivided participants into 3 groups by awareness for disease: full/ partial/ no, and by clinical dementia rating (CDR): 0.5/ 1/ 2. We compared the difference in neuropsychiatric inventory (NPI) according to the degree of awareness and the disease severity. Results: The percentage of anosognosia steadily increased as CDR worsened (8.6% vs 13.6% vs 26.2%). NPI total score was statistically high in anosognosia patients of CDR 0.5 and 1 group, by contrast, it was not associated with patients with anosognosia in CDR 2 group. Overall, anosognosia patients demonstrated delusion(P=0.015), hallucination(P=0.005), agitation(P=0.001), aberrant motor behavior(P=0.001), sleep(P=0.016), and appetite(P=0.040) statistically high. After stratification of CDR, anosognosia patients showed sleep(P=0.023) and appetite(P=0.025) among CDR 0.5 significantly high while delusion(P=0.035) and hallucination(P=0.049) among CDR 1. In CDR 2, there was no difference among 3 groups by awareness. Discussion: Anosognosia differs the incidence and associating factors by disease severity in EOAD patients. It is associated with specific NPS in very mild and mild stage rather than moderate stage. It would be recommended to confirm sleep and appetite problems in very mild group, and delusion and hallucination in mild group with anosognosia patients.

Special Issue on Controversies in Neurology. From the 10th World Congress on Controversies in Neurology (CONy), Lisbon, Portugal. 17–20 March 2016.

International Journal of Clinical Neurosciences and Mental Health 2016; 3(Suppl. 1):P54

Icon_pdf Download PDF

Poster


Immunocytochemical studies of the neurodegenerative diseases the ubiquitin proteasome system - read full article

By: Mohamed Zouambia

The present study is related to the immunoreactivities of the sub-units of 26S proteasome for the principal forms of tauo- and synucleinopathies. Several cerebral diseases were studied. Many studies showed that the weakening of the function of the proteasome is associated with the cellular senescence. However, the data available are reduced in fragments and are contradictory. Six tauopathies were studied. All showed the immunoreaction of ATPase S6b in the hippocampus and the temporal cortex. For the Alzheimer and Down Syndrome patients, the pyramidal cells of the CA1 and CA3 of the hippocampus were the most positive zones. CA4, dentate gyrus and subiculum were less reactive with ATPase S6b. Of the two synucleinopathies studied (LBD and MSA), Lewy bodies were less immunoreactive as visualized in some brains of patients having Lewy Body Disease. Our data suggest that the degree of weakening of the ubiquitin-proteasome system is much more dramatic in tauopathies than in the synucleinopathies. The evidence accumulates more and more for a participation of the ubiquitin-proteasome system in the degradation of abnormal proteins in a variety of neurological disorders.

Special Issue on Controversies in Neurology. From the 10th World Congress on Controversies in Neurology (CONy), Lisbon, Portugal. 17–20 March 2016.

International Journal of Clinical Neurosciences and Mental Health 2016; 3(Suppl. 1):P55

Icon_pdf Download PDF

Poster


The effect of intraperitoneal and intrathecal cobalt chloride administration on formalin-induced orofacial pain - read full article

By: T. Alexa, A. Luca, A. Negru, and C.R. Bohotin

Introduction: The exact mechanism by which cobalt chloride (CoCl2) exerts its effects is unclear. Suggested hypothesis include mitochondrial toxicity, ATP synthesis inhibition and reactive oxygen species production, mechanisms that are implicated in migraine and chronic pain. The aim of this study was to assess the effect of single-dose CoCl2 administered via central (intrathecal i.t.) versus peripheral (intraperitoneal -i.p.) route on formalin-induced orofacial pain (OFP). Materials and methods: Male BALB/c mice were divided in two groups that received CoCl2 (i.p. - 25mg/kg b.w. or i.t. - 0.025mg/kg b.w. administration) and two groups that received saline. Three hours later, mice received 20?L formalin into the right whisker pad; the time mice spent rubbing/liking the injected area was recorded. The results are expressed as percentages of inhibition. Results: Both routes of CoCl2 administration induced a significant decrease in pain behavior in phase one of the OFP test, with percentages of inhibition (PCIs) of over 30%. In the second phase, the decrease remained significant for both i.t. and i.p. CoCl2 groups, but the decrease after central administration was more important than after systemic administration (55.8% vs. 27.4% PCIs). For both administrations the CoCl2 groups were statistically different from control groups (p0.005). Conclusions: Our initial hypothesis was that CoCl2 would increase pain-related behavior. However, CoCl2 had a pronounced central effect on orofacial pain, with anti-inflammatory-like consequences. This may be secondary to CoCl2’s ability to induce neurotransmission inactivation by reducing Ca2+ pre-synaptic influx (synaptic blockade).

Special Issue on Controversies in Neurology. From the 10th World Congress on Controversies in Neurology (CONy), Lisbon, Portugal. 17–20 March 2016.

International Journal of Clinical Neurosciences and Mental Health 2016; 3(Suppl. 1):P56

Icon_pdf Download PDF

Poster


Use of botulinum neurotoxin in painful trigeminal neuropathy attributed to a multiple sclerosis plaque: a case report - read full article

By: Rui Araújo, Sónia Batista, Isabel Luzeiro, and Beatriz Santiago

Introduction: Painful trigeminal neuropathy attributed to a multiple sclerosis (MS) plaque is a disabling and difficult to manage condition. Recent evidence suggests a potential role for botulinum neurotoxin (BoNT) in trigeminal neuralgia (TN). We present a case of refractory painful trigeminal neuralgia attributed to a MS plaque with a good response to BT. Case report: 48, male, presents with recurrent daily episodes of electric shock-like pain on the right mandibular division of the trigeminal nerve, triggered by innocuous stimuli, with persistent background facial pain since 2012. Brain MRI revealed multiple lesions fulfilling the McDonald criteria for MS diagnosis, with one lesion on the pons adjacent to the trigeminal nucleus. Patient began immunomodulatory therapy with glatiramer acetate and for the neuralgia, he was prescribed carbamazepine (CBZ) and gabapentine (GP), which were progressively increased up to CBZ 400mg 3id and GP 300mg 3id. Due to side effects his medication was progressively altered to GP 800mg 3id and oxcarbamazepine 600mg 3id. Due to inadequate pain control, it was further added baclofen 25mg 2id, misoprostol 0.2mg 3id, phenytoin 100mg 3id, without achieving pain remission. Other drugs were initiated and then suspended due to intolerance or inefficacy (venlafaxine, lamotrigine, lacosamide). Abobotulinum toxin-A (Dysport®) was initiated (60 units, 20u/site intramuscular, 30G needle, 3/3 months). The patient reported significant reduction in pain frequency ( 80%) and on the intensity of the background facial pain and is currently reducing pain medication. Conclusion: Whilst BoNT remains a controversial option for TN, there is growing evidence supporting its use.

Special Issue on Controversies in Neurology. From the 10th World Congress on Controversies in Neurology (CONy), Lisbon, Portugal. 17–20 March 2016.

International Journal of Clinical Neurosciences and Mental Health 2016; 3(Suppl. 1):P57

Icon_pdf Download PDF

Poster


The effects of intrathecal methylene blue and glyceryl trinitrate administration on orofacial pain in mice - read full article

By: Catalina Roxana Bohotin, Teodora Alexa, Andrei Luca, Andrei Dondas, Adriana Negru, and Radu Iliescu

Purpose: Nitric oxide (NO) is involved in several types of pain processes. In patients with migraine, glyceryl trinitrate, a pro-drug for NO, produces a delayed migraine episode. In this study, we decided to evaluate the effects of intrathecal administration of a NO pro-drug (glyceryl trinitrate-GTN) and a NO scavenger (methylene blue–MB) on orofacial pain (OFP). Methods: 24 BALB/c mice were divided in 3 groups as follows: GTN group (0.1mg/kg, n=8), MB group (0.05mg/kg, n=8) and control group (NaCl, n=8). All groups received the substances intrathecally. Two hours after drug/saline administration, formalin was injected into the upper lip and the time mice spent rubbing/liking the injected area was recorded. The results for each phase are presented in seconds. ANOVA and Dunnett post-hoc test were used for statistical evaluation. Results: Intrathecal administration of MB and NTG had no effect on the acute phase of OFP when compared with control. In the second phase, however, both drugs had an analgesic tendency; for GTN, this was statistically significant (p=0.025), and for MB the effect was less important (p=0.083). Conclusions: By centrally administering a NO pro-drug and a NO scavenger, we expected to modulate NO production in formalin-induced OFP. Our results demonstrated that the acute phase of OFP does not depend on NO (neither of the drugs had any effect) and that both substances diminish pain perception in the persistent/inflammatory phase but only the NO pro-drug had a clear-cut antinociceptive effect.

Special Issue on Controversies in Neurology. From the 10th World Congress on Controversies in Neurology (CONy), Lisbon, Portugal. 17–20 March 2016.

International Journal of Clinical Neurosciences and Mental Health 2016; 3(Suppl. 1):P58

Icon_pdf Download PDF

Poster


Magnetic resonance imaging in patients with conventional cardiac devices—a case report - read full article

By: P. Brás, A. Sousa, G. Januário, C. Perry da Câmara, and R. Pedrosa

Introduction: It is estimated that during their lifetime, up to 75% of patients with cardiac pacemaker (PM) develop a medical condition, such as a neurological disorder, for which an MRI may be necessary for optimal diagnosis and treatment. The evidence around conventional PM being a contraindication to MRI is controversial. Case report: A 73 years-old man with a cardiac permanent pacemaker for atrial flutter with slow ventricular response, presented with a 12-month history of worsening neck pain radiating to both arms, associated with paraesthesias and bilateral arm weakness. Initial neurological examination revealed bilateral brachial paresis with upper limb hyporeflexia, pyramidal signs present in lower limbs, positive Lhermitte sign and no sensation loss. A week later he became quadriparetic, losing the ability to walk, and developed urinary retention. A CT-myelogram showed an abnormally expanded cervical spinal cord, requiring further imaging by MRI. With the collaboration of a cardiologist and an anesthesiologist, the pacemaker was programed to an asynchronous mode and the patient was successfully submitted to a 1,5T MRI scan. The device was then reprogrammed to original settings. The MRI revealed an intramedullary lesion suggestive of a spinal cord neoplasm and the patient was submitted to neurosurgical intervention. Conclusions: With the broad number of already existing implanted cardiac components, MRI in patients with conventional pacemaker will remain a dilemma over the next years. Based on findings from several clinical studies the risk may be lower than previously thought if a number of conditions are met and appropriate precautions are taken.

Special Issue on Controversies in Neurology. From the 10th World Congress on Controversies in Neurology (CONy), Lisbon, Portugal. 17–20 March 2016.

International Journal of Clinical Neurosciences and Mental Health 2016; 3(Suppl. 1):P59

Icon_pdf Download PDF

Poster


Disability of headache according to the presence of exercise - read full article

By: Soo-Jin Cho, M. Chu, H.S. Moon, and J.W. Park

Exercise or physical activity is not only a trigger of headache but also a recommended behavioral therapy in migraine. We want to know the influence of exercise on the severity and disability of headache and investigated it using smartphone application-based electronic headache diary (SHD). Migraine patients with average 2-14 headache days per month were recruited and were ask to write the occurrence, severity, duration, triggers of headache, and intensity and duration of exercise on SHD. Disability of headache by HIT-6 was assessed at the baseline and 3 months after initial visit. From 62 participants who kept the diary until the end of the study, diary data for 4,579 days were analyzed. Of these, 1,099 headache days (336 migraine, 763 non-migraine headaches) were recorded. Exercise as a risk factor for headache was listed in 3 patients on baseline survey and in 7 patients upon SA-E dairy. Headaches on the day with exercise were less impaired (disability 34% vs 50%, p=0.001) and less usage of abortive medication (51% vs 65%, p=0.0002), but had similar intensity and duration compared to the headache day without exercise by analysis using 1099 headache days. Worsening of HIT-6 score more than 1 point was present in 19.0% (8/42). Proportion of worsening of HIT-6 was less frequent among patient with GPA than those without GPA (14% vs. 20%, p0.001). GPA was not well performed among episodic migraineurs. This study suggested protective effect of exercise on disability of headache and no influence of headache on the exercise time.

Special Issue on Controversies in Neurology. From the 10th World Congress on Controversies in Neurology (CONy), Lisbon, Portugal. 17–20 March 2016.

International Journal of Clinical Neurosciences and Mental Health 2016; 3(Suppl. 1):P60

Icon_pdf Download PDF

Poster


Unmet sleep need is prevalent among migraineurs - read full article

By: Min Kyung Chu and Kyungmi Oh

Background: sleep disturbance is common among subjects with headache, especially migraine. Sleep disturbance is closely associated with sleep need, which may vary person to person. However, the association between individuals’ sleep need and migraine has not been reported. This study is to assess the association between migraine and unmet sleep need (USN) Methods: We selected a stratified random population sample of Koreans aged 19-69 and evaluated them by face-to-face interview using questionnaire. Sleep need was evaluated using a question “How many hours of sleep do you think is enough?” If a participant’s sleep need was more than her/his sleep duration, she/he was classified as having USN. Results: In a representative sample of 2,695 individuals, 1130 (41.9%) subjects and 143 (5.3%) subjects were classified as having non-migraine headache and migraine, respectively. 848 (31.5%) subjects were identified as having USN. The proportion of USN among migraineurs (48.3%) was significantly higher compared to non-headache controls (38.8%, p=0.031) or non-migraine headache (23.9%, p0.001). Among migraineurs, the proportion of USN was not significantly different among headache frequency of 1 attack per month (23/47, 48.9%), 1-10 attacks per month (44/80, 45.0%, p = 0.668) and 10 attacks per month (10/16, 62.5%, p = 0.351). Headache frequency, Visual Analogue Scale for headache intensity and Headache Impact Test Score were not significantly different between migraineurs with UNS and migraineurs without USN. Conclusions: Unmet sleep need is prevalent among migraineurs and is more frequently associated with migraine compared to non-migraine headache or non-headache controls.

Special Issue on Controversies in Neurology. From the 10th World Congress on Controversies in Neurology (CONy), Lisbon, Portugal. 17–20 March 2016.

International Journal of Clinical Neurosciences and Mental Health 2016; 3(Suppl. 1):P61

Icon_pdf Download PDF

Poster


Subjective cognitive symptoms during the migraine attack: a prospective study of a clinic based sample - read full article

By: Raquel Gil-Gouveia, A. Oliveira, and I. Martins

Background: A migraine attack aggregates a range of different symptoms, besides pain, that contribute to attack-related disability. Cognitive dysfunction is an unacknowledged part of the migraine attack. Objective: To provide a profile of the frequency and character of migraine attack-related cognitive symptoms occurring during the headache phase of the attack. Methods: We performed a cross-sectional survey of a clinic-based sample of sequential episodic migraine patients that were screened about the occurrence of cognitive symptoms during migraine attacks using an open-ended question followed by a self-fulfilled symptom checklist. Results: Of 165 migraine patients (15 males, age average 37.3 ± 10.7 years), 89.7% described cognitive symptoms during the headache phase of the migraine attack. On average 2.5±1.6 symptoms were reported per patient, uninfluenced by demographic or disease-related variables. The most common spontaneous symptoms related to executive functions, such as poor ability to concentrate (37%), difficulty in reasoning (25%) and thinking (23%). The pattern of responses on the symptoms checklist corroborated those reported spontaneously and quantitative scores of the checklist were higher in patients with spontaneous symptoms. Conclusions: This study detailed the frequency and characteristics of migraine attack-related subjective cognitive symptoms and found its frequency to be similar to reports of other migraine defining symptoms (e.g. nausea, photophobia) in recent clinical series. Patients’ reports were consistent and dominated by complaints of attention difficulties, diminished cognitive efficiency and processing speed impairment.

Special Issue on Controversies in Neurology. From the 10th World Congress on Controversies in Neurology (CONy), Lisbon, Portugal. 17–20 March 2016.

International Journal of Clinical Neurosciences and Mental Health 2016; 3(Suppl. 1):P62

Icon_pdf Download PDF

Poster


Evaluation of headache in children - read full article

By: Deniz Yilmaz, Didem Gokkurt, and Asli Celebi Tayfur

Objective: Although the majority of headaches are benign in children, they are still frightening for parents. The aim of this study was to determine headache types, associated symptoms, incidence of various triggers and the necessity of brain imaging techniques. Material and Methods: This study was performed on 3-17 year-old children with headaches from November 2014 to January 2015 who presented at a pediatric neurology clinic in Keçiören Education Hospital. The criteria defined by International Headache Society were used to classify the headache types. Results: One hundred patients were enrolled in this prospective study, 59 girls and 41 boys. The mean age on admission was 12.835±3.2084 years. The duration of headache was more than 2 years in 31% of patients. The types of headaches were comprised as follows: 58 cases of migraines, 26 cases of tension-type headaches, 15 cases of secondary headaches. Family history was present in 37 patients (44%) with primary headache. Six patients had cerebral magnetic resonance abnormalities. Conclusion: Headache is a very common complaint in children. The evaluation should include not only detailed history of children but also detailed general and neurological examinations. Brain imaging techniques are of limited value in the routine evaluation of headache.

Special Issue on Controversies in Neurology. From the 10th World Congress on Controversies in Neurology (CONy), Lisbon, Portugal. 17–20 March 2016.

International Journal of Clinical Neurosciences and Mental Health 2016; 3(Suppl. 1):P63

Icon_pdf Download PDF

Poster


Medicated photoprotective anticephalgic mask - read full article

By: Morton Hyson

A pre-medicated mask would serve not only as a delivery system for benign topical medication, but simultaneously provide photo relief and exert external pressure which may alleviate vascular headaches by collapsing painfully distended extracranial arteries and reducing peripheral sensitization. Thirty-three patients were given masks and tubes of topical medication containing the bryonia and rhus toxicodendron. They were instructed to apply the medication to their frontalis and/or temporalis regions in the event they should suffer a headache and apply a photoprotective mask. Furthermore, they were instructed to take their usual oral or parenteral medications if required for the relief of the headache. They subsequently filled out forms rating the degree of relief which they attributed to the topical medication and the mask using a 0-10 scale. At the interview following the completion of their participation in the study, the patients were also simply asked if this form of treatment helped or not. Thirty out of 33 patients stated the medication and the mask were effective over and above the normal degree of relief they were receiving from their oral and/or parenteral medications. This study demonstrated a significant efficacy rate (91%) in the treatment of migraine and/or tension headache with the anticephalgic mask in conjunction with a topical cream containing bryonia and rhus toxicodendron. This study demonstrated a significant efficacy rate in the treatment of migraine and/or tension headache with the anticephalgic mask in conjunction with a topical cream containing bryonia and rhus toxicodendron.

Special Issue on Controversies in Neurology. From the 10th World Congress on Controversies in Neurology (CONy), Lisbon, Portugal. 17–20 March 2016.

International Journal of Clinical Neurosciences and Mental Health 2016; 3(Suppl. 1):P64

Icon_pdf Download PDF

Poster


Clinical characteristics associated with the initial visits to emergency department in patients with migraine: a headache clinic-based study - read full article

By: Byung-Su Kim

Background: Migraine attack is common cause of the visits to emergency department (ED). The aim of this study is to investigate clinical characteristics associated with the initial visits to ED for migraine. Methods: This was a cross-sectional study using an outpatient headache-clinic registry from September 2014 to August 2015. Consecutive first-visit migraine patients aged ? 19 years were dichotomously classified according to visiting patterns: referral from ED vs. direct visit to headache clinic groups (ED vs. HC groups). Logistic regression analysis was conducted to evaluate the association of clinical characteristics of migraine patients referred from ED. Results: Of 257 patients (mean age: 43.6 ± 13.8 years, female: 76.7%) in this study, 38 (14.8%) were referred from ED during a 1-year period. Univariate analysis found that headache intensity (0–10 NRS), vomiting, and vestibular symptoms were associated with ED group, compared to HC group. In a multivariate-adjusted model, the odds ratios (95% CI) of headache intensity, vomiting, and vestibular symptoms for ED group were 1.31 (1.06–1.63), 2.60 (1.20–5.66), and 4.29 (1.84-10.00), respectively. Conclusions: Patients of ED group were likely to have more severe headache intensity, vomiting, and vestibular symptoms. Our study suggests that disabling characteristics of severe headache intensity or troublesome associated symptoms could be independent predictors for the initial visits to ED among migraine patients.

Special Issue on Controversies in Neurology. From the 10th World Congress on Controversies in Neurology (CONy), Lisbon, Portugal. 17–20 March 2016.

International Journal of Clinical Neurosciences and Mental Health 2016; 3(Suppl. 1):P65

Icon_pdf Download PDF

Poster


Electroacupuncture pretreatment at GB20 exerts anti-nociceptive effects via peripheral and central serotonin mechanism in conscious migraine rats - read full article

By: Lu Liu, P. Pei, L. Zhao, Z. Qu, and L. Wang

Background: While electroacupuncture (EA) pretreatment in migraine has been found to attenuate pain and frequencies of attacks, the mechanism of its anti-nociceptive effect remain poorly understood. Emerging evidence suggests that peripheral and central serotonin system may be involved in migraine. We hypothesized that EA would exert anti-nociceptive effects via modulation of serotonin system. Methods: We used a conscious migraine model induced by repeated electrical stimulation on the dural mater. Forty rats were randomly assigned to one of four groups: an EA group, which received EA at GB20 following dural stimulation; a sham acupuncture group, which received manual acupuncture at a non-acupuncture point following dural stimulation; a Model group, which received dural stimulation but no acupuncture; and a Control group, which received neither dural stimulation nor acupuncture. HomeCageScan was used to measure effects on the spontaneous nociceptive behaviors, radioimmunoassay and HPLC were used to investigate the expression of 5-HT in peripheral plasma and in the periaqueductal gray (PAG), rostroventromedial medulla (RVM), and trigeminal nucleus caudalis (TNC), three key structure of the descending pain modulatory system. Results: Our study showed that EA pretreatment could produce a significant reduction in resting, freezing and grooming, and a significant increase in exploration behavior. We found that the level of 5-HT in plasma were significantly increased, while significantly reduced in RVM, TNC in Model group. Furthermore, the above results were significantly reversed in EA at GB20. Conclusions: EA pretreatment exerts anti-nociceptive effects in a rat model of recurrent migraine, possibly via modulation of the serotonin system.

Special Issue on Controversies in Neurology. From the 10th World Congress on Controversies in Neurology (CONy), Lisbon, Portugal. 17–20 March 2016.

International Journal of Clinical Neurosciences and Mental Health 2016; 3(Suppl. 1):P66

Icon_pdf Download PDF

Poster


The effects of single and multiple curcumin doses on oro-facial pain in mice - read full article

By: A. Luca, T. Alexa, A. Negru, and C.R. Bohotin

Introduction: Curcumin protects from mitochondrial dysfunction and modulates endogenous antioxidant enzymes, by scavenging the ROS and NO-based radicals. The aim of our study was to assess if on the formalin-induced orofacial pain (OFP) in mice a single dose has the same efficiency as sub chronic administration. Materials and methods: 32 mice were divided into four groups group Cac received one dose curucmin, group C2w received curcumin daily for 2 weeks and two groups served as control and received an equal volume of olive oil (Group Oac and O2w). The curcumin (120 mg/kg b.w, dissolved in oil) and the oil were administrated by gastric gavage. After 2h in acute groups respectively 24h in subchronic groups 20?L formalin were injected into the whisker pad and the time mice spent rubbing/liking the injected area was recorded. The results for each phase was expressed as percentage of pain inhibition (PI). Results: For both OFP phases a single dose of curcumin had a strong analgesic effect when compared with control group (p=0.01). PI was 79% (phase I) respectively 51% (phase II). Subchronic treatment maintained curcumin analgesic effect for both phases (p=0.01 respectively p=0.01) with a PI of 34% respectively 45%. Conclusions: Our data demonstrates that curcumin has a strong analgesic effect on OFP induced by formalin but the long term treatment does not improve its analgesic propriety.

Special Issue on Controversies in Neurology. From the 10th World Congress on Controversies in Neurology (CONy), Lisbon, Portugal. 17–20 March 2016.

International Journal of Clinical Neurosciences and Mental Health 2016; 3(Suppl. 1):P67

Icon_pdf Download PDF

Poster


Botulinum toxin a for prophylaxis in chronic migraine in Korean patients - read full article

By: H.S. Moon, D.W. Namgung, W.T. Yoon, B.C. Suh, P.W. Chung, Y.B. Kim, Y.G. Jung, and W.H. Son

Botulinum toxin type A (BoNT-A) for the treatment of patients with chronic migraine (CM) has been studied, but there is a paucity of data in Korean patients. Our study was conducted to evaluate the efficacy of BoNT-A for the prophylaxis of CM in Korean adult patients. We retrospectively analyzed 65 patients who underwent BoNT-A treatment for CM at Kangbuk Samsung Hospital from Jan 2014 to Mar 2015. An injection in 31 sites according to the protocol of the PREEMPT study at the total dosage of 155 U/treatment. The efficacy analyses were based on the change from baseline in headache days/month, number of medication intake/month and Headache Impact Test (HIT)-6 score at week 12. Total 65 patients (mean age: 45.1.2±13.2, female/male ratio: 4.4:1) received BoNT-A injection for CM and 41 patients (63.1%) of them had medication overuse headache (MOH). Patients reported a significant decrease in headache days/month (pre 21.8± 5.5, post 12.8±7.1, P=0.001) and the number of medication intake (pre 21.8±5.5, post 11.9±6.9 P=0.001) after BoNT-A injections. Total HIT-6 score was decreased significantly after BoNT-A treatment (62.1± 10.0 vs 52.9±11.3 P=0.001). Thirty-five patients (53.8%) were 50% responder that at least a 50% decrease from baseline in the headache frequency. No difference were observed in a reduction in headache days/month and total HIT-6 score between patients with MOH and without MOH (p=0.635 and p=0.997). These results demonstrated that BoNT-A may be an effective treatment for CM in Korean patients. We can also expect the efficacy of BoNT-A treatment for patients with MOH.

Special Issue on Controversies in Neurology. From the 10th World Congress on Controversies in Neurology (CONy), Lisbon, Portugal. 17–20 March 2016.

International Journal of Clinical Neurosciences and Mental Health 2016; 3(Suppl. 1):P68

Icon_pdf Download PDF

Poster


Multidisciplinary approach to a common complaint—a rare cause of diplopia - read full article

By: A. Ponciano, C. Faria, J. Leite, and C. Fernandes

The etiology diagnosis of patient with diplopia is a clinical challenge. The presence of accompanying symptoms may also help in the investigation. Constant or intermittent pain and defects in visual acuity should be investigated and may correlate with neuromuscular dysfunction third cranial nerve injury, or orbital disease. A 82-year-old woman consulted the Emergency Department with a complaint of progressive binocular diplopia and proptosis with a 3-week evolution, with intermittent ocular pain episodes. There was no history of fever, weight loss or nocturnal sweating. Ophthalmologic examination revealed mild restriction of left eye abduction. External examination demonstrated proptosis of the left eye, soft tissue swelling in the upper and lower lids. The rest of the anterior and posterior segment examinations were unremarkable in both eyes. Enlarged, matted, and non-tender left axillary lymphadenopathy was also found. Further neurological and physical examination were completely normal. Brain Computed Tomography revealed a bilateral intra orbital mass suggestive of lymphoma and body Tomography showed multiple enlarged lymph nodes. Biopsy of the left axillary lymphadenopathy was performed and confirmed the diagnosis of follicular lymphoma, with immunohistochemical stains positive to CD20, CD79-?, Bcl-2 and Bcl-6. Follicular lymphoma is a subset of Non-Hodgkin’s lymphoma, characterized by B-cell proliferation, commonly affecting middle-aged to older adults. It is rare for this type of systemic non-Hodgkin`s lymphoma to infiltrate the ocular tissues and present with ocular complaints at presentation, mainly painless diplopia. With this case the authors want to give attention to the importance of multidisciplinary approach to diplopia.

Special Issue on Controversies in Neurology. From the 10th World Congress on Controversies in Neurology (CONy), Lisbon, Portugal. 17–20 March 2016.

International Journal of Clinical Neurosciences and Mental Health 2016; 3(Suppl. 1):P69

Icon_pdf Download PDF

Poster


Efficacy of LY2951742 in subgroups of patients with migraine of different frequency - read full article

By: V. Skljarevski, J. Martinez, T. Oakes, Y. Tanaka, Q. Zhang, M. Due, and A. Schacht

Background: In a recently reported study, LY2951742 significantly reduced the number of migraine headache days (MHD). The baseline frequency of MHD was 4 to 14 MHD per month. Objectives: To examine mean change in the number of MHD from baseline in subgroups of patients based on their baseline monthly frequency of MHD. Methods: The post-hoc analyses were conducted using data from a double-blind, phase 2a study in adult patients randomly assigned to LY2951742 or placebo for 12 weeks (NCT01625988). The primary endpoint was the mean change in the number of MHD during the last 28-day period. Subgroups were examined based on the number of MHD during the baseline period from 5 (i.e. ? 5 vs. 5 MHD) to 10. 50% response rates based on the number of MHD were also examined for the same subgroups. Findings: A total of 217 patients were randomized and received LY2951742 (n=107) or placebo (n=110). A significant difference from placebo was observed at month 3 from 1.5 days reduction from baseline in the number of MHD for the ? 5 MHD subgroup and continued to increase to 2.4 days reduction from baseline in the number of MHD for the ? 8 MHD subgroup. The increase in reduction of MHD failed to continue past the ? 8 MHD subgroup. Similarly, this trend was also observed when 50% response rates were examined for the same subgroups. Conclusion: LY2951742 effect appeared maximized for the high-frequency subgroup (? 8 MHD).

Special Issue on Controversies in Neurology. From the 10th World Congress on Controversies in Neurology (CONy), Lisbon, Portugal. 17–20 March 2016.

International Journal of Clinical Neurosciences and Mental Health 2016; 3(Suppl. 1):P70

Icon_pdf Download PDF

Poster


The association of cluster headache and symptomatic trigeminal neuralgia—case report - read full article

By: Zoran Vukojevic

Introduction: Cluster headache is characterised by unilateral, intermittent, recurrent, short-lived severe pain in orbito-temporal area along with unilateral autonomic symptoms (lacrimation, rhinorrhea). Painful attacks usually have circadian and circannual rhythmicity and they are rarely associated with trigeminal neuralgia. Case report: A 46-year old female patient had three episodes of cluster headaches which lasted for a month and were repeated biannually. The pain was in right orbitotemporal area, it was strong, sharp, occurred around 16:30 min., lasted for 15-30 min., repeated at 6-8 occasions and stopped around 23:30. During the pain attacks patient was experiencing ipsilateral lacrimation and nasal congestion (autonomic dysfunction). Patient was restless and constantly in motion. She was treated with prednisone and verapamil until the symptoms were gradually removed. Three months after the last episode she experienced severe, sharp pain in right side trigeminal nerve innervation (first and second branch) which intensified during speaking, chewing, face washing and touching. MRI and MRI angiography of the brain showed aberrant superior cerebellar artery which irritates proximal segments of right trigeminal nerve. She was successfully treated with oxcarbazepine and her pain was significantly reduced. Conclusion: Cluster headache has a characteristic clinical features and specific treatment in regard to other headaches. Occasionally cluster headaches are associated with symptomatic trigeminal neuralgia which makes them challenging in terms of differentiation and treatment.

Special Issue on Controversies in Neurology. From the 10th World Congress on Controversies in Neurology (CONy), Lisbon, Portugal. 17–20 March 2016.

International Journal of Clinical Neurosciences and Mental Health 2016; 3(Suppl. 1):P71

Icon_pdf Download PDF

Poster


Calcifying pseudotumor of the neuroaxis—a case report - read full article

By: R. Andrade Carmello, V. Rodrigues da Silva, M. Coutinho Studart, P.T. Galvão, J. Marcondes, L.M. Cardão Chimelli, and N. Henriques Silva Canedo

The calcifying pseudotumor of the neuroaxis (CAPNON) is a rare lesion affecting the central nervous system, still without a clear origin, both neoplastic and/or reactional processes being under consideration and investigation. It is considered benign and non-infiltrative, symptoms being associated with compression of the surrounding tissue. There are less than 60 cases reported worldwide, only one fourth located at the spinal cord. Our objective is to describe one of such cases due to its rarity and important differential diagnosis with neoplasia, where adjuvant treatment is eventually necessary, unlike CAPNON where excision is curative. A 31-year-old male with progressive paresis of the lower limbs for 9 years. CT at the beginning of the symptoms showed calcified intramedullar nodule at T8 level, measuring 1,9 x 0,9 x 0,6 cm. The lesion showed no growth in the period, but symptoms worsen and exeresis was performed. Gross appearance was of a soft mass covered by a calcified shell, and microscopic examination showed fibrous stroma surrounding highly pleomorphic epithelioid cells although no mitosis was identified. Osseous metaplasia was also extensively observed. Immunostaining showed EMA positivity and negative GFAP, CK pool and PR, eliminating carcinomas, gliomas and meningiomas as candidates. CAPNON must be considered a possible candidate when dealing with extensively calcified lesions of the SNC. Its morphology is extremely variable, and only a few of the aspects are generally present in every case. Immunohistochemistry and a benign evolution are fundaments of the diagnosis and help differentiating from neoplastic lesions.

Special Issue on Controversies in Neurology. From the 10th World Congress on Controversies in Neurology (CONy), Lisbon, Portugal. 17–20 March 2016.

International Journal of Clinical Neurosciences and Mental Health 2016; 3(Suppl. 1):P72

Icon_pdf Download PDF

Poster


Somatoform disorder presenting as psychogenic gait disorder - read full article

By: Hulya Apaydin and G. Benbir Senel

Introduction: Psychogenic movement disorders (PMD) could imitate any type of movement disorder (MD). Although MD specialists usually encounter less difficulty in recognizing patients with PMD, most patients seek medical help from different physicians and are exposed to many unnecessary treatments. PMD diagnosis is based on the exclusion of organic disorders. Detailed medical history and neurological examination usually aid the correct diagnosis./h2 Case report: A 27-year-old man was admitted to our outpatient MD clinics complaining of difficulty in maintaining his posture due to involuntary movements of the right leg. His symptoms have started almost 10 years ago with a sudden-onset, showed gradual increase during his military service. He also complained of sudden jerky tremor-like movements in his arms and legs, which appear and disappear periodically. He was diagnosed to have parkinsonism and chorea in different centers and given multiple drugs including levodopa, dopamine agonists, antipsychotics and benzodiazepines with no benefit. Neurological examination revealed bizarre atypical right leg movement occurring randomly with partial distractibility and exaggerated postural tremor. When he was asked to imitate his tremor-like movements he mentioned, he performed tic-like jerky erratic movements all over his body. He was diagnosed as having PMD, and consulted with psychiatry and had the diagnosis of somatoform disorder. Discussion: Bizarre, unusual or uneconomic movements performed with exaggerated efforts, together with distractibility, should suggest psychogenic origin. Currently, based on the detailed evaluation of PMD patients’ history and clinical signs, clinicians should be aware of specific clinical properties of PMD that differentiates them from other organic disorders.

Special Issue on Controversies in Neurology. From the 10th World Congress on Controversies in Neurology (CONy), Lisbon, Portugal. 17–20 March 2016.

International Journal of Clinical Neurosciences and Mental Health 2016; 3(Suppl. 1):P73

Icon_pdf Download PDF

Poster


Short-interval intracortical inhibition is decreased in patients with restless legs syndrome - read full article

By: Adriana Conforto, Joselisa Paiva, Gilmar do Prado, Edson Amaro Jr., Alan Eckeli, and Samir Magalhães

Introduction: GABAergic dysfunction in the motor cortex may be involved in the pathogenesis of Restless Legs syndrome. Decrease in short-interval intracortical inhibition (SICI) to transcranial magnetic stimulation (TMS) is considered a marker of GABAergic dysfunction, and has been described in patients with RLS. It is unknown if there is a correlation between abnormal SICI and severity of symptoms. Objectives: To compare SICI in patients with primary RLS and healthy subjects, and to evaluate a correlation between SICI and severity of RLS symptoms. Methods: Patients (n=33) and controls (n=24) underwent clinical evaluation and TMS testing. EMG was recorded from the dominant abductor digitus minimi (ADM). Severity of symptoms was assessed by the International RLS Severity Scale (IRLSS). RLS patients were grouped by IRLSS scores (mild/moderate [IRLSS20] or severe/very severe [IRLSS?20). SICI was compared in subjects with RLS and controls with Mann-Whiteny tests. The correlation between IRLSS and SICI in patients was investigated with Spearman´s rho. Results: There were no significant differences in age, gender, handedness, resting or active motor thresholds between patients with RLS and control subjects. Mean SICI (average ± standard deviation) was significantly deeper in controls (19.3±57.8%) than in patients (50.1±14.6%; p-value 0.001). The correlation between depth of SICI and IRLSS was not statistically significant. Discussion: Our work included the largest sample of patients with RLS reported until now. The results support the presence of a dysfunction in GABAa interneurons in the motor cortex in RLS.

Special Issue on Controversies in Neurology. From the 10th World Congress on Controversies in Neurology (CONy), Lisbon, Portugal. 17–20 March 2016.

International Journal of Clinical Neurosciences and Mental Health 2016; 3(Suppl. 1):P74

Icon_pdf Download PDF

Poster


Psychogenic facial movement disorder: a case report - read full article

By: Eren Gozke, Boran Saracoglu, Mustafa Eser, Aylin Reyhani, and Pelin Dogan Ak

Introduction: Psychogenic facial movement disorders (PFMD) can be confused with movement disorders of organic origin. Herein, a case misdiagnosed as peripheral facial paralysis (PFP) is presented together with video demonstrations. Case: A 44-year-old female patient was evaluated because of bending of her mouth developed 4 days ago. Cranial MRI performed in another hospital did not demonstrate any abnormality, and steroid therapy was initiated with the diagnosis of PFP by them. The patient presented to us because of bending of the mouth did not resolve completely. She had hypertension, diabetes, and depression. She was using indapamide, metformin, and citalopram. Neurologic examination revealed flattening of nasolabial fold which disappeared during talking and downward retraction of the contralateral edge of the mouth. She could close her eyes completely, and other neurologic examination results were not remarkable. EMG findings were normal. Fluctuant flattening of nasolabial fold, and the impression of downward retraction of one side of the mouth suggested PFMD. Her steroid therapy was discontinued, and treatment with alprozolam was initiated. A prominent resolution of her complaints was observed during posttreatment follow-up control visits. Conclusion: In all patients with PFMD phasic or tonic muscle contractions mimicking distonia can be seen. Most frequently downward retraction of the lip is seen. In nearly half of the patients symptoms follow a paroxysmal pattern. Usually involvement of one side is seen, however affected side may change. Extreme contractions can result in painful episodes. We wanted to present this case because it is especially confused with PFP.

Special Issue on Controversies in Neurology. From the 10th World Congress on Controversies in Neurology (CONy), Lisbon, Portugal. 17–20 March 2016.

International Journal of Clinical Neurosciences and Mental Health 2016; 3(Suppl. 1):P75

Icon_pdf Download PDF

Poster


Substantia nigra hyperechogenicity and motor severity in Parkinson’s disease: is there an association? - read full article

By: J. Jesus-Ribeiro, J. Sargento-Freitas, M. Sousa, F. Silva, A. Freire, and C. Januário

Introduction: The evaluation of hyperechogenicity of the substantia nigra (SN) by transcranial sonography (TCS) is validated for the diagnosis of Parkinson’s disease (PD). However, its correlation with the severity of motor involvement is still uncertain. Methods: We included patients with clinical diagnosis of idiopathic PD in a cross-sectional study. All patients were evaluated with Unified Parkinson’s Disease Rating Scale-motor score (UPDRS-III) and TCS at the same day with measurement of the area of SN hyperechogenicity for each side. We analysed the association between the area of SN hyperechogenicity and the contralateral motor scores of UPDRS-III, adjusting for age and dominance of the patient (statistical significance set to p=0.05). Results: 35 patients were analysed, 3 (8.6%) were excluded due to poor temporal acoustic bone window. From a total of 32 patients, the mean age was 58.4 (±11.2) years. The mean area of hyperechogenicity was 0.31cm2 (±0.1) and the mean score of UPDRS-III was 18.9 (±6.1). There were no statistically significant correlation between the scores of the UPDRS-III (rigidity, tremor and bradykinesia) and the area of SN hyperechogenicity contralateral. Conclusion: The area of SN hyperechogenicity did not correlate with motor deterioration in Parkinson’s disease.

Special Issue on Controversies in Neurology. From the 10th World Congress on Controversies in Neurology (CONy), Lisbon, Portugal. 17–20 March 2016.

International Journal of Clinical Neurosciences and Mental Health 2016; 3(Suppl. 1):P76

Icon_pdf Download PDF

Poster


Parkinson’s disease and factors influencing the quality of the dyadic relationship - read full article

By: Michaela Karlstedt, S.M. Fereshtehnejad, D. Aarsland, and J. Lökk

Objectives: The aim of this project is to explore how the quality of the dyadic relationship (mutuality) is affected by motor and non-motor symptoms, other perceived difficulties and quality of life (HRQoL) when one person in the dyad is having Parkinson´s disease (PD). Methods: Fifty dyads (age m=70.5[SD=8.5], PD-duration m=8.6[SD=6.6], Hoehn & Yahr md=2[IQR=1]) completed validated scales measuring mutuality (MS), caregiver burden (CB), caring difficulties (CADI), depression (GDS) and HRQoL (PDQ8). Spearman´s correlations were used to evaluate univariate associations. To investigate multivariate associations between independent factors and mutuality, multiple regression analysis was used. Results: Partner mutuality score was significantly associated with CB (rho=-0.69), CADI (rho=-0.61), partner GDS (rho=-0.52), patient MS (rho=0.49), patient GDS (rho=-0.42), and PDQ8 (rho=-0.38). Partner mutuality score did not strongly correlate with motor (rho=-0.24) and non-motor symptoms (rho=-0.24) or disease duration (rho=-0.11). Instead CADI, GDS, PDQ8, CB and patient MS score explained 62 % of the variance in partner mutuality. Of the included variables CADI and patient MS score showed the largest contribution (standardized beta=-0.43, p =.043 vs beta=0.35, p=0.005). Conclusion: Findings suggest that higher experience of carer difficulties and patient experience of mutuality may exert an effect on partner mutuality in care-dyads with mild to moderate PD. This ongoing longitudinal study aims now to explore how the course of PD affects mutuality, CB and HRQoL from the perspective of the care-dyad.

Special Issue on Controversies in Neurology. From the 10th World Congress on Controversies in Neurology (CONy), Lisbon, Portugal. 17–20 March 2016.

International Journal of Clinical Neurosciences and Mental Health 2016; 3(Suppl. 1):P77

Icon_pdf Download PDF

Poster


Parkinson’s disease patients’ willingness to pay for a new drug - read full article

By: Johan Lökk, S. Olofsson, and U. Persson

Objective/Aim: The expected value to the consumer can be measured using willingness to pay (WTP). To assess Parkinson´s disease (PD) patients´ WTP for newly developed microtablets of levodopa in combination with a drug delivering electronic device (M/E) compared to standard treatment with levodopa in combination with the COMT-inhibitor entacapone (L/e). Method: 2000 PD patients had a questionnaire on views on medication and WTP in 3 different hypothetical scenarios:1/ no change in effects or side effects; 2/ same effect and less side effects; 3/ improved effect and less side effects. These scenarios were coupled to different costs to choose from. Results: 50 % responded, mean age of 71 years and a mean PD duration of 9 years. 50% preferred M/E before L/e in scenario one with increasing preference to scenario three. The average monthly WTP among all respondents in scenario one was SEK 230 and SEK 226 in L/e, both with an almost longitudinal doubling up to scenario three. Duration of PD related symptoms, high education and high medication intake implied a higher WTP in all scenarios in contrast to age, gender, extra doses of levodopa. Conclusion: WTP for M/E increased gradually with high medication intake and education as well as with expected increased reduction of PD symptoms.

Special Issue on Controversies in Neurology. From the 10th World Congress on Controversies in Neurology (CONy), Lisbon, Portugal. 17–20 March 2016.

International Journal of Clinical Neurosciences and Mental Health 2016; 3(Suppl. 1):P78

Icon_pdf Download PDF

Poster


Spinal cord imaging in spastic paraparesis: are we cutting it thin enough? - read full article

By: C. Lopes, R. Soares-dos-Reis, L. Braz, J. Dias da Costa, and J. Guimarães

Introduction: Spinal dural arteriovenous fistula (SDAVF) is a rare condition, but accounts for great disability in those affected. Despite improvements in spinal imaging, SDAVF diagnosis is often difficult or masked by more common entities. Case report: A 42 year-old-woman, with a history of ileal resection 4 years prior, presented with a 6-month course of progressive walking difficulty, denying any sensory or bladder complaints. Physical examination revealed spastic paraparesis, brisk deep-tendon reflexes in the lower limbs, bilateral Babinsky sign and bilateral foot drop. Blood chemistry was normal except for low vitamin B12 levels. Her electromyogram was compatible with sensorimotor axonal polyneuropathy and cervico-dorso-lumbar spinal MRI was normal. Parenteral cyanocobalamin supplementation was initiated and the patient was discharged with a diagnosis of polyneuropathy and probable subacute combined degeneration. In the following months, the patient’s polyneuropathic gait improved, but the spastic paraparesis was unchanged. Repeat spinal cord MRI was reported as normal. Given the lack of improvement, a SDAVF was suspected. 3T Spinal MR-angiography was performed using 0.9 mm sections, revealing dilated vessels in the spinal periphery from T11 to L2 levels. Digital subtraction angiography confirmed the diagnosis and the patient is currently waiting surgery. Conclusion: We describe a case of a SDAVF with superimposed vitamin B12 deficiency, whose diagnosis required extra-thin cuts of MR-angiography. SDAVFs are potentially reversible causes of myelopathy, thus emphasizing the importance of their early identification.

Special Issue on Controversies in Neurology. From the 10th World Congress on Controversies in Neurology (CONy), Lisbon, Portugal. 17–20 March 2016.

International Journal of Clinical Neurosciences and Mental Health 2016; 3(Suppl. 1):P79

Icon_pdf Download PDF

Poster


Creatine food supplementation improves the phenotype and delays disease onset of the CMVMJD135 mouse model of Machado-Joseph disease - read full article

By: S. Duarte-Silva, A. Neves-Carvalho, J. Silva, A. Silva-Fernandes, and P. Maciel

Machado-Joseph disease (MJD) is an autosomal dominant neurodegenerative disorder caused by the expansion of a polyglutamine tract (polyQ) in the C-terminus of the ATXN3 gene product, ataxin-3. Mitochondrial dysfunction has been implicated in several neurodegenerative diseases. Creatine administration increases brain concentrations of phosphocreatine and an inactivation of the mitochondrial permeability pore, exerting neuroprotective effects. Here we performed two pre-clinical trials – PCT1 and PCT2 - using the CMVMJD135 mouse model of MJD (groups of animals with a 133 and 139 CAG repeat mean respectively), to which creatine 2% supplemented food was provided either for 19 (PCT1) or 29 (PCT2) weeks. Oral administration of creatine led to an overall improvement in the motor phenotype of CMVMJD135 mice on both trials. Interestingly, in PCT1, with shorter creatine treatment duration but with less disease severity, the muscular strength deficits of the CMVMJD135 were improved, while in PCT2, corresponding to a longer treatment but a high severity disease condition those improvements were not so evident. Creatine-treated animals did, however, show improvement in both trials in motor coordination, limb strength and gait quality, as well as in other neurological parameters. Creatine chronic treatment delayed the onset of several symptoms and, in some cases, completely abolished the appearance of the phenotype. Furthermore, creatine treatment showed to be neuroprotective by increasing the calbindin staining in the Purkinje cell layer and reducing the astrogliosis in the brainstem of the CMVMJD135 mice. The present findings support creatine supplementation as a useful strategy to slow the progression of MJD.

Special Issue on Controversies in Neurology. From the 10th World Congress on Controversies in Neurology (CONy), Lisbon, Portugal. 17–20 March 2016.

International Journal of Clinical Neurosciences and Mental Health 2016; 3(Suppl. 1):P80

Icon_pdf Download PDF

Poster


Lower motor neuron syndrome, anti-MAG neuropathy and Waldenström macroglobulinemia: Occam’s razor versus Hickam’s dictum - read full article

By: Inês Rosário Marques and M. Grunho

Background: Diseases selectively involving lower motor neurone (LMN) dysfunction have a limited differential diagnosis, including spinal muscular atrophies and motor neuropathies. Around 8-10% of patients who are initially diagnosed with motor neuron disease (MND) will eventually be found to have a different underlying condition. Others will turn out to have more than one. Case report: A 73-year-old caucasian male presented with progressive right upper limb (RUL) paresis with muscle atrophy and fasciculations. He was diagnosed with monomelic MND and started on riluzole. In the following years he developed RUL numbness, gait unsteadiness, left foot drop, and severe weight loss. He presented to us in 2015 with ongoing worsening of the symptoms. His neurological examination revealed tongue fasciculations, dysphagia and dysphonia, shoulder girdle and RUL atrophy with fasciculations, areflexic quadriparesis (RUL and left foot predominance), hypoesthesia and hypopallesthesia of RUL and distal lower limbs, overall suggestive of LMN syndrome and peripheral neuropathy. EMG was compatible with MND and sensorimotor polyneuropathy. Blood tests revealed an IgM kappa gammopathy with positive anti-MAG antibodies, and the myelogram confirmed Waldenstrom`s Macroglobulinemia (WM). The patient currently awaits chemotherapy initiation. Discussion: We present an interesting and controversial clinical case comprising three rare disorders concurring in the same patient, in a paradigmatic example of a diagnostic conundrum. Following the principle of Hickam`s dictum, could it be just an unfortunate coincidence? Alternatively, based on Occam`s razor, and according to published data, both LMN syndrome and anti-MAG neuropathy may represent different manifestation of WM and thus constitute a single disease.

Special Issue on Controversies in Neurology. From the 10th World Congress on Controversies in Neurology (CONy), Lisbon, Portugal. 17–20 March 2016.

International Journal of Clinical Neurosciences and Mental Health 2016; 3(Suppl. 1):P81

Icon_pdf Download PDF

Poster


Clinical manifestations of chemoradiotherapy-induced parkinsonism - read full article

By: Yoshitaka Narita, Yasuji Miyakita, Makoto Ohno, and Masamichi Takahashi

Objectives: Parkinsonism is a rare complication of chemoradiotherapy for high-grade gliomas, but the clinical manifestations were not fully understood. We examined cases of severe Parkinsonism after chemoradiotherapy for high-grade gliomas. Methods: Chemoradiotherapy-induced Parkinsonism was defined as Parkinsonism occurring after chemoradiotherapy in glioma patients without initial presentation of Parkinsonism. Two hundred forty-three patients with high-grade gliomas have been treated in our hospital from 2006 until 2015. Our basic protocol for high-grade gliomas consists of maximum safe resection and chemoradiotherapy with temozolomide. Age, tumor location, histology, initial symptoms, KPS, treatment, radiation dose, and chemotherapy for each patient were reviewed from clinical records. Results: Two hundred forty-three patients with high-grade glioma were treated in our center using temozolomide-based chemoradiotherapy. Ten patients without any hemiparesis were diagnosed with severe Parkinsonism with Yahr stage IV. The median age at initial treatment was 62.0 years, and the male:female ratio was 7:3. The median time from initial treatment to the diagnosis of Yahr stage IV was 23.8 months. Five patients (50%) presented severe Parkinsonism within 2 years from the initial treatment, whereas 2 patients presented it 3 years after the initial treatment. Among 173 patients who survived more than one year, 10 patients (5.8%) presented severe Parkinsonism. Five patients had frontal tumors, and 4 patients had parietal tumors. Three of them received dopamine therapy, but their symptoms were not completely relieved. Conclusions: Severe Parkinsonism after chemoradiotherapy is more common than expected and there is no effective treatment. Further examination is necessary to elucidate these clinical manifestations.

Special Issue on Controversies in Neurology. From the 10th World Congress on Controversies in Neurology (CONy), Lisbon, Portugal. 17–20 March 2016.

International Journal of Clinical Neurosciences and Mental Health 2016; 3(Suppl. 1):P82

Icon_pdf Download PDF

Poster


Shape analysis of subcortical structures in idiopathic rapid eye movement sleep behavior disorder - read full article

By: Shady Rahayel, J. Montplaisir, C. Bedetti, R.B. Postuma, S. Brambati, J. Carrier, O. Monchi, and J.F. Gagnon

Idiopathic rapid eye movement sleep behavior disorder (iRBD) is considered as a risk factor for the development of Parkinson`s disease. Structural brain abnormalities preceding onset of motor signs in Parkinson`s disease remain poorly understood and iRBD offers one way to better understand Parkinson`s disease in its preclinical stages. In iRBD, gray matter abnormalities involve both volume and cortical thickness. Another technique, vertex-based shape analysis, allows for quantification of surface differences in subcortical structures and overcomes some limitations of voxel-based measures. No study has yet studied shape of subcortical structures involved in cortico-subcortical loops in iRBD patients. Forty-one patients with iRBD and 41 controls underwent MRI examination. Voxel-based morphometry (VBM) was used to investigate local gray matter volume. Subcortical structures (i.e., putamen, caudate nucleus, globus pallidus, and thalamus) were studied for global volume and shape. VBM shows gray matter volume reductions in the frontal and insular lobes and the basal ganglia. Surface-based volumetric analysis shows reduced volume of the right putamen and the left globus pallidus. Shape analysis shows 2 clusters of abnormal surface displacement in the left putamen on the medial and lateral surfaces representing surface contraction and surface expansion. In summary, patients with iRBD present with shape and global volume abnormalities in the putamen and globus pallidus, along with local reductions of gray matter volume in the frontal lobes.

Special Issue on Controversies in Neurology. From the 10th World Congress on Controversies in Neurology (CONy), Lisbon, Portugal. 17–20 March 2016.

International Journal of Clinical Neurosciences and Mental Health 2016; 3(Suppl. 1):P83

Icon_pdf Download PDF

Poster


Analysis of GTP cyclohydrolase I gene (GCH1) by multiplex ligation-dependent probe amplification (MLPA) for diagnosis of Segawa disease - read full article

By: Haruo Shintaku, Hiroki Fujioka, Satoshi Kudo, Tomoko Sakaguchi, and Takashi Hamazaki

Objective: To evaluate the efficacy in diagnosis of Segawa disease by using MLPA (Multiplex Ligation-dependent Probe Amplification) method which can detect large deletions in patients who have no mutations by the direct sequencing method. Patients and Methods: We diagnosed 25 patients with Segawa disease by clinical symptoms and pteridines analysis in cerebrospinal fluid (CSF). Among 25 patients with Segawa disease 22 patients were confirmed genetically by direct gene analysis of GCH1. In the other 3 patients we performed gene analysis by using MLPA methods. Results: All 25 patients with Segawa disease showed significantly lower levels of both neopterin (N:6.59±4.09 nM) and biopterin (B:5.20±2.85 nM) in CSF than controls (N:19.5±2.10, B:23.7±8.50 nM). Twenty-two patients diagnosed by direct sequencing method had a point mutation or two bases deletion in one allele and the other 3 patients had a large deletion in their one allele which detected by MLPA method. Both N and B levels in CSF were significantly lower in the former 22 patients (N:6.92±3.92, B:5.58±2.74 nM) than in the latter 3 patients (N:1.98±0.94, B:1.67±1.46 nM). Conclusions: All patients with Segawa disease had very low N and B levels in CSF. Especially patients who had large deletion showed significantly lower levels of both N and B in CSF than the other patients who had a point mutation or 2 bases deletion. Patients suspected to be Segawa disease who had very low N and B levels in CSF should be analyze GCH1 gene by MLPA method.

Special Issue on Controversies in Neurology. From the 10th World Congress on Controversies in Neurology (CONy), Lisbon, Portugal. 17–20 March 2016.

International Journal of Clinical Neurosciences and Mental Health 2016; 3(Suppl. 1):P84

Icon_pdf Download PDF

Poster


Hereditary spastic paraplegia in a Filipino family: a case report - read full article

By: P. Ruth Siongco and Raymond Rosales

This is a case of a 50 year-old, male, from Bulacan, Philippines, who consulted due to difficulty in ambulation. His symptoms started with numbness of his left lower extremity that was aggravated by prolonged standing and relieved by rest. In 2012, he had lumbosacral pain and difficulty sitting and standing requiring assistance. He had difficulty in articulation and dysphagia. His weakness progressed involving his right lower extremity. He was hesitant to initiate a step, ambulated more slowly, had smaller steps, and a slightly wide-based gait. On ambulation, he had difficulty flexing his thigh muscle. He had a reduced sense of balance and a tendency to fall. There were no bowel and bladder disturbances. He consulted a neurosurgeon, where a series of neuroimaging studies of the spine revealed normal results. On examination, his cognitive function was intact with no memory disturbances. Visual acuity: 20/50 for both eyes, there was sensorineural hearing loss on his left ear, moderate dysarthria on pharyngeal sounds. He had normal muscle bulk, with spasticity on all extremities more profound on the left. He had left-sided hemiparesis, dysdiadochokinesia on both left extremities. Romberg’s sign positive. He had a crouch gait, wide-based stance, decreased cadence, and shortened step length. He had difficulty initiating a step and flexing his thighs. He was hyperreflexive on all extremities with Babinski and ankle clonus, bilateral. **Blood samples of the family were sent for genetic workup.

Special Issue on Controversies in Neurology. From the 10th World Congress on Controversies in Neurology (CONy), Lisbon, Portugal. 17–20 March 2016.

International Journal of Clinical Neurosciences and Mental Health 2016; 3(Suppl. 1):P85

Icon_pdf Download PDF

Poster


The effect of propofol and fentanyl on microelectrode recording and its clinical applicability during subthalamic nucleus deep brain stimulation surgery - read full article

By: Inho Song, Sung Keun Yoo, Jin Hee Moon, and Sun Ha Paek

We investigated the influence of propofol and fentanyl on microelectrode recording (MER) and its clinical applicability during subthalamic nucleus (STN) deep brain stimulation (DBS) surgery. We analyzed 8 patients with Parkinson`s disease, underwent bilateral STN DBS with MER. Their left sides were done under awake and then their right sides were done with a continuous infusion of propofol and fentanyl under local anesthesia. The electrode position was evaluated by preoperative MRI and postoperative CT. The clinical outcomes were assessed at six months after surgery. We isolated single unit activities from the left and the right side MERs. There was no significant difference in the mean firing rate between the left side MERs (38.7±16.8 spikes/sec, n=78) and the right side MERs (35.5±17.2 spikes/sec, n=66). The bursting pattern of spikes was more frequently observed in the right STN than in the left STN. All the electrode positions were within the STNs on both sides and the off-time Unified Parkinson`s Disease Rating Scale part III scores at six months after surgery decreased by 67% of the preoperative level. In this study, a continuous infusion of propofol and fentanyl did not significantly interfere with the MER signals from the STN. The results of this study suggest that propofol and fentanyl can be used for STN DBS in patients with advanced Parkinson`s disease improving the overall experience of the patients.

Special Issue on Controversies in Neurology. From the 10th World Congress on Controversies in Neurology (CONy), Lisbon, Portugal. 17–20 March 2016.

International Journal of Clinical Neurosciences and Mental Health 2016; 3(Suppl. 1):P86

Icon_pdf Download PDF

Poster


The effect of botox treatment in blepharospasm—an MRI pilot study - read full article

By: N. Szabó, G. Csete, E. Tóth, A. Király, P. Faragó, K. Kocsis, L. Vécsei, P. Klivényi, and T. Kincses

The pathophysiology of the blepharospasm (BPS) and the central effect of botulinum?neurotoxin (BNT) are poorly understood. The basal ganglia-thalamocortical motor circuit is thought to have a role in BPS and we suppose that BTN might have an influence on it. Ten BPS patients went under MRI scan before and after the regular BNT treatment. High resolution T1 weighted images, diffusion-weighted images and resting state functional MRI were done. The size, the structural and functional connectivity and diffusivity parameters of the basal ganglia were investigated with new MRI analytic methods. After BNT treatment the size of the left thalamus decreased in the antero-lateral region (pcorr. =0.0144). This affected region showed connection to the motor-premotor pathways, to the frontal cortex and to the cerebellum. No microstructural alterations of the white matter were found. Using the identified regions with tractography as seeds, functional connectivity analysis showed enhanced activity in the frontal lobe after BNT treatment. Also, the whole brain resting state functional MRI showed a partial restoration in visual component coherency (p=0.0266). Diffusivity parameters of the basal ganglia showed hemispheric differences after the BNT treatment. Our study supports the hypothesis that BNT treatment could generate functional and structural changes in the brain. Furthermore these results also serve an evidence for the crucial role of the deep brain structures in the pathophysiology of the dystonia and suggest, that BNT has a central effect and might due to plastic changes.

Special Issue on Controversies in Neurology. From the 10th World Congress on Controversies in Neurology (CONy), Lisbon, Portugal. 17–20 March 2016.

International Journal of Clinical Neurosciences and Mental Health 2016; 3(Suppl. 1):P87

Icon_pdf Download PDF

Poster


Investigation of vitamin D receptor (VDR) gene polymorphisms in sporadic amyotrophic lateral sclerosis - read full article

By: N. Török, R. Török, P. Klivényi, J. Engelhardt, and L. Vécsei

Background: There are aberrations in vitamin D–endocrine system in sporadic amyotrophic lateral sclerosis (SALS). Vitamin D deficiency and the rise of the levels of calcium and parathormon were measured in the sera of ALS patients. Diverse proteins were identified which link vitamin D to the theories of the selective degeneration of motor neurons too, albeit alterations of the VDR gene have not been reported. Objective: Our aim was to investigate the single nucleotide polymorphisms of VDR gene in SALS patients in Hungary. Methods: 75 SALS patients and 97 healthy controls were enrolled to reveal the supposed different proportion of the alleles of the VDR receptor. Restriction fragment length polymorphism was used. For data analysis, SPSS software version 20.0 was utilized. Results: ApaI SNP was associated with the disease (?2 = 11.09; P = 0.004), the A allele of this SNP proved to be significantly associated with the ALS group (?2 = 5.352, df = 1, P = 0.021, OR = 0.600, 95% CI = 1.080–2.569) so it may be an ALS risk factor. None of the investigated alleles influenced the age at disease onset. Conclusions: One allele of the examined polymorphisms of the VDR gene (ApaI A allele) seems to be a risk factor in the Hungarian SALS population. However, due to the low number of cases, another study from the Central European region is needed. To our knowledge, this is the second described VDR SNP investigation in this devastating disease.

Special Issue on Controversies in Neurology. From the 10th World Congress on Controversies in Neurology (CONy), Lisbon, Portugal. 17–20 March 2016.

International Journal of Clinical Neurosciences and Mental Health 2016; 3(Suppl. 1):P88

Icon_pdf Download PDF

Poster


Vascular degeneration in Parkinson’s disease - read full article

By: Panzao Yang, H.J. Waldvogel, R.L.M. Faull, M. Dragunow, and J. Guan

We have previously reported endothelial cell degeneration in Parkinson’s disease (PD) brain. The current study examined the changes of the function of the blood brain barrier (BBB), potential impairment of vascular remodelling and their association with vascular and neuronal degeneration in PD. The present study used the grey matter of middle frontal gyrus from post-mortem human PD brain and age-matched control cases where there was a significant neuronal degeneration in PD. Immunohistochemical staining of collagen IV for basement membrane (BM), platelet-derived growth factor receptor-beta (PDGF?R) for pericytes, NeuN for neurons, proliferating cell nuclear antigen (PCNA) for proliferation of endothelial cells, vascular endothelial growth factor (VEGF), fibrinogen for BBB function and phosphorylated insulin-like growth factor 1 receptor (IGF1Rp) were observed and quantified. Compared to controls, the BM was remained in PD leading to an increase in string vessels and there was no PD associated leakage of BBB. VEGF-positive neurons and pericyte-positive capillaries in PD were reduced with significant loss of vascular PCNA-positive cells. The trend toward reduction in vascular IGF1Rp-positive cells in PD was correlated with the decrease of vascular PCNA-positive cells. In conclusion, increased string vessel formation and maintained BBB may suggest the role for hypoperfusion in disease progress of PD rather than the BBB dysfunction associated neurodegeneration. The endothelial cell degeneration may be associated with impaired vascular remodelling due to the loss of trophic support from growth factors.

Special Issue on Controversies in Neurology. From the 10th World Congress on Controversies in Neurology (CONy), Lisbon, Portugal. 17–20 March 2016.

International Journal of Clinical Neurosciences and Mental Health 2016; 3(Suppl. 1):P89

Icon_pdf Download PDF

Poster


Arachidoyl-2’-chloroethylamide, a selective cannabinoid cb1 receptor agonist combined with valproate stimulates hippocampal neurogenesis in a mouse pilocarpine model of epilepsy - read full article

By: Marta Andres-Mach, A. Haratym-Maj, M. Zagaja, R. Rola, M. Maj, and J.J. LuszczkI

Rational polytherapy in the treatment of refractory epilepsy has been a main therapeutic modality for several years. Considering the treatment with two or more antiepileptic drugs (AEDs) it is of particular importance that the AEDs should be selected based on their high anticonvulsant properties but also high level of neuroprotection as well as minimal side effects. The aim of the study was in vivo evaluation of the relationship between treatment with synthetic cannabinoid arachidonyl-2´-chloroethylamide (ACEA) in combination with valproate (VPA) and hippocampal neurogenesis in a mouse pilocarpine model of epilepsy. All experiments were performed on adolescent CB57/BL mice. The following drugs were used: VPA, ACEA, phenylmethylsulfonyl fluoride (PMSF), pilocarpine (PILO), methyloscopolamine. We evaluated long term response to ACEA and VPA administration (BrDU, Neun, GFAP staining). Confocal microscopy and cell counting was done using Zeiss microscope and ImageJ software. Obtained results indicated clear decrease of neurogenesis in PILO control group compare to the non-PILO control mice. Moreover, ACEA with PMSF administered alone and in combination with VPA had a significant impact on neurogenesis increasing the total number of BrDU, particularly neurons (NeUN) comparing to the control group, whereas VPA administered alone significantly reduces the total number of NeUN/BrDU-positive cells compare to the control group. ACEA combined with VPA stimulates the process of neurogenesis, while chronic administration of VPA itself decreases neurogenesis in a mouse pilocarpine model of epilepsy. Obtained results make possible in vivo determination of the neurogenesis after antiepileptic drugs treatment.

Special Issue on Controversies in Neurology. From the 10th World Congress on Controversies in Neurology (CONy), Lisbon, Portugal. 17–20 March 2016.

International Journal of Clinical Neurosciences and Mental Health 2016; 3(Suppl. 1):P90

Icon_pdf Download PDF

Poster


Adults with epilepsy: cognitive impairment relationships with clinical aspects and quantitative EEG - read full article

By: L. Fonseca, G. Tedrus, R. Ballarin, L. Negreiros, and T. Marques

Introduction: Cognitive impairment frequently occurs in patients with epilepsy (PWE), but its pathophysiological basis is not well known. This study assessed cognition and its correlations with the clinical aspects and EEG coherence of PWE. Methods: Eighty patients with epilepsy seen consecutively at PUC-Campinas and 40 normal subjects (CG) were assessed by neurological evaluation, Mini-mental Status Examination, immediate and delayed recall of 10 simple figures, phonemic verbal fluency (FAS), clock drawing, and EEG. The mean global inter- and intrahemispheric coherences for the delta, theta, alpha and beta bands were calculated. Cognitive functions and EEG coherence of PWE and the CG were compared, and logistic regression analysis determined the factors associated with impaired cognitive functions in PWE. The significance level was set at p=0.05. Results: Cognitively, regression analysis showed that FAS impairment (14.5±8.6 x 24.3±15.7, respectively) and delayed recall of figures in PWE (7.3±2.07 x 8.6±1.48) differed significantly between PWE and the CG (R2 Nagelkerke=0.273). Beta interhemispheric coherence was higher in PWE than in the CG (0.446±0.044 x 0.425±0.036). Logistic regression analysis evidenced a significant association between beta inter-hemispheric coherence and schooling for FAS impairment (2 subgroups with cutoff at 12) (R2 Nagelkerke=0.290), and between the presence of EEG epileptiform activity and delayed recall of figures impairment (cutoff at 8)(R2 Nagelkerke=0.074). Other variables, such as epileptic seizure control and epileptic syndromes were not associated. Conclusions: Our findings suggest the importance of studying epileptiform activity and quantitative EEG for assessing cognitive changes in PWE.

Special Issue on Controversies in Neurology. From the 10th World Congress on Controversies in Neurology (CONy), Lisbon, Portugal. 17–20 March 2016.

International Journal of Clinical Neurosciences and Mental Health 2016; 3(Suppl. 1):P91

Icon_pdf Download PDF

Poster


The yield of non-elective inpatient video-EEG monitoring in adults - read full article

By: J. Theitler, D. Dassa, and Revital Gandelman-Marton

Background: Inpatient video-EEG monitoring (VEM) is used for the evaluation of patients with paroxysmal events of unknown nature and aids in the differentiation between seizures, psychogenic nonepileptic seizures and physiologic nonepileptic events. Most admissions to VEM are elective and are scheduled months ahead before the monitoring session. Objective: To retrospectively evaluate the yield of non-elective VEM sessions. Methods: We retrospectively reviewed the VEM recordings and medical records of all the patients admitted to our one-bed VEM unit from June 2007 to June 2015. A VEM session was diagnostic when a seizure, an event or previously unreported interictal epileptiform discharges were recorded. Results: The study group included 304 adults aged 18 to 92 years (mean- 40.4±17.4 years), 181 (59%) women. The diagnostic yield of non-elective and elective VEM session was similar (66% and 69%, respectively). In non-elective VEM, fewer patients had known epilepsy (p=0.0001), session duration was shorter (p=0.0001), and seizures and interictal epileptiform discharges were recorded less frequently compared to elective VEM (p=0.005 and p=0.0001, respectively). Conclusions: Non-elective VEM can provide useful information in patients admitted to the neurology department with recent neurological or behavioral events. A timely and correct diagnosis in these patients can potentially reduce unnecessary use of antiepileptic drugs in patients with psychogenic nonepileptic seizures and the morbidity and mortality associated with undiagnosed seizures.

Special Issue on Controversies in Neurology. From the 10th World Congress on Controversies in Neurology (CONy), Lisbon, Portugal. 17–20 March 2016.

International Journal of Clinical Neurosciences and Mental Health 2016; 3(Suppl. 1):P92

Icon_pdf Download PDF

Poster


Epilepsy and psychosis: when neurology and psychiatry come together - read full article

By: Tiago Geraldes, P. Breia, P. Sales, and G. Borges

Psychotic disorders are severe mental disorders that occur with changes in thinking and perception, with repercussions at personal and social levels. It is estimated that 2-9% of epileptic patients suffer from psychotic disorders. Although pathophysiological mechanisms remain unclear and psychiatric presentation may look similar to idiopathic schizophrenia, there are important clinical distinctions. There are various proposed classifications, the most consensual is performed according to their temporal relationship with the seizure itself. We present the case reports of two patients, a 56-year-old male and a 57-year-old female, with long-term temporal lobe epilepsy due to hippocampal sclerosis. Both had frontal and temporal lobes dysfunction in neuropsychological assessment, and they were referred to psychiatric consultation for behaviour changes and important psychotic symptoms. The male patient maintained a pattern of occasional complex partial seizures, showing a steady psychotic state with a good initial response to antipsychotic therapy. The female patient maintained frequent complex partial seizures even after progressive adjustment of anti-epileptic medication, culminating in right amygdalohippocampectomy. She experienced progressive worsening of psychiatric symptoms, with acute exacerbations that prompted several hospital admissions. Our aim is to draw attention to the prevalence of psychiatric disorders, particularly psychosis, affecting patients with epilepsy. These contribute to lower quality of life in these patients, and have a significant burden in society. We consider it is important to distinguish the different types of associated psychosis, not only to improve approach and therapeutic management, but also because it would contribute to the understanding of the pathophysiology of other primarily psychiatric disorders.

Special Issue on Controversies in Neurology. From the 10th World Congress on Controversies in Neurology (CONy), Lisbon, Portugal. 17–20 March 2016.

International Journal of Clinical Neurosciences and Mental Health 2016; 3(Suppl. 1):P93

Icon_pdf Download PDF

Poster


Cognitive functions in children with fetal antiepileptic drug exposure—study in Georgia - read full article

By: N. Gogatishvili, T. Ediberidze, S. Mamukadze, G. Lomidze, T. Gagoshidze, N. Tatishvili, and S. Kasradze

Background and aims: Influence of in utero antiepileptic drug (AED) exposure on cognitive development is limited and conflicting. We have assessed the late effects of fetal AEDs on cognitive development in children. Methods: In this prospective cohort study children aged 3-6 years with fetal exposure to AEDs were included. Individuals from the same age range but without fetal AED exposure were enrolled as a control group. In all cases Intelligence Quotient (IQ) were assessed. A two sample T test and multiple linear regression were used. Probability less than 0.05 was considered as statistically significant. Results: In total 100 subjects were evaluated. Among them 50 (mean age – 52.5 month; SD 12.8) have experienced AED exposure in utero and remaining 50 (mean age – 54.2 month; SD 14.5;) have not (unexposed group).In overall the mean IQ for exposed population was significantly lower (mean – 84.02; SD – 13.6) than in unexposed individuals (mean – 101.4; SD – 13.4)(p=0.001). Multiple regression analysis revealed mother’s non-verbal IQ (B; 0.447; p=0.001), age of walking (B; -2.1; p=0.009) and breastfeeding (B; 10.03; p=0.009) to be independent factors associated with IQ. No particular AED alone showed significant association with IQ compared to others. Conclusions: In utero AEDs exposure can hinder cognitive development. Breastfeeding, mother’s non-verbal IQ and age of walking could independently contribute in cognitive development of individuals during early childhood.

Special Issue on Controversies in Neurology. From the 10th World Congress on Controversies in Neurology (CONy), Lisbon, Portugal. 17–20 March 2016.

International Journal of Clinical Neurosciences and Mental Health 2016; 3(Suppl. 1):P94

Icon_pdf Download PDF

Poster


Super-refractory nonconvulsive status epilepticus secondary to cerebral fat embolism: a case report - read full article

By: Masa Hafner, S. Steblaj, B. Lorber, and G. Granda

Introduction: Cerebral fat embolism is a manifestation of fat embolism syndrome (FES) - a complication of long-bone fractures and joint reconstruction surgeries. It can show variable clinical manifestations: focal neurological signs, headache, behavioural disturbances, delirium, convulsions, or coma. Case report: A 72 - year old woman has had a total hip replacement revision surgery. The next day she had a paroxysm of right arm paresis and dysphasia. Brain CT scan and CT perfusion revealed no abnormalities. 48 hours after surgery the patient became restless and confused, later her consciousness suddenly deteriorated. An immediate EEG showed bilateral ictal epileptiform activity and the diagnosis of nonconvulsive status epilepticus (NCSE) was made. The patient was transferred to neurointensive care unit. Treatment with levetiracetam and lacosamide did not change her clinical state. Sedation and continuous EEG monitoring were started, propofol and midazolam were used. Magnetic resonance imaging (MRI) disclosed small scattered foci of acute ischemia and diffuse petechiae in deep grey matter, subcortical white matter in cerebrum, cerebellum and brainstem. Findings were consistent with cerebral fat embolism. After two weeks of deep sedation and different regimes of anticonvulsant drugs, super-refractory SE was terminated, and a month later the patient was discharged to a rehabilitation centre. Discussion: There is only one case of super-refractory NCSE secondary to fat embolism published in the medical literature and this is the first report of successful treatment of this rare clinical entity.

Special Issue on Controversies in Neurology. From the 10th World Congress on Controversies in Neurology (CONy), Lisbon, Portugal. 17–20 March 2016.

International Journal of Clinical Neurosciences and Mental Health 2016; 3(Suppl. 1):P95

Icon_pdf Download PDF

Poster


Molecular and biochemical criteria of the safety evaluation during anticonvulsant therapy - read full article

By: Oleksandr Kalbus and Natalia Shastun

Background: Epilepsy is one of the most common diseases of the nervous system. The efficacy of the treatment of epilepsy should be assessed not only by seizure frequency decrease, but also by the safety profile of the anticonvulsants. Purpose: To identify the diagnostic potential of glutathione and nitrothyrosine levels for assessment of the safety of anticonvulsant therapy (in experiment). Materials and Methods: Research was conducted on non-linear rats of both sexes (weight180-220g). The influence of anticonvulsants on cognitive processes was studied on a model of one-time learning - passive avoidance (CRPA) without amnesia factor. Metrazole kindling was used as an epilepsy model to evaluate the oxidative status of anticonvulsants. Discussion: Activation of nitrosating stress reactions on the ground of the deficiency of the recovered glutathione equivalents was established. Under endogenous neurointoxication even in the early stages, the nitrosating stress is developing, leading to nitro-replication of thiols and impacting the thiol-disulfide balance, which leads to the start of neuro-apoptosis. In the control group, the index nitrothyrosine-reduced glutathione ratio increased in 6 times compared to the intact group. Conclusion: The dependence of nitrothyrosine index/educed glutathione at metrazol kindling and action of anticonvulsants on cognitive processes in normal were established: as higher index is, as more negative effects anticonvulsants on cognitive function have

Special Issue on Controversies in Neurology. From the 10th World Congress on Controversies in Neurology (CONy), Lisbon, Portugal. 17–20 March 2016.

International Journal of Clinical Neurosciences and Mental Health 2016; 3(Suppl. 1):P96

Icon_pdf Download PDF

Poster


Headache as an aura of epilepsy: video-EEG monitoring study - read full article

By: Dong Wook Kim, Jun-Sang Sunwoo, and Sang Kun Lee

Background: Headache can be associated with epilepsy as pre-ictal, ictal, or post-ictal phenomenon, but there are only limited studies on the patients with headache as an epileptic aura. We performed the present study to investigate the incidence and characteristics of headache as an epileptic aura, with the confirmation of EEG change by video-EEG monitoring. Methods: Data of aura and clinical seizure episodes of 831 consecutive patients who undertook video-EEG monitoring were analyzed retrospectively. All auras described by the patients were classified into 54 categories, and the detailed features of headache were obtained in patients with headache as an aura. Video-recorded clinical seizures, EEG findings and neuroimaging data were used to determine the ictal onset areas of the patients. Results: Six out of 831 (0.7%) patients experienced headache as aura (2 men, 4 women; age range: 25-52 years), and all six patients had partial seizures. Five patients described headache as the most frequent aura, and headache was the second aura in one patient. The characteristics of headache were hemicrania epileptica in two patients, tension-type headache in another two patients, and migraine-like headache in the other two patients. No patient met the diagnostic criteria of ictal epileptic headache or migraine aura-triggered seizure. Conclusion: Our study shows that headache as an aura is uncommon in adult epilepsy patients, and the headache can present as diverse features including hemicrania epileptica, tension-type headache, and migraine-like headache. Further study is necessary to characterize the feature of headache as an epileptic aura in adult epilepsy patients.

Special Issue on Controversies in Neurology. From the 10th World Congress on Controversies in Neurology (CONy), Lisbon, Portugal. 17–20 March 2016.

International Journal of Clinical Neurosciences and Mental Health 2016; 3(Suppl. 1):P97

Icon_pdf Download PDF

Poster


Opercular myoclonic-anarthric status epilepticus: first manifestation of mitochondrial disorder? - read full article

By: Joana Martins, N. Vila-Chã, L. Cardoso, R. Taipa, and M. Magalhães

A 38-year-old woman presented at age of 32 with epilepsia partialis continuum characterized by spontaneous, regular and focal clonic muscular twitches, that were continuous for days and involved the right hemibody (face and distal limb muscles). Dysarthria and synchronous myoclonic movements of palate and tongue accompanied these movements. Brain MRI showed a cortico-subcortical lesion in posterior part of frontal inferior left gyrus, hyperintense on T2- weighted images with cortical restricted diffusion. Electroencephalogram was normal. She became asymptomatic with antiepileptic drugs, later tapered on. Brain MRI and PET scan were performed three months later and were both normal. Infections and inflammatory disorders were excluded. The patient remained asymptomatic until the age of 37. At that age she was readmitted with a subacute, distal and symmetrical tetraparesis with brisk reflexes without sensory or sphincter involvement. A new brain MRI showed bilateral T2 hyperintensities in both caudate and lenticular nucleus. Medullar MRI and spectroscopy were normal. Laboratory investigations including blood count, serum biochemistry and cerebrospinal fluid analysis, electromyography, evoked potentials, body CT-scan and bronchofibroscopy were normal or negative. Muscle biopsy showed rare negative COX/ SDH positive fibers. Gradually, neurological symptoms disappeared. One year later, brain MRI was almost normal. Opercular myoclonic-anarthric status epilepticus (OMASE) is an uncommon condition characterized by fluctuating cortical dysarthria associated with epileptic myoclonus involving glossopharyngeal musculature bilaterally. In the present case, OMASE was the first manifestation of the disease. Although the lack of definitive criteria for the diagnosis of mitochondrial disease, muscle findings suggest this etiology.

Special Issue on Controversies in Neurology. From the 10th World Congress on Controversies in Neurology (CONy), Lisbon, Portugal. 17–20 March 2016.

International Journal of Clinical Neurosciences and Mental Health 2016; 3(Suppl. 1):P98

Icon_pdf Download PDF

Poster


Focal vasogenic edema in the brainstem secondary to phenytoin toxicity - read full article

By: Gayane Melikyan, N. Mhjob, A. Tabouki, D. Deleu, V. Surjith, B. Mesraoua, and H. Al Hail

Despite its unique pharmacological properties with potential risk for toxicity, phenytoin is still widely used in many parts of the world. Brain lesions on neuroimaging have rarely been reported following phenytoin toxicity and affect almost invariably the corpus callosum. We report a patient who presented with severe phenytoin toxicity and focal vasogenic edema in the brainstem. A 26-year-old man presented with an acute-onset confusional state. Neurological examination was suggestive of encephalopathy. Routine laboratory evaluation, brain computed tomography and cerebrospinal fluid analysis were normal. Electroencephalogram showed no evidence of epileptiform activity. Subsequent information revealed that the patient was diagnosed with epilepsy three months earlier and was treated with phenytoin. His serum phenytoin level was 259 ?mol/l (N-40-80 ?mol/l). The patient underwent 3 sessions of hemodialysis which reduced the serum phenytoin level below 15?mol/l resulting in normalization of his mental status but still presented severe cerebellar signs, absent proprioception and diminished deep tendon reflexes in lower limbs. Brain magnetic resonance imaging (MRI) revealed a focal T2 weighted and FLAIR hyperintense signal in lower medulla/craniocervical junction lesion without diffusion restriction or contrast enhancement. One week later his cerebellar syndrome and sensory deficit had improved significantly, and follow-up brain MRI demonstrated partial resolution of the lesion. Transient focal vasogenic edema has previously been associated with phenytoin toxicity. However, there are no reports of phenytoin toxicity causing such lesions in the brainstem. Awareness of the possibility of these lesions is important since it may avoid unnecessary invasive diagnostic interventions.

Special Issue on Controversies in Neurology. From the 10th World Congress on Controversies in Neurology (CONy), Lisbon, Portugal. 17–20 March 2016.

International Journal of Clinical Neurosciences and Mental Health 2016; 3(Suppl. 1):P99

Icon_pdf Download PDF

Poster


Selection of anti-epileptic drugs in the initial phase of the treatment of epilepsy - read full article

By: O. Mostovaya

The problem of choice of antiepileptic treatment is the ambiguity of the proposed options. Therefore, in our clinic, we have developed a system EEG - control the selection of drugs. It is the following algorithm: (1) Night video monitoring with the daily record and conducting trial before and after sleeping, (2) The analysis conducted by the EEC and the choice of the segment that contains the abnormal patterns, (3) Appointment of anti-epileptic drugs from a first-line choice in the order, as proposed in the protocols followed by the EEG—a test action of the preparation on the selected segment of EEG (usually – it is 3 drugs), (4) The choice of the drug on the basis of a concrete manifestation of the effectiveness. Clinical example: Patient Ch, Man/ 30 years old; epileptic seizures from he was 2 years old; he was treated by carbamazepine, valproate; episodically recently become frequent bouts; constantly have a headache; at this time, no drugs does not accept; seizures generalized tonic-clonic, 3 times a month; MRI without pathology. Could the patient be cured if he was treated consistently? Figures 1–3 illustrate the follow-up of this patient. The selection of AEDs in the beginning stage of long-term treatment of epilepsy should be carried out with the help of EEG control.

Special Issue on Controversies in Neurology. From the 10th World Congress on Controversies in Neurology (CONy), Lisbon, Portugal. 17–20 March 2016.

International Journal of Clinical Neurosciences and Mental Health 2016; 3(Suppl. 1):P100

Icon_pdf Download PDF

Poster


Hippocampal involvement in physiological deja vu: subfield vulnerability rather than temporal lobe epilepsy - read full article

By: Eva Peslova, R. Marecek, D. Shaw, T. Kasparek, M. Pail, and M. Brazdil

Introduction: Brain morphological correlates of physiological déjà vu (DV) have been recently identified. Significantly reduced gray matter volume (GMV) in subjects experiencing DV mirrors the distribution of GMV reduction in mesial temporal lobe epilepsy (MTLE) patients. These patterns of GMV reduction vary in terms of the hippocampal region, however. Another condition associated with hippocampal GMV reduction is schizophrenia (SCH). Here we tested the hypothesis that hippocampal involvement in physiological DV resembles more closely the pattern of GMV decrease in MTLE compared with that in SCH. Methods: We compared GMV within hippocampal subfields in healthy individuals that have (DV+; N=87) and have not experienced DV (DV-; N=26), and patients with MTLE (N=47) and SCH (N=29). We then evaluated the spatial distribution of GMV decrease to compare the DV+ and DV- groups, and their resemblance to the MTLE and SCH groups. Results: Significant GMV decrease was found in all hippocampal subfields except CA1 for the DV+, MTLE and SCH groups relative to the DV- group. Concerning the spatial distribution, we found significant correlations both between DV+ and SCH, and DV+ and MTLE groups with higher correlations for SCH. Conclusions: Our findings reveal structural features of hippocampal involvement in physiological DV, MTLE and SCH. The pattern of GMV reduction in the DV+ relative to the DV- group does not resemble the pattern observed in MTLE any more than that observed in SCH. Nevertheless, the highly similar patterns of the three groups suggest an increased vulnerability of certain subfields: CA4 DG, CA 2-3 and subiculum.

Special Issue on Controversies in Neurology. From the 10th World Congress on Controversies in Neurology (CONy), Lisbon, Portugal. 17–20 March 2016.

International Journal of Clinical Neurosciences and Mental Health 2016; 3(Suppl. 1):P101

Icon_pdf Download PDF

Poster


Leukoencephalopathy related to phenytoin in a patient with methylenetetrahydrofolate reductase C6777T polymorphism - read full article

By: Hak Young Rhee, Young Nam Kwon, Sung Sang Yoon, and Boo Suk Na

We report a patient with a heterozygous CT variant of MTHFR who developed leukoencephalopathy after phenytoin medication. A 36-year-old man was admitted to our hospital for progressive worsening of mental status over one week after phenytoin medication. The patient had been diagnosed with juvenile rheumatic arthritis and ankylosing spondylitis in his preteens and suffered recurrent convulsive seizures from the age of thirties. The patient had recurrent convulsive seizures after he stopped taking the medication and eventually had received treatment as an inpatient for status epilepticus and aspiration pneumonia three weeks before this admission. Phenytoin had been prescribed to control the seizures and the patient had been improved and discharged. The patient was stuporous on this admission and routine serum chemistry and complete blood counts were normal. MRI of the brain demonstrated new onset of extensive leukoencephalopathy which was prominent on FLAIR images. Sequence analysis of the MTHFR revealed compound heterozygous mutation for 677CT. Serum homocysteine level was within normal limits and serum folate level was decreased (4.21 ng/mL). The neurological status of the patient did not improved after discontinuing phenytoin. In individuals heterozygous for MTHFR C677T polymorphism, the enzyme activity is decreased to 60% of wild type activity of MTHFR. The patient developed subacute onset of mental deterioration and diffuse white matter lesions on MRI. It is probable that impaired folate metabolism and enhanced vulnerability of the CNS to the effect of phenytoin in our patient are related to the development of the leukoencephalopathy.

Special Issue on Controversies in Neurology. From the 10th World Congress on Controversies in Neurology (CONy), Lisbon, Portugal. 17–20 March 2016.

International Journal of Clinical Neurosciences and Mental Health 2016; 3(Suppl. 1):P102

Icon_pdf Download PDF

Poster


Seizures in patients with newly diagnosed glioma: frequency and determinants - read full article

By: Dima Suki

Background: Seizures are a common manifestation of gliomas. The frequency of seizures is generally reported to be inversely correlated with tumor grade. Tumor resection is a favorable predictor of seizure control in these patients. The study aims at 1- assessing the frequency of seizures in a large group of patients with newly diagnosed glioma undergoing neurosurgery and identifying the factors associated with these seizures; and 2- assessing the seizure control rate in the postoperative period and its determinants. Methods: Patients with newly diagnosed glioma undergoing a biopsy or resection at MD Anderson Cancer Center between June 1993 and December 2015 were included. Excluded were patients with missing imaging data and those with greater than 3 tumors at diagnosis. Data on tumor histology, WHO grade, location, patient age, gender, use of anticonvulsants, and other relevant patient, tumor and clinical characteristcs were obtained. The study was conducted under the auspices of an institutional review board approved protocol. Results: Data was obtained on 2,106 patients with glioma (58% WHO grade 4; 18% grade 3; 20% grades 1 or 2; and 4% unclassified). Median age was 53 years (4% pediatric patients); 58% were males. The tumor was located supratentorially in 91% and infratentorially in 8% (1% had both locations). Seizures were noted preoperatively in 735 (35%). In the 30-day postoperative period, seizures were noted in 89 patients (4%) overall (6% among those with a preoperative history of seizures and 3% among those without). The full results/conclusions will be presented at the meeting.

Special Issue on Controversies in Neurology. From the 10th World Congress on Controversies in Neurology (CONy), Lisbon, Portugal. 17–20 March 2016.

International Journal of Clinical Neurosciences and Mental Health 2016; 3(Suppl. 1):P103

Icon_pdf Download PDF

Poster


Major depressive episode, cognition, quality of life, and epilepsy - read full article

By: G. Tedrus, L. Fonseca, M. Augusto, and F. Trindade

Background: Major depressive episode in adult patients with epilepsy (PWE) is frequent, but the associated factors remain controversial. Objective: To study the occurrence of depression in PWE and relate it to their clinical characteristics and quality of life (QoL). Sample and procedures: The study included 200 consecutive PWE from the neurology outpatient clinic of PUC-Campinas. The association between Neurological Disorders Depression Inventory for Epilepsy (NDDI-E) data and their clinical, cognitive, and QOLIE-31 characteristics was investigated at a significance level of p=0.05. Results: The sample had the following characteristics: 52.5% females; mean schooling of 5.7 years; mean age of 47.6 (±15.1) years; mean age at first epileptic seizure (ES) of 24.1 (±18) years; and 75 (37.5%) PWE had psychiatric disorders. The mean NDDI-E score was 10.3 (±4.0). NDDI-E was negatively correlated with age (Spearman correlation; -0.204; p=0.004); age at first ES (-0.168; p=0.018), and QOLIE-31 (domain and total scores). High ES frequency was associated with higher NDDI-E score (Kruskal-Wallis; p=0.006). Twenty-six cases had NDDI-E score 15, suggestive of major depressive episode, which was associated with lower performance in semantic verbal fluency and QOLIE-31 scores. Discussion and Conclusion: Major depressive episode was found in 13% of the cases. Clinical, cognitive, and quality of life aspects were correlated with NDDI-E scores.

Special Issue on Controversies in Neurology. From the 10th World Congress on Controversies in Neurology (CONy), Lisbon, Portugal. 17–20 March 2016.

International Journal of Clinical Neurosciences and Mental Health 2016; 3(Suppl. 1):P104

Icon_pdf Download PDF

Poster


Monitoring brain damage using surface current injection - read full article

By: Shimon Abboud, R. Cohen, and M. Arad

Disturbance in the blood supply to the brain causes a cerebrovascular accident (CVA). This can be due to ischemia (lack of blood flow) caused by blockage (thrombosis, arterial embolism) or a hemorrhage. In this study, the feasibility of injected low amplitude high frequency surface current over the center line of the scalp between the Nasion and the Inion points of the 10/20 EEG system, for monitoring such damage was analyzed in a computerized model. Simulations were conducted on a realistic 3D numerical model of the head. Tissues were assumed to act as linear volume conductors and electrical potentials were calculated by solving the volume conductor problem. Left-right asymmetry over the 10/20 EEG leads system was calculated for several conductivities and volumes of the damaged region. The results were compared with the left-right asymmetry found in a head model with normal brain. A negative asymmetry was revealed for ischemia (i.e. the potential amplitude over the ischemic hemisphere was greater than that over the intact hemisphere). In case of hemorrhage, a positive asymmetry was found. Furthermore, correlation was found between the location of the damaged region and the electrodes with significant asymmetry. The 3D numerical simulations revealed that the volume and the electrical conductivity of the damaged tissue are correlated with the left-right asymmetry of the surface potentials. These findings support the hypothesis that using surface current technique for monitoring brain damage is feasible.

Special Issue on Controversies in Neurology. From the 10th World Congress on Controversies in Neurology (CONy), Lisbon, Portugal. 17–20 March 2016.

International Journal of Clinical Neurosciences and Mental Health 2016; 3(Suppl. 1):P105

Icon_pdf Download PDF

Poster


Sight resolution and brain integrative role during painting of miniature portrait - read full article

By: Jacek Bojakowski

The report addresses miniature painting in the context of brain function and plasticity. Summary of own experience in watercolor portrait miniature painting, its perception, and possible correlation with the integrative and selective brain activities is presented. Sight resolution and integrative function of human central nervous system is analyzed and new idea of studying this function by neuroimaging is suggested.

Special Issue on Controversies in Neurology. From the 10th World Congress on Controversies in Neurology (CONy), Lisbon, Portugal. 17–20 March 2016.

International Journal of Clinical Neurosciences and Mental Health 2016; 3(Suppl. 1):P106

Icon_pdf Download PDF

Poster


Benign paroxysmal positional vertigo commonly recurs in the ipsilateral ear and the same canal after successful repositioning maneuvers - read full article

By: SooHyun Cho and B. Kim

Objectives: Benign paroxysmal positioning vertigo (BPPV) is the most common cause of vertigo. Although repositioning maneuvers have been demonstrated to be useful in its treatment, half of all patients experience recurrence after successful repositioning maneuvers. Nevertheless, the clinical characteristics of recurred BPPV have not been systematically evaluated. The aim of our study was to establish possible clinical factors associated recurred BPPV after successful repositioning maneuvers. Method: We analyzed the records of 216 patients who experienced recurrence after 1 month apart from successful repositioning. Results: The posterior semicircular canal was affected in 62.1% and the horizontal in 37.9%. 78.7% of the 216 cases affected the ear ipsilateral to the first episodes of BPPV. Moreover, 109 (71.7%) of cases of all recurrences affected the same canal. Conclusion: Our data revealed that the recurrence of BPPV after repositioning maneuvers commonly affects the ipsilateral ear and same canal. This can be related to the abnormal pathology at the first episodes of BPPV leading to frequent recurrence even after successful repositioning maneuvers.

Special Issue on Controversies in Neurology. From the 10th World Congress on Controversies in Neurology (CONy), Lisbon, Portugal. 17–20 March 2016.

International Journal of Clinical Neurosciences and Mental Health 2016; 3(Suppl. 1):P107

Icon_pdf Download PDF

Poster


Two weeks of intraperitoneally oxytocin treatment exerts facilitatory effects on working memory and anti-depressive effects in wistar rats - read full article

By: Alin Ciobica, Radu Lefter, Iulia Antioch, Manuel Paulet, and Manuela Padurariu

Introduction: Lately, there is increased interest in understanding the roles of oxytocin in the main neuropsychiatric disorders such as Alzheimer’s disease, anxiety, depression, schizophrenia or autism and the variety of behaviours exhibited by both the administration of intransal or peripheral oxytocin on the developed animal models for the aforementioned disorders. In this way, here we present some of our preliminary data regarding the administration of oxytocin for 2 weeks in some specific behavioural tasks used to assess working memory and antidepresive behaviour. Material and methods: Male Wistar (n=20) rats were used. Oxytocin was intraperitoneally injected in a dose of 10 mg/kg/b.w. for 14 consecutive days. The control rats were also injected with saline. The treatment began 12 days before the behavioural testing. Memory functions were tested through Y-maze, while antidepressive behaviour was evaluated by forced swim test, performed during the last 2 days of treatment (13th and 14th, respectively). Results: Our initial data is showing positive effects on immediate working memory for the oxytocin administration in the hippocampal-dependent Y-maze test, as showed by the significant increase of the spontaneous alternation behavior in the oxytocin group, as compared to saline. Moreover, the administration of oxytocin resulted in a significant increase of the total swimming time in the forced-swim-test, as compared to the control rats, suggesting some anti-depressive effects. Conclusions: It seems that the administration of intraperitoneally oxytocin in a dose of 10 mg/kg for 2 weeks in rats could exert some facilitatory effects on the hippocampus-dependent working memory Y-maze test and anti-depressive behavior in forced-swim-test.

Special Issue on Controversies in Neurology. From the 10th World Congress on Controversies in Neurology (CONy), Lisbon, Portugal. 17–20 March 2016.

International Journal of Clinical Neurosciences and Mental Health 2016; 3(Suppl. 1):P108

Icon_pdf Download PDF

Poster


Clinical spectrum of neurosyphilis: a 9-year retrospective study at a neurology department of a tertiary care hospital in Lisbon - read full article

By: Ary De Sousa, P. Brás, J. Sequeira, S. Dias, J. Morgado, C. Capela, M. Dias, and R. Pedrosa

Background: Neurosyphilis is characterized by a broad range of neurological findings, potentially complicating its diagnosis. Although neurosyphilis is no longer a common disorder, its prevalence is rising in Western countries and its past reputation as the great imitator should not be forgotten. The objective of this study is to describe the clinical spectrum of patients with neurosyphilis admitted to a Neurology department of a tertiary care hospital in Lisbon. Methods: A retrospective database search using the International Classification of Diseases (ICD) 9 codes was performed to identify all patients with the diagnosis of neurosyphilis, admitted between 2001 and 2009. Collected data included demographics, clinical features, cerebrospinal fluid (CSF) changes, neuroimaging findings and outcome. Results: We identified 16 patients that met diagnostic criteria for definite or probable neurosyphilis. Mean age was 48.5 years, males being more frequently involved. The most frequent clinical patterns were meningovascular (37.5%), general paresis (31.3%) and meningitis (25.0%). CSF pleocytosis and elevated CSF protein were found in 81.2%. Neuroimaging findings were nonspecific. In this study, 3 patients had a past history of primary syphilis and 2 were HIV seropositive. Conclusions: Compared to the preantibiotic era, a lower frequency of late neurosyphilis was observed, mainly of tabes dorsalis, similar to that reported in other modern series. Neurosyphilis is still characterized by clinical polymorphism. Providers should maintain a high index of suspicion for neurosyphilis among patients with syphilis, particularly those with HIV infection.

Special Issue on Controversies in Neurology. From the 10th World Congress on Controversies in Neurology (CONy), Lisbon, Portugal. 17–20 March 2016.

International Journal of Clinical Neurosciences and Mental Health 2016; 3(Suppl. 1):P109

Icon_pdf Download PDF

Poster


Head trauma and epilepsy as medical risk factors in the development of brain tumors in Albania - read full article

By: Pavllo Djamandi and G. Kaloshi

Introduction: Several diseases and medical treatments are discussed as risk factors for the development of brain tumors, including infections, allergy, alterations of immune system, cranial trauma, hormonal factors, epilepsy, cancer family history, etc. We discuss here the role of head trauma and epilepsy as medical risk factor in development of brain tumor. Results: A total 1883 patients with brain tumors are registered from 1993 -2013, 977 (49%) of them were interviewed to review the analysis of risk factors, during the period December 2010-December 2013. We found in our study a correlation between head trauma and brain tumor (meningeoma) around 1%, not a correlation between glioma and traumatic brain injury (TBI) in male, and no correlation between meningeoma, glioma and TBI in female. The role of epilepsy in development of brain tumors in our study is unclear, this for the stigma that exist in our country on epilepsy, only 0.87 % of patients diagnosed with brain tumors referred to suffer from epilepsy from 10-15 years. Conclusion: The role of medical factors in development of brain tumors is important. The role of head trauma is more evident in male than female in our study and is unclear the role of epilepsy.

Special Issue on Controversies in Neurology. From the 10th World Congress on Controversies in Neurology (CONy), Lisbon, Portugal. 17–20 March 2016.

International Journal of Clinical Neurosciences and Mental Health 2016; 3(Suppl. 1):P110

Icon_pdf Download PDF

Poster


The role and effect of modafinil on normal-physilological night sleep - read full article

By: Hakan Ekmekci, M.Ü.ÖZIÇ, and S. Oztürk

Modafinil is a unique wake-providing drug approved for narcolepsy, shift work sleep-disorder and as adjunctive treatment of OSAS. Modafinil is well-tolerated drug with low predisposition for abuse, it is very effective on narcolepsy and excessive daily sleep. But the role of modafinil on normal night-sleep is obscure. We studied the effect of modafinil on normal physiological sleep. Therefore we designed 33 double-blind and 30 placebo-controlled trials. All volunteers (33 patients and 30 control group) were evaluated at outpatient unit of Selcuk University Hospital, Department of Neurology. All patients indicated with usage of modafinil for narcoleptic situation were investigated just before and 90th day with Polysomnography. All data collected from pre and post-period of medications were compared in between and with the control-group data. This showed us that modaifinil is not just effect daily awakening but also with physiological sleep at night. Another important thing is that severity of Epworth score is not affective on PSG findings. With increasing age, the effectivity of Apnea-Hypopnea Index improvement is better with modafinil usage. The role of modafinil is well known in daily sleep condition, and narcolepsy; but the role of it on the coming nights-sleep is a strange and important concept. Utilizing GABA, serotonin, glutamate, epinephrine, histamine and hypocretin, are the well-known pathway for modafinil effect. But this interactions may make different effect on night sleep other than the awakening roles and the effects are mostly related with REM period, age, Epworth score, family history for narcolepsy, daily napping relaxation.

Special Issue on Controversies in Neurology. From the 10th World Congress on Controversies in Neurology (CONy), Lisbon, Portugal. 17–20 March 2016.

International Journal of Clinical Neurosciences and Mental Health 2016; 3(Suppl. 1):P111

Icon_pdf Download PDF

Poster


Post stroke depression - read full article

By: Irena Grkic, A. Zecevic, V. Miletic, S. Knezevic, V. Mileusnic, and K. Kacar

Depression after brain stroke is one of the very often complication which has a long run negative consecution on recovery of motor and cognitive deficit as well as death from brain stroke. Depression is most often appearance in period 3-6 months after brain stroke. This study was conducted on 52 patients with ischemic PSD. They were classified into 2 groups (21 patients with early PSD and 31 patients with late PSD). All patients were subjected to thorough neurological examination: C.T. of brain, clinical assessment of depression, Hamilton rating scale for depression and Barthel index scale for disability. All patients were hospitalized in a Specialized hospital for CVD„Saint Sava” due to instability in gait, hemiparesis of the lower level with the present partial deficit developed, without any disturbance of consciousness. During hospitalization a slight drop change of mood was registered. In therapy was introduced antidepressant with continuous monitoring. Early PSD was more common and severe in left cerebral hemispheric lesions (in the basal ganglia and frontal lobe). Late PSD was more common in cortical lesions either on the right or left sides particularly in parietal or frontal lobe lesions. There was a significant correlation between the size of the lesion and severity of late PSD. Early PSD was more common in patients with left subcortical lesions while late PSD was more common in patients with cortical lesions. Severity of late PSD was related to the size of the lesion.

Special Issue on Controversies in Neurology. From the 10th World Congress on Controversies in Neurology (CONy), Lisbon, Portugal. 17–20 March 2016.

International Journal of Clinical Neurosciences and Mental Health 2016; 3(Suppl. 1):P112

Icon_pdf Download PDF

Poster


Postactivation depression changes associated with improvement of motor ability in subacute stroke: a case series of three patients - read full article

By: Yu Kawaishi and Kazuhisa Domen

Postactivation depression is a presynaptic mechanism regulating the excitability of the stretch reflex. Postactivation depression of soleus H-reflex has been found to be lower in spastic patients, and a positive correlation has been reported between the diminished postactivation depression and the severity of spasticity following stroke. However, the effects of diminished postactivation depression on motor ability in stroke patients have been unclear. The purpose of this study was to measure postactivation depression post-stroke and to examine the relationship between postactivation depression and motor ability. The study included three subacute stroke patients with lower limb hemiparesis. Postactivation depression, quiet standing balance, walking velocity, Fugl-Meyer, Ashworth, were assessed three times per 4weeks. All patients have been participated in conventional physical therapy in the rehabilitation hospital while investigating. Postactivation depression was evaluated by frequency-related changes of soleus H-reflex. It was quantified as the ratio: mean amplitude of the H-reflexes obtained at 1 Hz/mean amplitude of the H-reflexes obtained at 0.1 Hz. For all patients, postactivation depression showed increasing associated with improvement of quiet standing balance, walking velocity, and Fugl-Meyer. On the other hand, Ashworth didn’t show changing while investigating. Results suggests that the improvement of motor ability after stroke is associated with recovery of postactivation depression.

Special Issue on Controversies in Neurology. From the 10th World Congress on Controversies in Neurology (CONy), Lisbon, Portugal. 17–20 March 2016.

International Journal of Clinical Neurosciences and Mental Health 2016; 3(Suppl. 1):P113

Icon_pdf Download PDF

Poster


Is the role of BDNF in depression and dementia already proved? - read full article

By: L. Kruglov

The structural changes of the aging brain lead to cognitive decline which can end in dementia. But why almost the same pathological changes are often found in patients with late-life depression? Does this mean that depression and dementia are two links of one continuing process? The same concerns the issue of neurochemical changes found in patients with dementia and depression. One of the prominent neurochemical findings of last years is the fact that the concentration of the brain-derivated neurotrophical factor /BDNF/ in patients with dementia and depression is declined. It is raised again when effective treatment of depression is carried out but it seems that the same doesn`t happen during the drug treatment of patients with dementia. Perhaps it could be understood according to the fact that the results of such treatment are much poorer than in the depression cases. But still there is no understandable explanation of the raised concentration of BDNF in patients with co-morbidity of dementia and depression. Besides there is obvious data that the concentration of BDNF decreases along the aging. So further studies are needed for assessing the role of BDNF and other neurotrophic factors oscillations in patients with neurodegenerative processes and psychopathological states as well as their dynamics during the therapy.

Special Issue on Controversies in Neurology. From the 10th World Congress on Controversies in Neurology (CONy), Lisbon, Portugal. 17–20 March 2016.

International Journal of Clinical Neurosciences and Mental Health 2016; 3(Suppl. 1):P114

Icon_pdf Download PDF

Poster


The effects of functional electrical stimulation cycle on non-hemiplegic quadriceps in stroke patients (pilot study) - read full article

By: H.J. Lee, S.Y. Kim, B.S. Kwon, J.H. Shim, and J.H. Lee

Objective: To investigate the effect of functional electrical stimulation (FES) cycle on strengthening of non-hemiplegic limb and gait performance in stroke patients. Methods: Fourteen hemiplegic patients after stroke were recruited. They underwent FES cycle for 30 minutes (five times every week for 4 weeks) with conventional therapeutic exercise. Primary outcome was isokinetic/isometric torque in non-hemiplegic limb. Secondary outcomes were gait performance measured with walking velocity (10 meter walk test; 10 MWT) and timed up and go test (TUG), motor function with Motricity Index (MI) and Modified Motor Assessment Scale (MMAS), strength of paralyzed limb with Medical Research Council (MRC), spasticity with Modified Ashworth Scale (MAS), functional ambulation ability with Functional Ambulation Category (FAC) and activities of daily living with Modified Barthel Index (MBI). They were recorded at before and 1 month after training. Results: Isometric torque of quadriceps of non-hemiplegic limb and MRC grade of hamstring of hemiplegic limb were significantly improved after training. TUG, FAC and MBI were also significantly improved after treatment. 10 MWT, MI, MMAS, spasticity and muscle power of quadriceps and isokinetic torque of hamstring and quadriceps did not show significant difference after training. There were no adverse events during experiment. Conclusion: FES cycling improved muscle strength of quadriceps of non-hemiplegic limb and gait performance. FES cycling may be helpful for improvement of gait in stroke patient. However, randomized control study is necessary to confirm the therapeutic effect of FES cycle.

Special Issue on Controversies in Neurology. From the 10th World Congress on Controversies in Neurology (CONy), Lisbon, Portugal. 17–20 March 2016.

International Journal of Clinical Neurosciences and Mental Health 2016; 3(Suppl. 1):P115

Icon_pdf Download PDF

Poster


Is irritable bowel disease a neurological disorder? The oxidative stress and inflammation connection - read full article

By: Radu Lefter, Miruna Ioana Balmus, Anca Trifan, Alin Ciobica, and Carol Stanciu

Irritable bowel syndrome (IBS) is a symptom-based diagnosis with unknown organic mechanisms, mainly characterized by cramping, abdominal pain and general discomfort of bowel. Still, consistent evidences are lately suggesting that irritable bowel disease may be associated to depression, anxiety, autism, posttraumatic stress disorder, psychological stress and even dementia. Moreover, lately there is an increased interest towards the relevance of the oxidative stress modifications in IBS pathological manifestations. In this context, we will discuss here about the possible correlation between the neurological effect of oxidative stress and IBS mechanistics. As it is already known, the nervous system is highly susceptible to oxidative damage and inflamation due to its particular lipidic structures and low antioxidant defence. Also, several reports showed that an oxidative stress implication in IBS would be probable, but no mechanism is yet clear. Moreover, some reports are already suggesting a possible pathway of neuroinflammation involved in enteric nerve system impairment that would lead to hyperexcitability followed by impaired intestinal motility. Moreover, it is well possible that a close relationship between neuro-visceral impairments followed by impaired gut-brain axis and IBS gastrointestinal symptomatology to exist. Furthermore, it would be possible that these symptoms to occur in the absence of a nutritional of infectious stimuli and therefore not being characterized by direct inflammation and oxidative stress, but these to occur as collateral effect to impaired neurostimulation. Based on this information, the correlation between IBS, the neurological impairment of enteric nerve system and oxidative stress/inflammation remains to be further explained and discussed.

Special Issue on Controversies in Neurology. From the 10th World Congress on Controversies in Neurology (CONy), Lisbon, Portugal. 17–20 March 2016.

International Journal of Clinical Neurosciences and Mental Health 2016; 3(Suppl. 1):P116

Icon_pdf Download PDF

Poster


Terminal care in patients with multiple systemic atrophy - read full article

By: Akihisa Matsumoto, T. Harada, M. Kudo, and Y. Nakagawa

In order to investigate the palliative care in end stage of MSA (Multiple Systemic Atrophy), we investigated the details of medical care and rehabilitation in patients with MSA who admitted in our hospital.74 patients with MSA (MSA-P:45 patients, MSA-C:29 patients) who died in our hospital from 2005-2014 were analyzed as to the details of therapy especially in the end stage. These patients who admitted in our hospital had been already noticed diagnosis and prognosis. As the results, among 74 patients who received the terminal care and died in our hospital, non-invasive mechanical ventilation had been already used in 3 patients before admission to our hospital. Nutritional deficiency had also relieved by percutaneous endoscopic gastrostomy in 12 patients. They also decided not to use the tracheotomy ventilation. As to the therapy after admission to our hospital, rehabilitation was done in all patients. In the end stage of MSA with respiratory failure, 4 patients were done tracheotomy with informed concept. 7 patients used oxygen therapy. Rehabilitation had been done in all patients until the end stage of MSA. Rehabilitation in the end stage was mainly for the relaxation of pain, and continued from the day of admission to our hospital until the 3-7 days before the death in 46 patients. Details of rehabilitation in the end stage were the positioning for prevention of bedsore, relaxation of muscles by stimulating the tactile sense and training of excursion of joints without using apparatus for pain elicited by movement disorder.

Special Issue on Controversies in Neurology. From the 10th World Congress on Controversies in Neurology (CONy), Lisbon, Portugal. 17–20 March 2016.

International Journal of Clinical Neurosciences and Mental Health 2016; 3(Suppl. 1):P117

Icon_pdf Download PDF

Poster


Vascular and mixed dementia: immune state and effectiveness of multimodal treatment - read full article

By: N. Mikhaylova, L. Androsova, S. Zozulya, and T. Kliushnik

The aim was to study some clinical and immunological characteristics of vascular dementia (VaD) compared with mixed dementia (MD). Vascular dementia was diagnosed in 26.5% since mixed dementia was in 33.2% of all patients firstly admitted to the psychogeriatric unit. Some indices of an innate immunity including leukocyte elastase activity (LE), the functional activity of ?1-protein inhibitor (?1-PI), C-reactive protein (CRP) and interleukin-6 (IL-6) concentration were measured in blood plasma of in-patients. Both forms of dementia (VaD, MD) are characterized by the appearance of inflammatory markers (LE, ?1-PI, CRP and IL-6) in patients’ blood plasma. The level of these markers was found to depend on the severity of dementia. Increased levels of CRP and IL-6 are probable the biological markers of mild VaD. Mild MD was characterized by the significant increase in activity of ?1-PI, but not the level of CRP, IL-6 and activity of LE. The state of moderate MD was determined by the significant increase in activity/level of ?1-PI, CRP and IL-6. The significant positive correlation between the level of CRP and IL-6 were found in the groups of patients with moderate dementia MD only. An open study of multimodal long-term treatment with memantine combined with vascular risk factors correction and with course of citicoline (1000 mg N=20 i.v. infusions) was carried out in 20 in-patients. An augmented therapeutical effect was shown on CGI-I assessment in mild and moderate VaD and in mild MD. The innate immune indices are needed to study as markers of anti-dementia treatment’s effectiveness.

Special Issue on Controversies in Neurology. From the 10th World Congress on Controversies in Neurology (CONy), Lisbon, Portugal. 17–20 March 2016.

International Journal of Clinical Neurosciences and Mental Health 2016; 3(Suppl. 1):P118

Icon_pdf Download PDF

Poster


Late recognition of Tapia’s syndrome following orotraheal intubation leads to poor recovery - read full article

By: Mihael Misir, D. Czersky-Hafner, A. Vceva, and B. Kristek

Tapia’s syndrome is known rare complication of orotracheal intubation, until now described only in a few case reports. Pathological process consists of high cervical extracranial neuropraxia of the recurrent laryngeal nerve and the hypoglossal nerve with consequent ipsilateral paralysis of the vocal cord and the tongue. We present a case of 69 years old male, operated laparoscopically, due to the acute cholecystitis, and reoperated four days later due to the colon perforation and peritonitis, in general anesthesia. The day after second operation aphonia developed, with chewing problems because of tongue weakness. The symptoms persisted and 35 days later he was eventually sent to neurologist. Dysphonia and tongue deviation to right side was noticed with atrophy of right side of tongue, fasciculations on the same side, difficulties in chewing food and oral phase dysphagia. Oral sensation was normal as were palatal and pharyngeal reflexes. All other cranial nerves were unaffected and he had no signs of other brain, spinal or peripheral nerve lesions or other neurological deficits, so Tapia’s syndrome was diagnosed. Videolaringoscopical evaluation revealed fixated right and mobile left vocal cord on phonation and respiration, rima glottidis was sufficient. Right pyriphorm sinus was shallow and left normal. Other diagnostic tests, including MRI of brain, scull base and neck were normal as expected. Patient was treated with steroid therapy, vitamin B complex therapy and had some improvement of tongue weakness and dysphonia, but not complete resolution of neurological symptoms probably due to the late recognition of syndrome and introduction of therapy.

Special Issue on Controversies in Neurology. From the 10th World Congress on Controversies in Neurology (CONy), Lisbon, Portugal. 17–20 March 2016.

International Journal of Clinical Neurosciences and Mental Health 2016; 3(Suppl. 1):P119

Icon_pdf Download PDF

Poster


Advanced MRI applications for mild traumatic brain injury - read full article

By: Teena Shetty, Megan Parmenter, Lorena Loci, Kelianne Cummings, Charlotte Ching, Aashka Dalal, and Joseph Nguyen

Objective: To correlate clinical neurological symptoms with mTBI biomarkers during the acute and subacute period following mTBI. Background: Subjective assessment remains the standard of care for patients with mTBI. Methods: 86 patients enrolled in the study within 72 hours or 8(±2) days of head injury for the first encounter (E1). Two or three subsequent visits followed: 8(±2) days for E2, 22(±7) days for E3, and 90(±7) days for E4. Chi-square and linear mixed models were used to assess changes across encounters. Results: Most prevalent symptoms at E1 were “Headache” (92.5%), “Don’t feel right” (84.6%), and “Feeling slowed down” (82.5%). 26.1% of patients continued to experience headaches at E4. On average, patients reported 18.5, 19.2, 12.7, and 5.4 symptoms between each respective encounter. Significant decrease was found between E1 (p=0.017) and E4 (p=0.001), suggesting possible symptom resolution three months after injury. Neurological measures tested immediate recall and delayed concentration. There was a significant increase in word recall between E1 to E3 and E1 to E4 (p=0.002 for both). Only five digit recall demonstrated significant change between encounters (p=0.043). When comparing performance on three digit recall with symptomology, patients who incorrectly recalled three digits had prolonged symptoms. By E4 incorrect responders had almost six times as many symptoms (p=0.015). Conclusion: We can potentially identify clinical symptoms which support the natural history of TBI in patients. Advanced imaging techniques may bolster current treatment of TBI and allow objective diagnosis. Further study is necessary to determine better treatment pathways in caring for these injuries.

Special Issue on Controversies in Neurology. From the 10th World Congress on Controversies in Neurology (CONy), Lisbon, Portugal. 17–20 March 2016.

International Journal of Clinical Neurosciences and Mental Health 2016; 3(Suppl. 1):P120

Icon_pdf Download PDF

Poster


Magnetic resonance brain imaging in patients with visual vertigo - read full article

By: Lea Pollak

Introduction: Patients with visual vertigo (VV) report dizziness provoked by moving visual surroundings. It has been suggested that these subjects develop a compensation strategy for a vestibulo-proprioceptive deficit and rely excessively on visual input. We have postulated that patients with VV might have brain abnormalities that interfere with appropriate processing of visual stimulation and performed a brain MRI study to verify this hypothesis. Materials and methods: Patients with VV of more than three months duration were included. They were asked to complete The Situational Characteristic Questionnaire (SCQ) that scores for the symptoms of VV. Dizzy patients without VV served as controls. A brain MRI was performed with a Siemens 1.5 Tesla scanner in patients and controls. Results: Twenty four patients with VV were included. Their mean SCQ score was 1.45±0.9 (normal 0.16±0.28). In 50% abnormalities on MRI imaging were found. Thirty three percent of 27 controls demonstrated an abnormal brain MRI. The two groups were similar in respect to the prevalence of a localized hemispheric or posterior fossa lesion (p=0.13) but VV patients had more unspecific white matter brain changes than controls (p=0.009). Patients and controls did not differ in age and gender distribution (p=0.9) or the history of a neurotological event preceding their symptoms (p=0.3). Conclusions: Our study suggests that multiple white matter lesions might contribute to occurrence of the phenomenon of VV. Future prospective large scale studies by specific MR techniques are indicated to validate our preliminary findings and elucidate the pathological mechanism of VV.

Special Issue on Controversies in Neurology. From the 10th World Congress on Controversies in Neurology (CONy), Lisbon, Portugal. 17–20 March 2016.

International Journal of Clinical Neurosciences and Mental Health 2016; 3(Suppl. 1):P121

Icon_pdf Download PDF

Poster


Relapsing-remitting facial palsy and brachial plexopathy caused by HSV-1 - read full article

By: K. Alstadhaug, H. Kvarenes, J. Prytz, and C. Vedeler

The etiologies of Bell’s palsy and brachial neuritis remain uncertain, and the conditions rarely co-occur or reoccur. Here we present a woman in her twenties who had several relapsing-remitting episodes with left-sided facial palsy and brachial neuropathy. The episodes always started with painful left-sided oral blisters. Repeat PCRs HSV-1 DNA from oral vesicular lesions were positive. Extensive screening did not reveal any other underlying cause. Except a mannose-binding lectin (MBL) deficiency, a congenital complement deficiency that is frequently found in the general Caucasian population, no other immunodeficiency was demonstrated in our patient. In vitro resistance to acyclovir was tested negative (IC50 ? 2 ?g/ml), but despite prophylactic treatment with the drug in high doses, relapses recurred. However, the stereotype neurological symptoms, confined to the same anatomical areas during each episode, and with short latency of the HSV-1 reactivation, favors a local infectious neuropathy. Findings on MRI T2-weighted brachial plexus STIR images, using a 3.0-Tesla scanner during an episode, were compatible with brachial plexus neuritis. To our knowledge, this is the first ever reported documentation of relapsing-remitting facial and rachial plexus neuritis caused by HSV-1.

Special Issue on Controversies in Neurology. From the 10th World Congress on Controversies in Neurology (CONy), Lisbon, Portugal. 17–20 March 2016.

International Journal of Clinical Neurosciences and Mental Health 2016; 3(Suppl. 1):P122

Icon_pdf Download PDF

Poster


Peripheral nerve hyperexcitability syndrome: longitudinal follow up of three patients - read full article

By: Rositsa Baltadzhieva and K. Kiprovski

Introduction: Peripheral Nerve Hyperexcitability (PNH) is characterized by continuous muscle fiber activity (CMFA). PNH is the chief manifestation of Isaacs’ syndrome and cramp-fasciculations syndrome (CFS). Antibodies to voltage gated potassium channels (VGKC-Ab) can be present. We report longitudinal observation of three patients. Case presentations: A 35-year-old female with mixed connective tissue disorder treated with hydroxychloroquine and prednisone, experienced muscle twitching, stiffness, cramps, delayed muscle relaxation, numbness in toes and difficulties walking. EDX testing showed generalized CMFA, (fasciculations, myokymic discharges, neuromyotonia) and axonal neuropathy. VGKC-Ab were negative. Anti-CASPR2 antibody was equivocal. Plasmapheresis and IVIG improved her walking. Long term treatment with carbamazepine was effective in alleviating the involuntary movements. Her function status remained improved on a three year follow-up. A 65-year-old male one year following resolved Guillain-Barré syndrome developed new symptoms of progressive generalized cramps, muscle twitching and difficulties walking on an incline. EDX revealed generalized CMFA compatible with CFS. VGKC-Ab were positive. Gabapentin, but not carbamazepine alleviated the symptoms. Three year follow-up showed continuous normal functional status. A 67-year-old presented with four years history of cramps and involuntary muscle twitching in the calves. EDX revealed CMFA compatible with CFS including afterdischarges. There were no identifiable comorbidities. VGKC-Ab were negative. Brief trial of gabapentin and later of carbamazepine provided no satisfactory relief and the patient declined further treatment. His neurological status did not change over the course of ensuing two years. Conclusions: PNH syndrome is a heterogeneous disorder. Longitudinal follow-up of our three patients showed good prognosis.

Special Issue on Controversies in Neurology. From the 10th World Congress on Controversies in Neurology (CONy), Lisbon, Portugal. 17–20 March 2016.

International Journal of Clinical Neurosciences and Mental Health 2016; 3(Suppl. 1):P123

Icon_pdf Download PDF

Poster


Analysis of EEG changes in patients with neurally mediated syncope - read full article

By: Magdalena Bosak and B. Song

Rationale: Neurally-mediated syncope is a common cause of transient loss of consciousness (TLOC). It is well established that convulsive movements often accompany syncopal events. Basic diagnostic workup of TLOC includes electroencephalogram (EEG). Misinterpretation of the EEG and the association of a TLOC with involuntary motor activity often leads to the wrong diagnosis of epilepsy. EEG during syncope shows either a ‘slow-flat-slow’ or a ‘slow’ pattern. However, it is difficult to monitor the EEG during a tilt table test, therefore the two tests are done separately. The aim of this study was to asses changes in EEG in patients with vasovagal syncope. Methods: 81 patients who were confirmed via tilt table testing to have neurally-mediated syncope were enrolled in the study. EEG with 5 minutes hyperventilation (HV) was performed in patients with syncope, and in 90 healthy age and sex matched controls. Results: During HV, more abundant and pronounced delta-theta activities were found in patients than in control subjects. Delta-theta activities were found in 48.5% of patients (vs. 11% of controls, p0.001). Generalized slow activity was found in 41.3% patients, while focal slow activity was found in 7.2% patients. Slow activities consisted mainly of bilateral synchronous high amplitude delta activity. No interictal epileptiform discharges were found. Conclusion: EEG in patients with neurally mediated syncope shows pronounced “pseudoparoxysmal” slowing during HV. These distinctive EEG changes should not be confused with interictal epileptiform discharges. Further studies are needed to confirm these findings and clarify its pathophysiology.

Special Issue on Controversies in Neurology. From the 10th World Congress on Controversies in Neurology (CONy), Lisbon, Portugal. 17–20 March 2016.

International Journal of Clinical Neurosciences and Mental Health 2016; 3(Suppl. 1):P124

Icon_pdf Download PDF

Poster


Incidence and risk factors for neuropathy following primary total hip arthroplasty - read full article

By: J. Nguyen, E. Su, S. Lyman, E. Manning, K. Cummings, C. Ching, A. Dalal, A. Wu, M. Sasaki, and T. Shetty

Background: Post-surgical neuropathy is a rare, but potentially devastating complication following total hip arthroplasty (THA). Previous literature suggests that prevalence of post-operative neuropathy ranges from 0.2% to 1.9% in primary THA cases. Aims: This study identifies potential risk factors for neuropathy after primary THA at a tertiary orthopedic institution. Methods: Patients who developed neuropathy following THA between January 1, 1998 and December 31, 2013 were identified by electronic hospital records and matched with 2 controls. The controls were matched by surgical date. Patient and surgical variables were reviewed using data from patient charts. Results: There were 81 neuropathy cases identified out of 39,056 primary THAs (0.21%) performed at our institution during the study period. The cases were matched with 162 controls. Patients older than 50 years were found to be less at risk for developing neuropathy (OR 0.38). Conversely, patient history of smoking (OR 3.45), lumbar spine disease or surgery (OR 2.29), and spinal stenosis (OR 4.31) were associated with increased risk. Surgeries between 10AM to 1PM (OR 1.71) and 1PM or later (OR 3.98) were also found to increase risk. Conclusions: The study demonstrates neuropathy is a rare complication following primary THA at our institution. Afternoon surgeries should be investigated, as personnel fatigue or shift change may be a cause for increased risk. Spinal stenosis and lumbar spine disease, and smoking history should be closely monitored to inform the patient and surgeon for the potential increased risk of post-operative neuropathy following THA.

Special Issue on Controversies in Neurology. From the 10th World Congress on Controversies in Neurology (CONy), Lisbon, Portugal. 17–20 March 2016.

International Journal of Clinical Neurosciences and Mental Health 2016; 3(Suppl. 1):P125

Icon_pdf Download PDF

Poster


Long-term survival of 3000 transthyretin familial amyloid polyneuropathy patients over a century - read full article

By: T. Coelho, M. Inês, I. Conceição, P. Saramago, M. de Carvalho, and J. Costa

Background: Comprehensive long-term survival data on transthyretin familial amyloid polyneuropathy (TTR-FAP) are scarce. We aimed to estimate long-term survival in this rare disease using data from the largest and oldest cluster of patients in the world. Methods: Registry data from the Portuguese referral centres were merged encompassing 3,026 Val30Met patients until Dec2015. Patient groups analysed comprised natural disease (n=1,675), treatment with liver transplant (LTx) (n=978) and disease modifying oral treatment with tafamidis (n=373). Kaplan-Meier survival estimates and Cox proportional hazards model were used to adjusted by gender, late-onset, treatment and time until treatment. Results: Overall, long-term median survival since disease onset was 13.29 years (95%CI: 13.01-13.94): 11.55 years (95%CI: 11.01-11.99) in the natural disease and 25.07 years (95%CI: 23.23-27.25) in the LTx group. Median survival was not reached in the tafamidis group, with 5 and 10 years’ survival rate of 99.70% (95%CI: 97.91%-99.96%) and 94.55% (95%CI: 85.73%-97.98%). LTx (HR 0.15, 95%CI: 0.12-0.19) and tafamidis (HR 0.04; 95%CI: 0.02-0.12) are associated with increased survival, compared with natural disease progression. Being male (HR 1.19, 95%CI: 1.08–1.31), late-onset (HR 1.46, 95%CI: 1.27–1.68) and time until treatment (HR 1.07, 95%CI: 1.03–1.10) were found to be important risk factors associated with increased mortality. Conclusions: Long-term survival of TTR-FAP Val30Met patients is poor. Although with higher short-term mortality, LTx significantly improved long-term survival. Tafamidis is associated with higher survival though longer follow-up data is needed. Shorter time between disease onset and treatment is associated with increased survival. In case of clinical progression under drug treatment it’s important to further study how and when to cross over to other options in order to maximize long-term survival from sequential treatments.

Special Issue on Controversies in Neurology. From the 10th World Congress on Controversies in Neurology (CONy), Lisbon, Portugal. 17–20 March 2016.

International Journal of Clinical Neurosciences and Mental Health 2016; 3(Suppl. 1):P126

Icon_pdf Download PDF

Poster


Cerebrospinal fluid markers of neuronal and glial cell damage to monitor disease activity and predict long-term outcome in autoimmune encephalitis - read full article

By: Radu Constantinescu, D. Krysl, F. Bergquist, K. Andrén, C. Malmeström, F. Asztély, M. Axelsson, E. Ben Menachem, K. Blennow, L. Rosengren, and H. Zetterberg

Background: Clinical symptoms and long-term outcome of autoimmune encephalitis are variable. Diagnosis requires multiple investigations, and treatment strategies must be individually tailored. Better biomarkers are needed for diagnosis, to monitor disease activity, and to predict long-term outcome. We investigated the value of cerebrospinal fluid (CSF) markers of neuronal (neurofilament light chain protein = NFL, and total tau protein = T-tau) and glial cell (glial fibrillary acidic protein = GFAP) damage in patients with autoimmune encephalitis. Methods: Demographic, clinical, magnetic resonance imaging, CSF and antibody-related data of 25 patients hospitalized for autoimmune encephalitis and followed for one year were retrospectively collected. Correlations between these data and consecutive CSF levels of NFL, T-tau, and GFAP were investigated. Disability, assessed by the modified Rankin scale, was used for evaluation of disease activity and long-term outcome. Results: The acute stage of autoimmune encephalitis was accompanied by high CSF levels of NFL and T-tau, whereas normal or significantly lower levels were observed after clinical improvement one year later. NFL and T-tau reacted in a similar way but at different speeds, with T-tau reacting faster. CSF levels of GFAP were initially moderately increased, but did not change significantly later on. Final outcome (disability at one year) directly correlated with CSF-NFL and CSF-GFAP levels at all time-points and with CSF-T-tau at LP2. This correlation remained significant after age-adjustment for CSF-NFL and T-tau, but not for GFAP. Conclusion: In autoimmune encephalitis, CSF levels of neuronal and glial cell damage markers appear to reflect disease activity and long-term disability.

Special Issue on Controversies in Neurology. From the 10th World Congress on Controversies in Neurology (CONy), Lisbon, Portugal. 17–20 March 2016.

International Journal of Clinical Neurosciences and Mental Health 2016; 3(Suppl. 1):P127

Icon_pdf Download PDF

Poster


Monitoring brain damage using surface current injection - read full article

By: Shimon Abboud, R. Cohen, and M. Arad

Disturbance in the blood supply to the brain causes a cerebrovascular accident (CVA). This can be due to ischemia (lack of blood flow) caused by blockage (thrombosis, arterial embolism) or a hemorrhage. In this study, the feasibility of injected low amplitude high frequency surface current over the center line of the scalp between the Nasion and the Inion points of the 10/20 EEG system, for monitoring such damage was analyzed in a computerized model. Simulations were conducted on a realistic 3D numerical model of the head. Tissues were assumed to act as linear volume conductors and electrical potentials were calculated by solving the volume conductor problem. Left-right asymmetry over the 10/20 EEG leads system was calculated for several conductivities and volumes of the damaged region. The results were compared with the left-right asymmetry found in a head model with normal brain. A negative asymmetry was revealed for ischemia (i.e. the potential amplitude over the ischemic hemisphere was greater than that over the intact hemisphere). In case of hemorrhage, a positive asymmetry was found. Furthermore, correlation was found between the location of the damaged region and the electrodes with significant asymmetry. The 3D numerical simulations revealed that the volume and the electrical conductivity of the damaged tissue are correlated with the left-right asymmetry of the surface potentials. These findings support the hypothesis that using surface current technique for monitoring brain damage is feasible.

Special Issue on Controversies in Neurology. From the 10th World Congress on Controversies in Neurology (CONy), Lisbon, Portugal. 17–20 March 2016.

International Journal of Clinical Neurosciences and Mental Health 2016; 3(Suppl. 1):P128

Icon_pdf Download PDF

Poster


Clinical presentation and predictors of outcome in adult patients with mitochondrial diseases - read full article

By: J. Durães, C. Duque, P. Garcia, L. Diogo, M. Grazina, and M. Macário

Introduction: Mitochondrial diseases have diverse clinical, biochemical and genetic presentations. Patients can have a “classic” mitochondrial syndrome or a more heterogeneous phenotype, leading to a challenging prediction of the clinical course and long-term outcome. Aim: To describe the clinical presentations in a cohort of adults with mitochondrial disease and determine predictors of their outcome. Methods: Demographics and clinical data were collected for all patients with a probable or definite diagnosis of mitochondrial disease according to the Bernier criteria. Outcomes were defined as death related to complications of the disease and degree of dependency, evaluated with the Katz Index of Independence in Activities of Daily Living. Results: 60 patients were included, 57% had an adult-onset form and the majority were female (62%). The most common phenotype was chronic progressive external ophthalmoplegia (46%). 6 patients died within follow-up (10%). Death was significantly associated with cardiac involvement (p=0.03). The mean Katz score was 5. Patients with a younger age at onset (p=0.05), presence of generalized myopathy (p=0.002), developmental delay (p=0.005) or cardiac involvement (p=0.05) as well as a history of encephalopathy (p=0.01), epilepsy (p=0.01) or stroke-like episodes (p=0.03) had a higher degree of dependency (defined as Katz score ?2). Conclusions: Our patients had mainly mild presentations with ocular involvement. The presence of other clinical findings is important for the degree of dependency and outcome. Cardiac involvement seems to be the main clinical factor related to death in mitochondrial disease, highlighting the importance of systematic cardiac study in these patients.

Special Issue on Controversies in Neurology. From the 10th World Congress on Controversies in Neurology (CONy), Lisbon, Portugal. 17–20 March 2016.

International Journal of Clinical Neurosciences and Mental Health 2016; 3(Suppl. 1):P129

Icon_pdf Download PDF

Poster


Temporal trends in transthyretin familial amyloid polyneuropathy survival over a century - read full article

By: T. Coelho, M.Inês, I. Conceição, P. Saramago, M. de Carvalho, and J. Costa

Background: Comprehensive long-term data on transthyretin familial amyloid polyneuropathy (TTR-FAP) survival are scarce. We estimated disease natural long-term survival using data from the largest and oldest patient’s cluster in the world. Methods: Registry data from the Portuguese referral centres were merged until Dec2015 encompassing 1,675 Val30Met untreated patients. Kaplan-Meier survival estimates were obtained and Cox proportional hazards model used to estimate hazard ratios (HR) and 95% confidence intervals (CI). We analysed survival trends using five cohorts: born before 1934, 1934–43, 1944–53, 1954–63 and after 1963, adjusted by gender and late-onset. Results: Natural long-term median survival since disease onset is 11.55 years (95%CI: 11.01-11.99) and has increased from 10.01 years (born before 1934, 95%CI: 9.38-11.01) to 11.92 years (born after 1963, 95%CI: 9.44-12.34). Being male (HR 1.29, 95%CI: 1.15–1.43) and late-onset (HR 1.38, 95%CI: 1.18–1.61) were found to be important risk factors associated with increased mortality. The 1934–43, 1944–53, 1954–63 cohorts are associated with increased survival (p0.01) as compared with those born before 1934. The cohort born after 1963 also has a positive trend (p=0.059) however without statistical significance, possibly due to higher selection into disease modifying interventions that impacted negatively the number and characteristics of untreated patients. Conclusions: If untreated, long-term survival since TTR-FAP disease onset is very poor, particularly in males and late-onset patients. Surveillance enhancement and multidisciplinary care provided by FAP referral centres can explain part of the observed increase in survival. Improvement in early referral to specialized centres is warranted. This may be achieved through better disease awareness and definition of a well identified network of referral centres.

Special Issue on Controversies in Neurology. From the 10th World Congress on Controversies in Neurology (CONy), Lisbon, Portugal. 17–20 March 2016.

International Journal of Clinical Neurosciences and Mental Health 2016; 3(Suppl. 1):P130

Icon_pdf Download PDF

Poster


Controversy lies in the eye of the beholder: video-oculography in chronic inflammatory demyelinating polyneuropathy - read full article

By: I.M. Ion, A. Corlobé, M. De Verdal, D. Renard, E. Thouvenot, and G. Castelnovo

Introduction: Chronic inflammatory demyelinating polyneuropathy (CIDP) is an acquired immune-mediated inflammatory disorder of the peripheral nervous system that affects motor and sensory fibers of the limbs. Less than 5% of the patients develop symptomatic ocular movement disorders. To the best of our knowledge, quantitative analysis of both saccadic and smooth pursuit eye movements has never been studied in CIDP. Methods: Fifthteen consecutive CIDP patients followed in our neurological department were invited to undergo video-oculography (VO, Eye-Brain Tracker) in December 2015. Results: Our group included 2 cases with pure motor, 7 with pure sensitive, and 6 with motor-sensory type CIDP. The sex ratio was 9M/6F and the mean age 58 years. The mean disease duration was 10 years. Mean overall neuropathy limitations scale score (range 0 to 12) was 3.5. None of the patients had ocular movement abnormalities on clinical (including complete oculomotor) examination. VO showed at least one saccadic or pursuit abnormality in all patients. Four patients had slow vertical saccades and three patients had slow horizontal saccades. Hypometric vertical and horizontal saccades were found in 5 and 6 patients respectively. Saccadic intrusions were observed in 4 cases and horizontal smooth pursuit was impaired in 2 patients. No specific oculomotor patterns were observed in the different CIDP types. Conclusion: All CIDP patients in our study had abnormal VO despite normal bedside oculomotor examination. Hypometria and slowing of vertical saccades were the most common ocular motor disorders found in our CIDP patients.

Special Issue on Controversies in Neurology. From the 10th World Congress on Controversies in Neurology (CONy), Lisbon, Portugal. 17–20 March 2016.

International Journal of Clinical Neurosciences and Mental Health 2016; 3(Suppl. 1):P131

Icon_pdf Download PDF

Poster


Electomyographic (EMG) peculiarities of neuromuscular transmission damage in patients with myasthenia gravis (MG) and Lambert-Eaton syndrome (LES) - read full article

By: Nana Kvirkvelia, Roman Shakarishvili, Rusudan Nikolaishvili, Maia Jibladze, Nino Mikava, and Nino Khizanishvili

Objectives: To reveal different pathogenic mechanisms reflecting EMG correlates of MG and LES. Methods: 89 MG and LES patients were EMG investigated. The functional state of neuromuscular transmission was determined by the decrement of M-response amplitude and area during the stimulation of different frequency. While stimulating with low frequencies, the determination of the decrement of the amplitude and area of the fifth M-response has been made by comparing the appropriate parameters of the first M-response and every next M-responses with the previous. Results: In patients with MG during the stimulation of low frequencies, the most significant decrement of the M-response was found between the second and first and the third and second responses. In patients with LES the decrement of M-response was manifested in all five responses toward the previous ones. Conclusion: The EMG peculiarities manifested during the stimulation with low frequencies in MG and LES explain different pathologic mechanisms of these two diseases. In this thesis the revelation of EMG peculiarities of human synaptic diseases will promote timely diagnostic and adequate therapy of these pathologies. Key message: EMG data of MG and LES will help to correctly diagnose these diseases and timely apply adequate therapy.

Special Issue on Controversies in Neurology. From the 10th World Congress on Controversies in Neurology (CONy), Lisbon, Portugal. 17–20 March 2016.

International Journal of Clinical Neurosciences and Mental Health 2016; 3(Suppl. 1):P132

Icon_pdf Download PDF

Poster


Colchicine-induced myopathy with myotonia - read full article

By: Jie-Yuan Li, C. Lee, and Y. Lo

Background: Acute gastrointestinal upset from the use of colchicine in the treatment of acute gouty arthritis is common. However, routine doses of colchicine may cause severe myopathy in patients with impaired renal function. Clinical or electrophysiological myotonia secondary to colchicine has very rarely been reported. Patient: A 79-year-old man presented with progressive weakness especially in the muscles of his lower limbs for about ten days before admission. He was diabetic, hypertensive and had coronary arterial disease with congestive heart failure for many years. He also had chronic renal insufficiency with a serum creatinine of 1.9 mg/dL. He had been treated with colchicine for gouty arthritis for the past 25 days. Neurological examination revealed proximal muscles weakness of four limbs, more prominent in the legs than in the upper arms. His deep tendon reflexes were absent. Percussion myotonia was present in the thenar muscles. Results: Laboratory evaluation demonstrated an increased level of serum creatine kinase (CK), lactate dehydrogenase (LDH) and aspartate aminotransferase (AST). Serum creatinine was 2.2 mg/dL. Electromyography revealed myopathy pattern and abundant widespread myotonic discharges in all muscles examined. Fibrillations and complex repetitive discharges were also widespread. Muscle biopsy findings showed prominent vacuolar formation in the myocytes. Electron microscopy revealed subsarcolemmal vacuoles containing multiple electron-dense lysosomal granules. After withdrawal of colchicine, marked improvement of his muscle strength occurred two weeks later. Conclusions: Colchicine-induced myopathy associated with clinical and electrophysiological myotonia is very rare. Colchicine should be used with caution in elderly patients with chronic renal insufficiency.

Special Issue on Controversies in Neurology. From the 10th World Congress on Controversies in Neurology (CONy), Lisbon, Portugal. 17–20 March 2016.

International Journal of Clinical Neurosciences and Mental Health 2016; 3(Suppl. 1):P133

Icon_pdf Download PDF

Poster


Long-term management of anti-n-methyl-d-aspartate receptor (NMDAR) encephalitis in young children—still a matter of debate - read full article

By: Sandra Moreira, P. Pires, and C. Garrido

Anti-NMDAR encephalitis is the best-characterized and most common antibody-mediated encephalitis. With early aggressive immunosuppression, prognosis is usually good, although recurrences have been reported in up to 20-25% of patients, mostly in patients without teratoma. Guidelines for the best medical management are still lacking, especially concerning its duration, the comparative efficacy of individual treatments and the role of corticoid-sparing agents. It is also unclear if tumors should be sought after an initial negative screening in males and females younger than 18. We report the case of a 30-month boy with previous speech delay, who presented with insidious onset of irritability, asymmetric dystonia and chorea, sleep disturbance and consciousness fluctuations. Infections and metabolic disturbances were excluded. NMDAR antibodies were identified in serum and CSF. MRI showed right insular and frontal cortex T2-hyperintensity. Tumor screening was negative. He was initially treated with metilprednisolone pulses and IVIG and then kept on monthly IVIG and prednisolone 1mg/Kg/day, followed by slowly tapering after 2 months of sustained clinical improvement. Follow-up MRI disclosed some brain atrophy and the patient remains with a significant speech delay after 5 months. Despite the good response to first-line treatments, as in this case, corticoid side effects in children may be severe and irreversible. On the other hand, quick withdrawal may compromise recovery and increase relapse probability, especially in cases without associated tumor. This case is illustrative of the difficulties faced by clinicians in the long-term management of NMDAR-encephalitis, namely in respect to the need of corticoid-sparing agents and tumor screening repetition.

Special Issue on Controversies in Neurology. From the 10th World Congress on Controversies in Neurology (CONy), Lisbon, Portugal. 17–20 March 2016.

International Journal of Clinical Neurosciences and Mental Health 2016; 3(Suppl. 1):P134

Icon_pdf Download PDF

Poster


Neurodegeneration in TTR amyloid neuropathy: schwann cell hypothesis - read full article

By: Tatsufumi Murakami, K. Sango, K. Watabe, N. Niimi, Z. Li, Z. Yamamura, and K. Sunada

TTR amyloid neuropathy is characterized by extracellular amyloid deposits and peripheral nerve involvement. Sensory dominant polyneuropathy and autonomic neuropathy are usually observed as early features in the patients. Though axonal degeneration is the primary change in TTR amyloid neuropathy, segmental demyelination and Schwann cell abnormalities have also been described. We previously demonstrated that the TTR gene is significantly expressed in Schwann cells of the dorsal root ganglia (DRG) and peripheral nerves. Then, we established a spontaneously immortalized Schwann cell line, TgS1, derived from the transgenic mice expressing human TTR Met30 gene in a mouse null background. TgS1 cells synthesized variant TTR and secreted it into the medium. The conditioned medium (CM) derived from TgS1 cells and recombinant variant TTR inhibited neurite outgrowth from DRG sensory neurons. Immunohistochemistry revealed TTR aggregates in the cytoplasm of Schwann cells and satellite cells of the DRG of aged transgenic mice. In a few satellite cells, TTR positive inclusions were observed in the cytoplasm. TTR immunoreactivity was also detected in the cytoplasm of myelinating Schwann cells. Proteasome inhibition induced TTR aggregates as aggresomes in the TgS1 cells. Electron micrographs of the cells showed autolysosomes. These findings support the hypothesis that Schwann cells might trigger neuropathy in TTR amyloidosis.

Special Issue on Controversies in Neurology. From the 10th World Congress on Controversies in Neurology (CONy), Lisbon, Portugal. 17–20 March 2016.

International Journal of Clinical Neurosciences and Mental Health 2016; 3(Suppl. 1):P135

Icon_pdf Download PDF

Poster


Parsonage Turner syndrome - read full article

By: Diana Naco

Parsonage Turner Syndrome is a neurological syndrome characterized by severe pain in the shoulder and arm. Is also known as brachial neuritis or neuralgic amyotrophy, is a peripheral nerve disorder . PTS may develop after trauma, viral or bacterial infection or vaccination, but the etiology it is still unknown. Parsonage-Turner Syndrome has an incidence of 1.64 cases in 100,000 people. Case Our patient, a 55 years old male, is presented in our clinic with several in the left shoulder and left arm. Patient underwent a detailed neurological examination. The x ray (radiograph) of the neck and shoulder was ordered. The orthopedic and rheumatic etiology was excluded. MRI cervical column is normal. The electromyography test result with denervation in involved muscles, conclude diagnosis. A review of literature for Parsonage turner syndrome is done.

Special Issue on Controversies in Neurology. From the 10th World Congress on Controversies in Neurology (CONy), Lisbon, Portugal. 17–20 March 2016.

International Journal of Clinical Neurosciences and Mental Health 2016; 3(Suppl. 1):P136

Icon_pdf Download PDF

Poster


Neurological complications of common variable immunodeficiency: the immune system in chaos - read full article

By: Ana Novo, P. Carvalho, A. Nogueira, J. Pita, C. Constanço, F. Vieira, L. Sousa, E. Faria, and S. Batista

Introduction: Autoimmune disorders and granulomatous disease are well established complications of Common Variable Immunodeficiency (CVID). However, central nervous system (CNS) involvement is rare in these disorders. Case 1: 42-year-old woman with recurrent occipital headaches since the age of 32 (1997). Brain-MRI showed hyperintense periventricular T2-lesions. Autoimmunity, serologic and CSF tests, SACE and visual evoked potential were normal. Protein electrophoresis revealed hypogammaglobulinemia G and A. In 2006, the patient presented left hemiparesis and hemihypoesthesia with spontaneous remission after 3-4 days, and recurrent mucocutaneous infections. Brain-MRI: multiple T2 hyperintense lesions in periventricular and bilateral frontal subcortical white matter. Cerebral vasculitis associated with CVID was diagnosed. Patient started a 30gr/month dose intravenous immunoglobulin (IVIG) therapy and achieved remission of infections and neurological symptoms. Case 2: 21-year-old man with a previous severe dental abscess, megaloblastic anemia and hypogammaglobulinemia (G and A). Bone marrow biopsy showed non-caseous granulomas. Infectious and neoplastic causes were excluded. In 2014, the patient was hospitalized due to new onset headache. Brain-MRI: multiple large and enhancing brain lesions. Granulomatous disease associated with CVID with CNS involvement was diagnosed. A 35gr/month IVIG therapy was started. In 2015, patient was rehospitalized due to flaccid paraparesis and urinary retention. Neuraxis-MRI: new multiple brain lesions and active cervicothoracic lesions. Improvement was observed in response to corticotherapy. Due to persistence of lesional activity, cyclophosphamid 400mg/m2/month was initiated. Conclusion: These cases illustrate the difficulty in diagnosis and treatment of CVID with neurological complications, since they entail the approach of a paradoxically hypoactive and hyperactive immune state.

Special Issue on Controversies in Neurology. From the 10th World Congress on Controversies in Neurology (CONy), Lisbon, Portugal. 17–20 March 2016.

International Journal of Clinical Neurosciences and Mental Health 2016; 3(Suppl. 1):P137

Icon_pdf Download PDF

Poster


Multiple sclerosis, Sjogren and/or another autoimmune disorder? - read full article

By: Adriana Rua, J. Alves, C. Pereira, G. Carvalheiras, S. Cavaco, and A. Martins da Silva

A 28-year-old female, with prior history of peripheral facial paralysis at age 12, developed signs of depression four months after giving birth to a healthy son. In the following years, her behaviour deteriorated (e.g., carelessness with chores, childish behaviour, hypersomnia, memory difficulties, psychomotor slowness, irritability, inappropriate laughter, unawareness of behavioural changes, and occasional incontinence). At 33, the patient was referred to neurology and the neurological examination only revealed fragmented saccadic movements and horizontal-torsional nystagmus. The neuropsychological assessment showed significant impairment in multiple cognitive domains (attention, psychomotor speed, visuo-spatial functions, memory, and executive functions). MRI scans disclosed multiple T2-weighted hyperintense lesions in supratentorial region (e.g., periventricular, subcortical, juxtacortical areas, and corpus callosum), infratentorial territory (cerebellum and brainstem), and cervical medulla suggestive of inflammatory/demyelinating aetiology. There were also signs of subcortical atrophy. To exclude other causes of white matter disease, a comprehensive series of laboratory studies were carried out. CSF had elevated IgG index and oligoclonal bands. Visual evoked potentials revealed bilateral prolonged latencies. The immunological tests found ANA=1/640 and high anti-thyroid antibodies. These set of paraclinical findings were supportive of Multiple Sclerosis–cortical variant. A course of methylprednisolone did not have a significant effect. One year later, the patient developed Sicca syndrome and diarrhoea of unknown aetiology. Additional investigation revealed ANA=1/1280 and salivary gland scintigraphy and biopsy compatible with Sjogren syndrome. Neuropsychological and MRI findings did not show significant changes from prior examination. The prolonged neuropsychiatric symptoms associated with a puzzling set of clinical and paraclinical findings pose a diagnostic challenge.

Special Issue on Controversies in Neurology. From the 10th World Congress on Controversies in Neurology (CONy), Lisbon, Portugal. 17–20 March 2016.

International Journal of Clinical Neurosciences and Mental Health 2016; 3(Suppl. 1):P138

Icon_pdf Download PDF

Poster


Recurrent coma in patient with Hashimoto’s encephalitis: a case report - read full article

By: Ia Rukhadze, T. Kishmaraia, M. Mgaloblishvili, T. Chanishvili, and G. Kiliptari

Hashimoto's encephalitis is very rare neurological disorders. It presented of many different types of neurological features. This form of encephalitis is in many cases difficult statement of diagnosis. 53 year old woman with unknown comas was hospitalized three times in different clinics during 4 months. Each attack was repeated about one month period. In all cases patient’s relatives have found her in loss of consciousness and after this they have made patient hospitalized. Because of acute breathing problem artificial respiration of lungs was needed. In the first and second cases there were generalized and myoclonic seizures associated with deep coma. Between recurrent coma periods patient was in normal condition, but the only clinical signs were tremor of limbs. According to the following observations: MRT, CT and EEG and also to the several laboratory features, there weren’t any pathological changes. After the second comatose statement, lowp recorder was inserted. We haven’t found any pathological disorders. Only in the third episode of coma TSH was increased till 10. Also, anti TPO and anti TG parameters were higher. PET observation showed encephalitic injuries in both thalamus. After this, patient was treated with hormonotherapy. Patient was positively affected by this kind of treatment. After 10 month remission patient was again in comatose condition. Nowadays, patient is in normal condition and takes prednisolon. Rare forms of Hashimoto’s encephalitis are especially severe development forms. They need timely differential diagnosis and despite of treatments have recurrent evolvement.

Special Issue on Controversies in Neurology. From the 10th World Congress on Controversies in Neurology (CONy), Lisbon, Portugal. 17–20 March 2016.

International Journal of Clinical Neurosciences and Mental Health 2016; 3(Suppl. 1):P139

Icon_pdf Download PDF

Poster


Cognitive impairment in patients with autoimmune thyroiditis: an underdiagnosed entity? - read full article

By: Ricardo Soares-dos-Reis and Joana Guimarães

Introduction: Autoimmune thyroiditis with hypothyroidism is an undisputed cause of cognitive dysfunction and encephalopathy. However, attributing mild cognitive complaints to this condition, in patients under adequate T4 supplementation, remains controversial. Case: A 39 year-old woman complained of cognitive impairment when performing complex tasks or multi-tasking, accompanied by occasional dizziness and headache, which had been waxing and waning for 5 years. Prior medical history revealed an autoimmune thyroiditis with a high anti-peroxidase antibody titer (683 IU/mL), diagnosed when the symptoms started, currently under adequate T4 supplementation. Her neurological examination was normal, except for slow speech and frequent pauses, losing narrative flow. Cerebral and cervical MRI and MRA, vestibular testing, ambulatory blood pressure and 24h Holter monitoring were normal. Remaining immunological testing, insulin levels and catecholamine metabolites were within normal range. A 24h EEG consistently revealed bouts of mainly alpha, but also theta activity in a left anterior temporal location, reflecting dysfunction in those areas, during the complaints of clouding of consciousness. Formal neuropsychological testing showed mild executive dysfunction. A 3-day intravenous pulse of 1gr methylprednisolone was tried, with subjective improvement and normalization of speech. A repeat 24h EEG showed no bouts of theta waves and a marked reduction in the periods of abnormal alpha activity. Conclusion: We describe a case of subjective cognitive complaints with objective EEG findings and improvement after corticosteroids. The association of subtle cognitive deficits with autoimmune thyroiditis is seldom reported, making this a rare, or underdiagnosed, entity.

Special Issue on Controversies in Neurology. From the 10th World Congress on Controversies in Neurology (CONy), Lisbon, Portugal. 17–20 March 2016.

International Journal of Clinical Neurosciences and Mental Health 2016; 3(Suppl. 1):P140

Icon_pdf Download PDF

Poster


Meningitis-retention syndrome - read full article

By: Ana Luísa Sousa, Raquel Samões, Ana Trepa, and Luís F. Maia

Meningitis-retention syndrome (MRS) is a rarely reported and poorly understood entity that combines urinary retention and aseptic meningitis. The etiology remains unknown, although both infectious and inflammatory causes have been proposed. A 35-year-old female presented with a history of flu-like symptoms and fever followed by urinary retention of more than 1000ml two weeks later. On examination she had mild nuchal rigidity and generalized hyperreflexia. The CSF showed 96 leukocytes (86 lymphocytes and 10 polymorphonuclear cells), mild proteinorraquia (0,46g/L) and normal glucose (0.51g/L). Herpes simplex virus PCR was negative as were serologies for EBV, CMV, borrelia, bartonella, mycoplasma and mycobacterium tuberculosis. The neuroaxis MRI was normal and the urodynamic study revealed a hyposensitive and acontractile detrusor. She was treated with 3 weeks of antibiotics, tamsulosin and intermittent urinary catheterizations. There was only partial clinical and CSF cell count improvement. She then had a 3-day course of methylprednisolone 1gr/day with gradual but complete resolution. An uroflowmetry performed 5 months after the onset of symptoms showed significant improvement: voiding became possible without straining and the residual volume decreased dramatically. MRS should be considered in the differential diagnosis of urinary retention and meningitis. Whether this syndrome represents a sacral myeloradiculitis, a parasympathetic pelvic ganglia involvement or another lesion throughout the neuroaxis remains controversial. Corticoid pulses have been used with inconsistent results. In this case, clinical recovery coincided with high dose steroid treatment, suggesting that an immune-mediated mechanism may underlie such condition, in line with what is predicted to occur in acute disseminated encephalomyelitis (ADEM).

Special Issue on Controversies in Neurology. From the 10th World Congress on Controversies in Neurology (CONy), Lisbon, Portugal. 17–20 March 2016.

International Journal of Clinical Neurosciences and Mental Health 2016; 3(Suppl. 1):P141

Icon_pdf Download PDF

Poster


Guillain Barre syndrome variant with facial diplegia and paresthesias associated with systemic lupus erythematosus - read full article

By: Sung Sang Yoon, H.Y. Rhee, B.S. Na, and Y.N. Kwon

Bilateral facial palsy is a rare clinical presentation and extensive diagnostic work-up is mandatory for identifying the cause. We present a case of variant GBS showing bilateral facial palsy, which could be a presenting manifestation of SLE. A 58-year-old woman admitted to our hospital for the development of bilateral symmetrical facial weakness. She had upper respiratory infection symptoms two weeks prior to the admission. Six days before the admission, she noticed that she could not close her right eyelid completely. One day before the admission, she was unable to close the left eyelid and move cheeks properly. High resolution CT of chest showed subpleural reticular opacities, interlobular saptal thickening, and ground glass opacities in both lung fields. Laboratory data about autoimmunity revealed that ANA (homogenous 1:640, cytoplasmic 1:160) and anti-dsDNA, nucleosome, and ribosomal P protein were positive. Nerve conduction studies showed the evidence of demyelinating sensorimotor polyneuropathy. The clinical and laboratory features of the patient, which include a history of antecedent infection, acute onset and rapidly progressive bilateral facial palsy, paresthesia in the distal limbs, electrophysiologic evidence of systemic polyneuropathy, and CSF albuminocytologic dissociation, support the diagnosis of a regional GBS “facial diplegia with limb paresthesias”. The peripheral manifestations in patients with SLE include polyneuropathy, mononeuritis multiplex, cranial neuropathy, and mononeuroapthy. It also is possible that a variant form of GBS is associated with one of neurological manifestation of SLE.

Special Issue on Controversies in Neurology. From the 10th World Congress on Controversies in Neurology (CONy), Lisbon, Portugal. 17–20 March 2016.

International Journal of Clinical Neurosciences and Mental Health 2016; 3(Suppl. 1):P142

Icon_pdf Download PDF

Guest Editorial


CONy 2016: Controversies in Neurology were ignited in Lisbon and acknowledged in the International Journal of Clinical Neurosciences and Mental Health - read full article

By: Elsa Azevedo and Amos D. Korczyn

Controversy was ignited in Lisbon during March 2016 by one of the most important meetings in clinical neurology worldwide. The 10th Meeting of Controversies in Neurology (CONy) took shape along four days of intense debate and rich scientific overview. Leading experts from all subspecialties of clinical neurology and neuroscience coming from all corners of the world got together to challenge paradigms, update knowledges and identify the boundaries of current clinical reasoning. The program was organized across seven main areas of debate (Multiple Sclerosis, Stroke, Dementia, Headache, Movement disorders, Epilepsy and Neuromuscular), predated by discussions on the locally identified Machado-Joseph’s Disease and Portuguese amyloid neuropathy, followed by insights on the Neurology beyond the horizon. The present special issue of the International Journal of Clinical Neurosciences and Mental Health devoted to the 10th Meeting on Controversies in Neurology includes the abstracts of all the invited lectures and free communications of this meeting, as well as full articles proceeding from CONy 2016, as reviews, original research, viewpoints or case reports. It is a tribute to this event, allowing it to remain immortalized in an international academic journal. We look forward for more debates and enlightening discussions in CONy 11th, which will take place shortly (March 23-26, 2017) in Athens, Greece (www.comtecmed.com/cony).

Special Issue on Controversies in Neurology. From the 10th World Congress on Controversies in Neurology (CONy), Lisbon, Portugal. 17–20 March 2016.

International Journal of Clinical Neurosciences and Mental Health 2016; 3(Suppl. 1):S01 

Icon_pdf Download PDF

Review Article


Does the diagnosis of Alzheimer's Disease imply immediate revocation of a driving license? - read full article

By: Sokratis G. Papageorgiou, Ion N. Beratis, Dionysia Kontaxopoulou, Stella Fragkiadaki, Dimosthenis Pavlou, and George Yannis

Driving competence is strongly related to the autonomy and the feelings of self-worth of advanced agers. At present, older drivers appear to retain their driving license for longer periods of time as well as to drive more commonly and to cover longer distances as compared to the past. Nonetheless according to epidemiological data, older individuals appear to be a vulnerable driving group that manifests increased rates of road fatalities. Along this vein, several lines of previous research have focused on exploring the driving behavior of individuals with two common cognitive disorders, namely Alzheimer-dementia (AD) and Mild Cognitive Impairment (MCI). Based on previous findings, patients with AD commonly present increased driving difficulties at a level that clearly supports the discontinuation of driving. Nonetheless, some patients with AD, especially in the mild stages, retain adequate driving skills that are similar to those of cognitively intact individuals of similar age. As concern the group of drivers with MCI, it seems that there is an accentuated risk to develop driving difficulties, but their performance is not consistently worse than that of healthy control drivers. Nonetheless, additional studies are warranted for detecting useful predictors of driving behavior in the specific clinical group. Under this perspective and by integrating the previous findings, we suggest the need for implementing a personalized approach when taking decisions about the driving competence of drivers with AD and MCI that is based on the effective synthesis of multimodal driving-related indexes by the specialties of neurology, neuropsychology and transportation engineering.

Keywords: Driving, Dementia, Alzheimer disease, Mild Cognitive Impairment, Driving behavior.

Special Issue on Controversies in Neurology. From the 10th World Congress on Controversies in Neurology (CONy), Lisbon, Portugal. 17–20 March 2016.

International Journal of Clinical Neurosciences and Mental Health 2016; 3(Suppl. 1):S02 

Icon_pdf Download PDF

Original Article


A comparative study of innate immunity markers in Alzheimer's disease, Mixed dementia and Vascular dementia - read full article

By: Liubov Androsova, Nataliya Mikhaylova, Svetlana Zozulya, Aleksandr Dupin, and Tatyana Klyushnik

Background: Innate immunity is currently considered to be an important component of pathological cascade in old age dementia. The aim of this study was to evaluate activity of inflammatory markers such as leukocyte elastase and alpha-1 proteinase inhibitor, as well as concentration of C-reactive protein and interleukin-6 in blood plasma of patients with pure’ AD, mixed dementia and VaD of varying severity. 
Methods: Several parameters of innate immunity such as leukocyte elastase activity (LE), the functional activity of ?1-proteinase inhibitor, the concentration of C-reactive protein (CRP) and interleukin-6 (IL-6) were measured in blood plasma of elderly patients with main forms of dementia including: Alzheimer’s disease (AD), mixed dementia (MD) and vascular dementia (VaD).
Results: A total of 161 in-patients and 39 control subjects were included in the study. The levels of innate immunity markers were found to depend on the severity of dementia. The decreased activity of LE in AD and MD is suggested to be due to the alteration of neutrophils degranulation activity or to changes in enzyme properties. A negative correlation between the level of IL-6 and degree of cognitive impairment in AD (Spearman r= -0.43; p<0.05) indicates significantly that levels of proinflammatory cytokines may characterize the severity of the process having the great impact on (lower) total MMSE score. Elevated level of CRP is likely to be a biological marker of an early stage of disease in VaD. 
Conclusions: Our results confirm the presence of an inflammatory component in the pathological cascade of AD, MD and VaD. 

Keywords: Alzheimer’s disease, Mixed dementia, Vascular dementia, Innate immunity, Leukocyte elastase activity, Functional activity of ?1-proteinase inhibitor; C-reactive protein, Interleukin-6 


Special Issue on Controversies in Neurology. From the 10th World Congress on Controversies in Neurology (CONy), Lisbon, Portugal. 17–20 March 2016.

International Journal of Clinical Neurosciences and Mental Health 2016; 3(Suppl. 1):S03 

Icon_pdf Download PDF

Original Article


Chronic obstructive pulmonary disease as a risk factor for dementia - read full article

By: Saule T. Turuspekova, Dmitriy Mitrokhin, Almaz Zhanayev, Aigerim Ablayeva, Gaukhar Zhilkibayeva, and Asiya Umarbayeva

Introduction: Chronic obstructive pulmonary disease (COPD) remains a major public health problem. According to data released by the World Bank and the World Health Organization (WHO), it is expected that in 2020 it will be on the 5th place on the damage caused by diseases globally. Pulmonary pathology leads to disruption of cerebral blood flow. Insufficient oxygen supply to the brain at bronchial obstruction negatively affects the brain functions such as memory, attention, thinking. This study aims to identify the state of higher brain functions in patients with chronic obstructive pulmonary disease. 
Methods: There were studied 40 patients aged 26 to 87 years (28 men and 12 women) with COPD II, III and IV. Pulse oximetry was used to determine blood oxygen saturation. The study was conducted using the Montreal Cognitive Assessment Scale. 
Results: The study showed a significant reduction of memory, attention, thought in 14 patients (35% -<19 points), moderate decline of higher brain functions in 14 patients (35% -20 and 23 points ), a slight decrease - in 8 patients (20% -<25 points), and the norm– in 4 patients (10%). At the same time found a direct correlation between cognitive impairment and peripheral oxygen saturation: <95% saturation correlated with cognitive impairment and <85% saturation correlated with dementia. 
Conclusion: The present study indicates a significant impact of COPD on higher brain functions. 

Keywords: Chronic obstructive pulmonary disease (COPD), Mild Cognitive Impairment, Dementia

Special Issue on Controversies in Neurology. From the 10th World Congress on Controversies in Neurology (CONy), Lisbon, Portugal. 17–20 March 2016.

International Journal of Clinical Neurosciences and Mental Health 2016; 3(Suppl. 1):S04 

Icon_pdf Download PDF

Review Article


The improvement of MAO-B inhibitors in Parkinson’s disease is clinically irrelevant: a review - read full article

By: Alexandros Yiannakis and Spiros Konitsiotis

Introduction: The purpose of this review is to examine the clinical relevance of the statistically significant effects of monoamine oxidase-B inhibitors (MAO-B) inhibitors in Parkinson's disease (PD). 
Methods and Results: We applied the Minimal Clinically Important Difference (MCID) as a way to evaluate results as clinically significant and make a reference to the studies that calculated MCID for PD. The calculated MCID values were applied to the large-scale studies of the MAO-B inhibitors Selegiline, Rasagiline and Safinamide to evaluate the clinical importance of Unified Parkinson's Disease Rating Scale (UPDRS) Part III and Total mean changes. Only the PRESTO and LARGO studies for Rasagiline manage to exceed both UPDRS III and UPDRS Total MCID. In a similar manner, we applied the MCID to the large-scale studies of MAO-B inhibitors to evaluate OFF-time reduction mean changes. No study manages to exceed the OFF-time MCID. Finally, we compared the clinical outcome of Rasagiline with the Substantial Clinical Difference and with that of Levodopa and the Dopamine Agonist Pramipexole. 
Conclusion: Even if statistically significant, the MAO-B inhibitors' clinical efficacy is at least marginal and controversial, especially in comparison with that of Dopamine Agonists or Levodopa.

Keywords: Minimal clinically important difference, Parkinson’s disease, Monoamine oxidase-B inhibitors

Special Issue on Controversies in Neurology. From the 10th World Congress on Controversies in Neurology (CONy), Lisbon, Portugal. 17–20 March 2016.

International Journal of Clinical Neurosciences and Mental Health 2016; 3(Suppl. 1):S05 

Icon_pdf Download PDF

Review Article


Current targeted therapeutic strategies for oculopharyngeal muscular dystrophy: from pharmacological to RNA replacement and gene editing therapies - read full article

By: Aida Abu-Baker, Nawwaf Kharma, Christian Neri, Sarah Rasheed, Patrick A. Dion, Luc Varin, and Guy A. Rouleau

Oculopharyngeal muscular dystrophy (OPMD) is a midlife onset hereditary disease affecting skeletal muscles. It is characterized by progressive eyelid drooping, swallowing difficulties and proximal limb weakness. The distinct pathological hallmark of OPMD is the presence of filamentous intranuclear inclusions (INI) in patient's skeletal muscle cells. OPMD is caused by a mutation in the poly (A) binding protein nuclear 1 protein (PABPN1) gene, located on chromosome 14q. The normal PABPN1 gene has a (GCG)6 repeat encoding a polyalanine stretch at the 5’ end, while in OPMD patients this repeat is expanded to (GCG)8-13. Currently there is no effective treatment for OPMD. In this review, we discuss our current treatment strategies for OPMD. We present three experimental therapeutic approaches: pharmacological, RNA replacement, and gene editing. Our scientific findings could ultimately lead to an effective therapy for OPMD patients. 

Keywords: Oculopharyngeal muscular dystrophy, Pharmacological treatment, RNA replacement therapy, Gene editing, Polyalanine disorders, Protein aggregation, PABPN1

Special Issue on Controversies in Neurology. From the 10th World Congress on Controversies in Neurology (CONy), Lisbon, Portugal. 17–20 March 2016.

International Journal of Clinical Neurosciences and Mental Health 2016; 3(Suppl. 1):S06 

Icon_pdf Download PDF

Review Article


The role of rehabilitation in multiple sclerosis—is it worth it? - read full article

By: Isabel Amorim, Carolina Falcão, Daniela Pinto, Sofia Proença, and Jorge Jacinto

Introduction: Multiple Sclerosis (MS) is a complex immune-mediated disease that causes demyelination and degeneration within the brain and spinal cord. This may result in muscle weakness, abnormal tone, visual disturbances, decreased sensation, tremor/ataxia, bladder, bowel and sexual dysfunction, fatigue and impaired ambulation. Those symptoms cause disability and have a huge impact on quality of life (QoL). 
Methods: Literature review about the evidence assessing the rehabilitation interventions for maintaining functional capacity and reducing risk of losing important abilities and independence. Databases of Cochrane Library/Pubmed/Medline were searched, from 2004-2016 with the keywords "Physical therapy", "rehabilitation", "multiple sclerosis", "review". 
Results and Discussion: Physical exercise is safe and should be encouraged. Even though rehabilitation has no direct influence on disease progression, studies have shown that this intervention reduces the limitations, and helps to maintain QoL. Timing and setting of rehabilitation interventions should be selected individually. Benefits are generally higher in earlier phases of MS. A multidisciplinary approach, is the basic concept of any rehabilitation program. The main impairments that need to be specifically managed are spasticity, cognitive impairment, motor, sensory and visual deficits, fatigue and bladder/bowel dysfunction. Ambulation difficulties should be addressed to improve efficacy, efficiency and to reduce falls. Compensation through appropriate prescription of assistive devices, bracing, and/or wheelchairs will help improve safety. Cognitive training can improve memory span, working memory and immediate visual memory. New promising rehabilitation techniques may also be useful: impairment-oriented training, electromyogram-triggered neuromuscular stimulation, and robotic interactive therapies.
Conclusion: Rehabilitation has significant impact on achieving and maintaining QoL as well as on improving independence in patients with MS. A multidisciplinary and multimodal approach is the recommended model for neurorehabilitation interventions.

Keywords: Multiple sclerosis, Rehabilitation, Physical therapy, Quality of Life. 

Special Issue on Controversies in Neurology. From the 10th World Congress on Controversies in Neurology (CONy), Lisbon, Portugal. 17–20 March 2016.

International Journal of Clinical Neurosciences and Mental Health 2016; 3(Suppl. 1):S07 

Icon_pdf Download PDF

Viewpoint


My MRI worsened but I didn't. Should I change my disease-modifying treatment? - read full article

By: Uros Rot

It is imperative to recognize multiple sclerosis (MS) patients with high risk of disability progression as soon as possible and offer them more potent treatment. Data about the influence of early conventional MRI parameter worsening (without clinical progression or relapses) on early or late disability in treated MS patients are available mainly for interferons beta. Some of the studies showed that the development of new T2 or Gd enhancing lesions in the first year of interferon beta treatment predicted second and third year disease activity or worse late clinical outcome, but some of the studies were negative. The first-year MRI activity was not associated with clinical worsening of the disease in the next two years in patients treated with glatiramer acetate. There are no data which would indicate that the MRI-only worsening in patients treated with the oral drugs or monoclonal antibodies predicts poor outcome. There are many caveats which also need to be taken into account when considering an individual patient with the MRI-only worsening for escalation of therapy such as adherence to the injectables, presence of neutralizing antibodies, large interrater variability for comparative MRI data and adverse effects of the second-line drugs. Therefore a close clinical and MRI follow-up of patients with the MRI-only worsening is appropriate but escalation should be given only to those with more realistic risk of a poor prognosis. 

Keywords: Multiple sclerosis, Treatment, Prognosis, MRI

Special Issue on Controversies in Neurology. From the 10th World Congress on Controversies in Neurology (CONy), Lisbon, Portugal. 17–20 March 2016.

International Journal of Clinical Neurosciences and Mental Health 2016; 3(Suppl. 1):S08 

Icon_pdf Download PDF

Case Report


Acute demyelination in childhood associated with TNF alpha-inhibitor therapy - read full article

By: Sara Vila Bedmar, Emmanuelle Waubant, and Jennifer Graves

Introduction: Tumor necrosis factor- alpha inhibiting medications (TNFi) have revolutionized the treatment of autoimmunity. These are the most common medications used for conditions such as rheumatoid arthritis, juvenile idiopathic arthritis and for many other rheumatologic disorders (uveitis, vasculitidies, granulomatous disorders). These drugs have made possible long-standing disease remission. Regarding the large number of people on active treatment with TNFi, their benefits must be balanced against concerns for side effects. 
Case report: We report a case and discuss a rare, but serious adverse event associated with TNFi usage: central nervous system (CNS) demyelination. 
Discussion: Possible side effects related to TNFi include CNS acquired demyelinating disorders. After starting any immune modulating therapy, such as TNFi, there should be close monitoring of side effects or new disease symptoms. 

Keywords: Tumor necrosis factor (TNF) , Monoclonal antibodies, Anti-TNF treatment, Acute demyelination, Multiple sclerosis, Optic neuritis.

Special Issue on Controversies in Neurology. From the 10th World Congress on Controversies in Neurology (CONy), Lisbon, Portugal. 17–20 March 2016.

International Journal of Clinical Neurosciences and Mental Health 2016; 3(Suppl. 1):S09 

Icon_pdf Download PDF

Case Report


Long-term management of anti-N-methyl-D-aspartate receptor (NMDAR) encephalitis in young children—still a matter of debate - read full article

By: Sandra Moreira, Paula Pires, and Cristina Garrido

Background: Anti-NMDAR encephalitis is the best-characterized and most common antibody-mediated encephalitis. With early aggressive immunosuppression, prognosis is usually good, although recurrences have been reported in up to 20–25% of patients, mostly in patients without teratoma. Guidelines for the best medical management are still lacking, especially concerning its duration, the comparative efficacy of individual treatments and the role of corticoid-sparing agents. It is also unclear if tumors should be sought after an initial negative screening in males and females younger than 18. 
Case report: We report the case of a 30-month boy with previous speech delay, who presented with insidious onset of irritability, asymmetric dystonia and chorea, sleep disturbance and consciousness fluctuations. Infections and metabolic disturbances were excluded. NMDAR antibodies were identified in serum and CSF. MRI showed right insular and frontal cortex T2-hyperintensity. Tumor screening was negative. He was initially treated with metilprednisolone pulses and IVIG and then kept on monthly IVIG and prednisolone 1mg/Kg/day, followed by slowly tapering after 2 months of sustained clinical improvement. Follow-up MRI disclosed some brain atrophy and the patient remains with a significant speech delay after 5 months. Despite the good response to first-line treatments, as in this case, steroid side effects in children may be severe and irreversible. On the other hand, quick withdrawal may compromise recovery and increase relapse probability, especially in cases without associated tumor.
Conclusions: This case is illustrative of the difficulties faced by clinicians in the long-term management of NMDAR-encephalitis, namely in respect to the need and best choice of second-line treatments. 

Keywords: Anti-NMDAR encephalitis, Autoimmunity, Cognitive disturbance, Movement disorders. 

Special Issue on Controversies in Neurology. From the 10th World Congress on Controversies in Neurology (CONy), Lisbon, Portugal. 17–20 March 2016.

International Journal of Clinical Neurosciences and Mental Health 2016; 3(Suppl. 1):S10 

Icon_pdf Download PDF

Viewpoint


Endovascular therapy in acute stroke: directly to the catheter lab! - read full article

By: Ana Inês Martins and João Sargento-Freitas

The recent compelling evidence of intra-arterial therapies in acute ischemic stroke have urged the revision of local algorithms in stroke units across the globe. In fact, in the presence of a proximal intracranial occlusion endovascular treatments reached unprecedented hemodynamic and functional efficacy in an otherwise problematic clinical scenario. Up until recently, the attempt to reperfuse the symptomatic area was limited to the “old” intravenous infusion of alteplase (IVtPA). Albeit its merits, the clinical impact caused is significantly impaired due to its narrow therapeutic window, extensive list of contra-indications and limited efficacy in large vessel occlusions. In acute ischemic stroke with salvageable cerebral tissue a simplistic and pragmatic approach could define three main clinical scenarios: patients with contra-indication to IVtPA, patients with and those without large-vessel occlusions. For the first clinical scenario the answer is straightforward: to the catheter lab in all those with proximal occlusions. The answer is more troublesome in the advent of a large vessel occlusion without contra-indication to IVtPA. In this setting IVtPA has a reported recanalization rate of 10-20% with very limited clinical impact. On the other hand, it is not without side effects in the ischemic area, in remote cerebral areas as well as other organs susceptible to bleeding, not rarely in uncompressible locations. Ultimately, it may represent exposing the patient to potentially severe risks for minimal impact in the ischemic brain. For patients without proximal intracranial occlusions IVtPA is highly efficacious, rendering intra-arterial therapies as unnecessary. In conclusion, IVtPA will remain the mainstay of acute stroke treatment for all those with clear clinical indications. However, the advent of intra-arterial therapies has had a dramatic impact on stroke algorithms worldwide. Particularly, in the subset of patients with large vessel occlusions the option of going straight to the catheter laboratory is appealing as it would prevent the use of a marginally effective therapy with rare but potentially severe complications, promoting the need for urgent intra-arterial recanalization. 

Keywords: Acute stroke, Fibrinolysis, Neurosonology

Special Issue on Controversies in Neurology. From the 10th World Congress on Controversies in Neurology (CONy), Lisbon, Portugal. 17–20 March 2016.

International Journal of Clinical Neurosciences and Mental Health 2016; 3(Suppl. 1):S11 

Icon_pdf Download PDF

Case Report


Magnetic resonance imaging in patients with conventional cardiac devices: a case report - read full article

By: Pedro Brás, Ary de Sousa, Gonçalo Januário, Catarina Perry da Câmara, and Rui Pedrosa

Introduction: Many patients with pacemaker develop a medical condition for which a magnetic resonance imaging (MRI) may be necessary. The evidence around conventional pacemaker being a contraindication to MRI is controversial. 
Case report: A 73-year-old man presented with a 12-month worsening history of neck pain radiating to both arms with paresthesias and weakness in both arms. He had a conventional pacemaker implanted 5 years before. A week later he became quadriparetic, losing the ability to walk. MRI was deemed necessary and it was successfully performed with collaboration of cardiology and anesthesiology specialist. MRI revealed an intramedullary lesion suggestive of neoplasm and he was submitted to neurosurgical intervention. 
Discussion: Based on the findings from several clinical studies the risk of MRI in patients with conventional pacemaker may be lower than previously thought if a number of conditions are met and appropriate precautions are taken.

Keywords: Magnetic resonance imaging, Pacemaker, Cardiac devices.

Special Issue on Controversies in Neurology. From the 10th World Congress on Controversies in Neurology (CONy), Lisbon, Portugal. 17–20 March 2016.

International Journal of Clinical Neurosciences and Mental Health 2016; 3(Suppl. 1):S12 

Icon_pdf Download PDF

Case Report


Nonaneurysmal sulcal subarachnoid hemorrhage in a patient with atherosclerotic intracranial stenosis - read full article

By: Ana Gouveia, Ana Inês Martins, João Sargento-Freitas, Luciano Almendra, Fernando Silva, Bruno Rodrigues, Cristina Machado, Gustavo Cordeiro, and Luís Cunha

Background: Nonaneurysmal sulcal subarachnoid hemorrhage (sSAH) is a rare cause of cerebrovascular disease and represents a small proportion of nontraumatic SAH. 
Case report: We report the case of a 54-year-old male patient, who presented with severe abrupt headache, followed two days later by right visual field defect and dysphasia. Head CT revealed left peri-rolandic sSAH and two hypodense lesions (left cortical parieto-occipital and left subcortical parietal). Additional investigation found a severe MCA atherosclerotic stenosis. 
Discussion: The case reported represents a rare cause of sSAH. We discuss possible pathophysiological mechanisms.

Keywords: Sulcal subarachnoid hemorrhage, Atherosclerotic disease, Intracranial stenosis

Special Issue on Controversies in Neurology. From the 10th World Congress on Controversies in Neurology (CONy), Lisbon, Portugal. 17–20 March 2016.

International Journal of Clinical Neurosciences and Mental Health 2016; 3(Suppl. 1):S13 

Icon_pdf Download PDF

Case Report


Neurosonology: a potential diagnostic tool in central retinal vein occlusion - read full article

By: Ana Inês Martins, João Sargento-Freitas, Fernando Silva, José Beato-Coelho, Gustavo C. Santo, Cláudia Farinha, João Figueira, and Luís Cunha

Introduction: Central retinal vein occlusion (CRVO) is a common vascular retinal pathology. It produces a subacute monocular severe visual loss, usually painless. Retinal and iris neovascularization can result in vitreous hemorrhages, neovascular glaucoma and tractional retinal detachment. The diagnosis is clinically-based, through funduscopic exam, and supported by fluorescein angiography, an invasive technique requiring intravenous contrast administration. The diagnosis becomes harder in the presence of local complications preventing ocular fundus observation, as hemovitreous, sometimes requiring clarifying surgical intervention. Neurosonology, a non-invasive and safe technique, has not yet been pointed out as a definite diagnostic tool in CRVO. 
Case Report: An 82-years-old female with known and poorly controlled essential hypertension and type 2 diabetes mellitus, developed a subacute visual acuity impairment in her left eye, allowing solely hand movements visualization. Ophthalmoscopy reveled a total hemovitreous of the left eye. Ocular echography did not show any other lesions. Differential diagnosis stood between CRVO and ocular arterial ischemic syndrome. Transorbital colour coded Doppler identified a preserved left ophthalmic artery and a reverberant flow in the central retinal vein, suggesting CRVO. The patient underwent pars plana vitrectomy associated to endolaser as management of this secondary complication of CRVO. 
Discussion: The present clinical case underlines a potential new neurossonologic application, as a diagnostic tool in CRVO, particularly useful when ocular fundus cannot be properly visualised. 

Keywords: Neurosonology, Central retinal vein occlusion, Hemovitreous.

Special Issue on Controversies in Neurology. From the 10th World Congress on Controversies in Neurology (CONy), Lisbon, Portugal. 17–20 March 2016.

International Journal of Clinical Neurosciences and Mental Health 2016; 3(Suppl. 1):S14 

Icon_pdf Download PDF

Viewpoint


Sight resolution and brain integrative role during painting of miniature portrait - read full article

By: Jacek Bojakowski

The report addresses miniature painting in the context of brain function and plasticity. Summary of own experience in watercolor portrait miniature painting, its perception, and possible correlation with the integrative and selective brain activities is presented. Sight resolution and integrative function of human central nervous system is analyzed and a new idea for studying this function by neuroimaging is suggested.

Keywords: Sight resolution, Brain integration, Miniature portrait.

Special Issue on Controversies in Neurology. From the 10th World Congress on Controversies in Neurology (CONy), Lisbon, Portugal. 17–20 March 2016.

International Journal of Clinical Neurosciences and Mental Health 2016; 3(Suppl. 1):S15

Icon_pdf Download PDF

Case Report


A cluster-tic syndrome: a case report - read full article

By: Zoran Vukojevic, Aleksandra Dominovic-Kovacevic, Sanja Grgic, and Srdjan Mavija

Introduction: Cluster headaches and trigeminal neuralgia have typical clinical features with recurrent, attacks of severe pain in orbito-temporal area along with unilateral lacrimation and rhinorrhea (cluster headache) or within the innervation area of the roots of trigeminal nerve branches (trigeminal neuralgia). Co-occurrence of these two conditions, as it is often referred in the literature, is named cluster-tic syndrome. 
Case report: A 46-year-old, female patient was presented with episodic form of cluster headaches and concurrent trigeminal neuralgia. Painful attacks had a different time distribution and matching localization. Specific treatment led to relief in both types of headaches. MRI of the brain showed aberrant superior cerebellar artery which contacts with proximal segments of right trigeminal nerve, possibly leading to neuropathic pain. 
Discussion: Cluster headache has characteristic clinical presentation with intermittent, recurrent, severe pain and dysautonomic features in the orbito-temporal area, specific treatment of acute pain attacks (oxygen inhalation, subcutaneous sumatriptan injections) and specific prevention therapy (verapamil, prednisone), different from other primary headaches. Trigeminal neuralgia is presented with attacks of stabbing unilateral facial pain following the sensory distribution of one or more of the branches of trigeminal nerve. Both conditions are rare and its association is even more rare and called cluster-tic syndrome and they produce a strong and exhausting pain which requires a immediate attention and treatment. 

Keywords: Cluster headache, Trigeminal neuralgia, Cluster-tic syndrome. 

Special Issue on Controversies in Neurology. From the 10th World Congress on Controversies in Neurology (CONy), Lisbon, Portugal. 17–20 March 2016.

International Journal of Clinical Neurosciences and Mental Health 2016; 3(Suppl. 1):S16 

Icon_pdf Download PDF

Original Article


The effects of intrathecal methylene blue and glyceryl trinitrate administration on orofacial pain in mice - read full article

By: Catalina Bohotin, Teodora Alexa, Andrei Luca, Andrei Dondas, Adriana Negru, and Radu Iliescu

Background: Nitric oxide (NO) is involved in several types of painful conditions. In patients with chronic migraine, glyceryl trinitrate, a pro-drug for NO, can induce a delayed migraine episode. In this study, we decided to assess the effects of intrathecal administration of a NO pro-drug (glyceryl trinitrate-GTN) and a NO scavenger (methylene blue–MB) on orofacial pain (OFP). 
Methods: 24 BALB/c mice were divided into three groups as follows: GTN group (0.1mg/kg, n=8), MB group (0.05mg/kg, n=8) and control group (NaCl, n=8). All groups received the substance by the intrathecal route. Two hours after drug/saline administration, formalin was injected into the upper lip and the time mice spent rubbing/liking the injected area was recorded. 
Results: Intrathecal administration of MB and NTG had no effect on the acute phase of OFP when compared with control. In the second phase, however, both drugs had an analgesic tendency; for GTN, this was statistically significant (p=0.025), and for MB the effect was less important (p=0.083). 
Conclusions: By centrally administering a NO pro-drug and a NO scavenger, we expected to modulate NO production in formalin-induced OFP. Our results demonstrated that the acute phase of OFP does not depend on NO (neither of the drugs had any effect) and that both substances diminish pain perception in the persistent/inflammatory phase but only the NO pro-drug has a clear-cut antinociceptive effect. 

Keywords: Orofacial Pain, Nitric Oxide, Nitroglycerin, Methylene Blue, Analgesia, Intrathecal Injections

Special Issue on Controversies in Neurology. From the 10th World Congress on Controversies in Neurology (CONy), Lisbon, Portugal. 17–20 March 2016.

International Journal of Clinical Neurosciences and Mental Health 2016; 3(Suppl. 1):S17 

Icon_pdf Download PDF

Case Report


Psychogenic facial movement disorder: a case report - read full article

By: Eren Gozke, Boran Can Saraçoglu, Mustafa Eser, Aylin Reyhani, and Pelin Dogan Ak

Background: Psychogenic movement disorders (PMD) include a wide range of involuntary motor function disturbances that lack an organic cause. Presentation with the form of any known organic movement disorder can be seen. Psychogenic facial movement disorder (PFMD) is an interesting form of PMD and it is not yet fully characterised. 
Case report: A 44-year-old female patient was evaluated because of deviation of her mouth. She was admitted to another hospital before, in which cranial MRI had been performed and did not demonstrate any abnormality. Steroid therapy had been initiated with the diagnosis of peripheral facial paralysis (PFP). The patient was admitted to our outpatient clinic because the deviation of her mouth was not resolved completely. Neurological examination revealed flattening of the right nasolabial fold and downward retraction of the contralateral edge of the mouth, which disappeared during talking and exacerbated at rest. These findings suggested psychogenic facial dystonia and she was diagnosed as having PFMD. Her steroid therapy was discontinued and treatment with alprazolam was initiated. A prominent resolution of her complaints was observed during post-treatment follow-up control visits. 
Discussion: Although PFMD is not a rare condition, it is still under-recognized and under-treated. In patients with PFMD, phasic or tonic muscular spasms resembling dystonia can be seen. It involves most commonly the lips. A prompt diagnosis based on positive clinical signs will prevent unnecessary investigations and lessen the morbidity. 

Keywords: Psychogenic movement disorders, Facial movement disorders, Peripheral facial paralysis.

Special Issue on Controversies in Neurology. From the 10th World Congress on Controversies in Neurology (CONy), Lisbon, Portugal. 17–20 March 2016.

International Journal of Clinical Neurosciences and Mental Health 2016; 3(Suppl. 1):S18 

Icon_pdf Download PDF

Case Report


Spinal cord imaging in spastic paraparesis: are we cutting it thin enough? - read full article

By: Carolina Lopes, Ricardo Soares-dos-Reis, Luís Braz, Paulo Pereira, José Dias da Costa, and Joana Guimarães

Introduction: Spinal dural arteriovenous fistula (SDAVF) is a rare condition, but accounts for great disability in those affected. Despite improvements in spinal imaging, SDAVF diagnosis is often difficult or masked by more common entities. 
Case report: A 42-year-old-woman, with a history of ileal resection 4 years prior, presented with a 6-month course of progressive walking difficulty, denying any sensory or bladder complaints. Physical examination revealed spastic paraparesis, brisk deep-tendon reflexes in the lower limbs, bilateral Babinski sign and bilateral foot drop. Blood chemistry was normal except for low vitamin B12 levels. Electromyogram was compatible with sensorimotor axonal polyneuropathy and cervical, thoracic and lumbar spinal MRI revealed no signal change. Parenteral cyanocobalamin supplementation was initiated and the patient was discharged with a diagnosis of polyneuropathy and probable subacute combined degeneration. In the following months, the patient’s gait improved, but the spastic paraparesis was unchanged. Repeat spinal cord MRI revealed no signal change. Given the lack of improvement, a SDAVF was suspected. Spinal MR-angiography and volumetric T1 acquisitions after contrast were obtained using thin-slice and multiplanar reconstruction, revealing dilated vessels in the spinal periphery from T11 to L2 levels. Digital subtraction angiography confirmed the diagnosis and the patient was referred for surgical occlusion of the fistula. After surgical intervention, there was a clinical improvement. 
Conclusion: We describe a case of a SDAVF with superimposed vitamin B12 deficiency, whose diagnosis required extra-thin cuts of MR-angiography. SDAVFs are potentially reversible causes of myelopathy, thus emphasizing the importance of their early identification. 

Keywords: Magnetic Resonance Angiography, Subacute Combined Degeneration, Dural Arteriovenous Fistula, Spastic Paraparesis

Special Issue on Controversies in Neurology. From the 10th World Congress on Controversies in Neurology (CONy), Lisbon, Portugal. 17–20 March 2016.

International Journal of Clinical Neurosciences and Mental Health 2016; 3(Suppl. 1):S19 

Icon_pdf Download PDF