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Background: The extent of neurodegeneration in the earliest stages of central nervous system (CNS) demyelination is not known. Optical coherence tomography (OCT) is a powerful tool to study neurodegeneration in demyelinating disorders. Objectives: To study neuroaxonal loss in the retina of individuals with radiologically isolated syndrome (RIS) and investigate whether OCT measurements are associated with brain volumetrics and clinical conversion to multiple sclerosis (MS). Methods: Subjects fulfilling the Okuda criteria for RIS ( n = 15 patients, 30 eyes) and age- and sex-matched healthy controls (HC) underwent spectral-domain OCT and magnetic resonance imaging for volumetric measurement of brain structures. Results: Macular ganglion cell-inner plexiform layer (mGCIPL), macular retinal nerve fiber layer (mRNFL), and temporal peripapillary RNFL (pRNFL) thickness; normalized total brain volume (nTBV); and normalized thalamic volume (nTV) were reduced in RIS compared to HC. mGCIPL, mRNFL, and pRNFL measurements were associated with nTBV, nTV, and normalized gray and white matter volumes in the RIS group. pRNFL was thinner in individuals with RIS who converted to MS in 5 years. Conclusions: Retinal neurodegeneration can be detected in the papillomacular region in the earliest stages of CNS demyelination and reflects global disease processes in the brain. OCT can be potentially useful for predicting prognosis in RIS.

Objective: to identify circulating myelin oligodendrocyte glycoprotein (MOG)-specific B cells in the blood of patients with MOG antibodies (Abs) and to determine whether circulating MOG-specific B cells are linked to levels and epitope specificity of serum anti-MOG-Abs. Methods: we compared peripheral blood from 21 patients with MOG-Abs and 26 controls for the presence of MOG-specific B cells. We differentiated blood-derived B cells in vitro in separate culture wells to Ab-producing cells via engagement of Toll-like receptors 7 and 8. We quantified the anti-MOG reactivity with a live cell-based assay by flow cytometry. We determined the recognition of MOG epitopes with a panel of mutated variants of MOG. Results: MOG-Ab-positive patients had a higher frequency of MOG-specific B cells in blood than controls, but MOG-specific B cells were only detected in about 60% of these patients. MOG-specific B cells in blood showed no correlation with anti-MOG Ab levels in serum, neither in the whole group nor in the untreated patients. Epitope analysis of MOG-Abs secreted from MOG-specific B cells cultured in different wells revealed an intraindividual heterogeneity of the anti-MOG autoimmunity. Conclusions: This study shows that patients with MOG-Abs greatly differ in the abundance of circulating MOG-specific B cells, which are not linked to levels of MOG-Abs in serum suggesting different sources of MOG-Abs. Identification of MOG-specific B cells in blood could be of future relevance for selecting patients with MOG-Abs for B cell-directed therapy., DFG; Munich Cluster for Systems Neurology EXC 1010 SyNergy and EXC 2145 SyNergy; Clinical Competence Network for Multiple Sclerosis; European Academy of Neurology; Scientific and Technological Research Council of Turkey (TÜBİTAK) 2219 Program; Alexander von Humboldt Foundation; Werner Reichenberger Stiftung; Verein zur Therapieforschung fur Multiple Sklerose-Kranke

Background Antibodies to the aquaporin-4 (AQP4) water channel in neuromyelitis optica spectrum disorder (NMOSD) are reported to trigger the complement cascade, which is implicated in astrocyte damage and subsequent neuronal injury. The PREVENT study demonstrated that the terminal complement inhibitor eculizumab reduces adjudicated relapse risk in patients with anti-AQP4 immunoglobulin G-positive (AQP4+) NMOSD. The objective of this analysis was to evaluate the efficacy of eculizumab in reducing relapse risk and its safety in AQP4+ NMOSD across clinically relevant subgroups in PREVENT. Methods In the randomized, double-blind, time-to-event, phase 3 PREVENT trial, 143 adults received eculizumab (maintenance dose, 1200 mg/2 weeks) or placebo (2:1), with stable-dose concomitant immunosuppressive therapy (IST) permitted (except rituximab and mitoxantrone). Post hoc analyses of relapses and adverse events were performed for prespecified and post hoc subgroups based on concomitant IST and prior rituximab use, demographic and disease characteristics, and autoimmune comorbidity. Results The significant reduction in relapse risk observed for eculizumab versus placebo in the overall PREVENT population was consistently maintained across subgroups based on concomitant IST and previous rituximab use, age, sex, region, race, time since clinical onset of NMOSD, historical annualized relapse rate, baseline Expanded Disability Status Scale score, and history of another autoimmune disorder. The serious infection rate was lower with eculizumab than placebo regardless of rituximab use in the previous year, concomitant IST use, or history of another autoimmune disorder. Conclusion Across a wide range of clinically relevant AQP4+ NMOSD patient subgroups in PREVENT, eculizumab therapy was consistently effective versus placebo in reducing relapse risk, with no apparent increase in serious infection rate. Trial registration NCT01892345 (ClinicalTrials.gov).

Background/Aim Neurological involvement (Neuro-Behcet's Disease: NBD) is a rare manifestation of Behcet's Disease (BD) and it is related with significant mortality and morbidity. We aimed to evaluate disease course and outcome of NBD patients registered in Hacettepe University Vasculitis Center (HUVAC) prospective database starting from October 2014. Methods Totally, 419 patients (329 of the patients had fulfilled the International Study Group (ISG) criteria and 90 patients were considered as incomplete BD) were recorded as BD to March 2018. We retrospectively reviewed the charts of 123 patients with neurological complaints/ symptoms according International Consensus Recommendations (ICR) Criteria for Neuro-Behcet's disease. In final analysis, 77 NBD patients (Definite NBD = 61, possible NBD = 16) were included. Demographics, clinical features, treatment characteristics, disability status and survival status of the patients were evaluated. Results Forty-seven (61%) of the patients were male. Median time to neurological involvement from first diagnosis of BD is 6 (IQR = 8.8) years in patients who had diagnosis of BD before neurological involvement. Distribution of NBD: parenchymal (pNBD), non-parenchymal (npNBD), mixed (mNBD) and peripheral nervous system (pnsNBD) were 47 (61%), 22 (28.6%), 5 (6.5%), 3 (3.9%), respectively. Eye involvement was more frequent in pNBD compared to npNBD. Brainstem (72.9%) was the most frequently affected parenchymal area and followed by cerebellum (43.8%) and diencephalon (37.5%). Twelve patients had spinal cord involvement (n = 12, 24.5%). Among the patients with pNBD and mNBD (total n = 52), 48 patients were considered as acute onset parenchymal disease and 4 patients were evaluated as chronic progressive disease. Fifty-eight percent of the patients with acute onset parenchymal disease had only one attack. Totally 14 BD patients deceased during a median 9.4 (IQR = 13) years disease duration and 9 of these patients had NBD (pNBD = 6, mNBD = 2, pnsNBD = 1). Corticosteroids (IV pulse = 75.5% and oral medium-high dose = 90%), alpha-interferon (76.9%), cyclophosphamide (57.1%), and TNF inhibitors (23.5%) were the most frequently preferred treatment options for pNBD. Conclusions Neurological involvement is seen about 5 years after the diagnosis of BD, and ocular involvement more commonly seen in these patients than non-NBD patients. More than half of the patients with acute onset parenchymal NBD had only one attack. No death was observed in the patients with non-parenchymal NBD. Biologic agents (Interferon-alpha and anti-TNF agents) were used in most patients.

Boz, Cavit/0000-0003-0956-3304 WOS: 000475740000018 PubMed: 31176296 Susac's Syndrome (SS), which was first described in 1979, is a rare and presumably autoimmune disorder characterized by encephalopathy, hearing loss, and visual disturbance resulting from branch retinal artery occlusion (BRAO). This study reports 19 SS patients' clinical characteristics, MRI features, CSF analysis, treatment strategies and outcomes. At initial presentation, only three of 19 patients demonstrated the complete clinical triad. Clinic presentation varied from isolated hemiparesis to the full triad (encephalopathy, hearing loss and visual disturbances). Corpus callosum (CC) involvement was noted in the MRI of 18 patients (97%) and BRAO was detected in 17 (95%) patients. All patients were treated with intravenous methylprednisolone after the initial assessment. This case series is presented to emphasize the differences in clinical presentation of SS and the importance of MRI and FFA in diagnosis.

To investigate the effects of different exercise protocols on ataxia in patients with multiple sclerosis (MS).A total of 42 MS patients, 17 male and 25 female (Expanded Disability Status Scale (EDSS): 3-5), were enrolled in this randomized controlled study. The patients were divided into three groups: a balance training (BT) group, a lumbar stabilization (LS) group and a task-oriented training (TT) group. All groups received balance training; additionally, the LS group received lumbar stabilization exercises, and the TT group received task-oriented training. The Berg Balance Scale (BBS), International Cooperative Ataxia Rating Scale (ICARS), Functional Reach Test (FRT), 2-Minute Walk Test (2MWT), Sensory Organization Test (SOT), and measurement of Somatosensory Evoked Potentials (SSEPs) were performed before and at the end of the 18 training sessions.The BBS, ICARS, FRT, 2MWT, and composite balance score of the SOT were improved in all groups. The ICARS kinetic function sub-score and the left limb cortical onset amplitudes of SSEPs were increased significantly in both the TT and the LS groups. The ICARS total score, composite balance score, and 2MWT were different between groups (p 0.05). According to multiple comparison analyses of the ICARS total score and the composite balance score, the LS, and the TT group were different from the BT group (p 0.005), while the LS and the TT groups improved similarly (p 0.005). The 2MWT results were better for the LS group than the BT group, while the BT and the TT groups improved similarly.Balance training alone is not sufficient for rehabilitation of ataxic MS patients. A combination of lumbar stabilization exercises or task-oriented training increases the success of balance rehabilitation. Implications for rehabilitation Multiple sclerosis is a chronic inflammatory and autoimmune disease of central nervous system and ataxia is one of the most challenging symptoms of this disease. Different exercise modalities are commonly employed to control ataxic symptoms in MS patients. Lumbar stabilization exercises or task-oriented training should be considered as complementary approach to improve balance and coordination in ataxic multiple sclerosis patients.

Background: Acute disseminated encephalomyelitis (ADEM) is a rare demyelinating disease of the central nervous system, commonly attributed to infections or vaccinations. Toxic or allergenic compounds can also trigger a response in the immune system and may cause demyelination. We present a case with ADEM after using oral herbal medications. Case Report: A 25 year-old male developed bilateral central facial palsy and severe quadriparesis after taking herbal drugs (containing echinacea and many other herbal ingredients) for two weeks. He had used the extract to increase his potency and reproductivity. He had no past history of recent immunization or viral infection. The clinical findings, cerebrospinal fluid (CSF) analysis and brain magnetic resonance imaging (MRI) were compatible with ADEM. The neurological findings were improved after seven doses of pulse methylprednisolone treatment. To our knowledge, this is the third report in the literature that links herbal therapy and demyelinating disease. Conclusion: Most of the ADEM cases related to herbal therapy in the literature similarly used echinacea. It is our opinion that other ingredients of the herbal extract used by our case, besides echinacea, could have the potential to cause a trigger in the immune system. Further studies are needed to clarify the immunological effects of different kinds of herbal compounds, as well as the effects of different parts of the plants and the results of various dosages. Moreover, ingredients should also be tested for toxicity, adverse effects and drug interactions.

Clinically isolated syndrome (CIS), an inflammatory demyelinating disorder of the central nervous system, is the first clinical episode with features predictive of multiple sclerosis (MS) (1). Many environmental risk factors for conversion from CIS to MS were shown in recent studies (1, 2). Among these, cigarette smoking was shown to increase the risk of developing MS even in passive smokers (3), worsen clinical disability, and exacerbate disease progression (4). Diffusion tensor imaging (DTI) gives the opportunity to evaluate the tissue integrity, mainly the white matter (WM). Through changes in metrics such as fractional anisotropy (FA) and mean diffusivity (MD), DTI enables the assessment of axonal organization and myelin attenuation in addition to the WM lesions evaluated by conventional magnetic resonance imaging (MRI) sequences (5). The brains of MS patients have demonstrated that an increase in MD and a decrease in FA values were far beyond fluid attenuation inversion recovery (FLAIR) hyperintense lesions, commonly used as a clinical parameter of MS (6, 7). Brain parenchyma with no apparent lesion, namely, the normal-appearing white matter (NAWM), has drawn much attention due to the presence of not only histopathologic and radiologic abnormalities but also a close association with clinical disability and disease progression (8). Changes in the NAWM may also be responsible for the clinicoradiologic discrepancy observed in many patients (6). In addition, several MRI studies have shown significantly altered FA measures in specific brain regions in healthy smoker individuals (9, 10). Although a number of studies have investigated the impact of smoking on patients with MS (4, 11), to the best of our knowledge, no study has studied the influence of smoking on the WM in patients with CIS using DTI. In this study we sought to determine the effects of smoking on NAWM, lesions, and perilesional WM of patients with CIS. The secondary objective was to examine whether diffusion tensor changes relate to the duration of disease, clinical disability and degree of smoking exposure.

INTRODUCTION Listeria monocytogenes-related central nervous system infections may involve the cerebral parenchyma. Meningitis and meningoencephalitis are the most commonly seen forms and mainly affect immunocompromised patients; however, a less frequent form, rhombencephalitis, can occur in otherwise healthy people. Early treatment with appropriate antibiotic therapy is crucial for this otherwise fatal disorder. However, it is not always possible to rapidly establish the diagnosis because of varying presentations and discrepancies in diagnostic tests. CASE REPORT Herein we report 3 cases of listerial infections involving the central nervous system parenchyma, with versatile diagnostic challenges and related possible solutions and radiologic hints to overcome similar issues in the future. CONCLUSIONS We point out the importance of nonconventional magnetic resonance imaging techniques in the diagnosis, as we detected petechial hemorrhages in the brain parenchyma in all cases, which can be a diagnostic clue.

Objective: This study aimed to evaluate laboratory oligoclonal band (OCB) patterns together with related IgG results and compare these results with data obtained through final clinical diagnosis. Also, to evaluate electrophoretic patterns based on reibergrams and the diagnostic value of OCBs in patients with multiple sclerosis (MS). Methods: Patients were grouped based on their diagnosis. Six classic patterns were determined. Oligoclonal band patterns and related IgG results were evaluated and these results were later compared with final clinical diagnoses. Results: A total of 1022 patients with known diagnoses were studied. Electrophoretic patterns and band counting based on Reibergram depictions were significantly different among patients with MS and other neurologic diseases. For all patients with MS, the OCB band positivity rate was 82.4%. Additionally, in the MS group, a significantly higher percentage (36.60%) of OCB positivity with more than 10 bands was detected. When reibergram results in the intrathecal IgG synthesis area and OCB counts (>10) were evaluated together, the diagnostic sensitivity (37%) and specificity (95%) were increased. Conclusion: OCB positivity, band counts, and Reibergram depictions contribute further to the diagnosis of ms when performed together for the neurologic diseases spectrum. OCB count, IgG index values, and Reibergram depictions should all be included in cerebrospinal fluid electrophoresis reports. The combined use of several laboratory test results are expected to provide valuable input for differential diagnosis of neurologic diseases.

Kansu, Tulay/0000-0002-1986-4680; Siva, Aksel/0000-0002-8340-6641; Altintas, Ayse/0000-0002-8524-5087; Mangan, Mehmet Serhat/0000-0001-7720-9003 WOS: 000369951300002 PubMed: 26468870 Background: Neuromyelitis optica (NMO) is an immune-mediated, chronic relapsing, inflammatory disease characterized by severe attacks of optic neuritis and myelitis. Objective: To determine the demographic, clinical, and laboratory features; antibody status; and treatment modalities of patients with NMO and neuromyelitis optica spectrum disorders in a Turkish cohort from 11 centers. Methods: A total of 182 patients were included in this study. Data on age at disease onset, sex, type of attacks, clinical presentation, analysis of cerebrospinal fluid, serum antiaquaporin-4 antibody status, annual progression index, and medical and family histories were collected. Results: Mean age was 38.43 +/- 12.40 years (range, 13 to 75 y), and mean age at disease onset was 31.29 +/- 12.40 years (median, 29 y; range, 10 to 74 y). In NMO group, the rate of NMO immunoglobulin (Ig)G positivity was 62.5%. The annual progression index was significantly higher in the longitudinally extending spinal cord lesion. The mean Expanded Disability Status Scale score was higher in the late than early-onset NMO group. Conclusion: Our results revealed a lower rate of NMO IgG positivity, more severe disability in patients with NMO/neuromyelitis optica spectrum disorders presenting with either transverse myelitis or late-onset NMO, and no correlation between disability and NMO IgG status.

Background Toscana virus (TOSV) is a sandfly-borne pathogen causing febrile diseases and neuroinvasive infections in humans. Definitive diagnosis of TOSV infections frequently requires the detection of viral RNA in cerebrospinal fluid (CSF) or in circulation, which can be achieved prior to seroconversion. Objectives To evaluate TOSV excretion in urine and impact of urine as a diagnostic specimen. Study design A total of 82 plasma, CSF and urine samples were collected from 24 individuals with a preliminary diagnosis of atypical viral encephalitis, where frequent bacterial fungal and viral causes were ruled out. Phlebovirus and WNV nucleic acids were investigated via real-time and nested polymerase chain reaction (PCR) assays. Commercial immunofluorescence assays were employed for viral IgM detection. Amplicons were characterized via cloning and sequencing. Results Phlebovirus PCR yielded positive results in 7 out of 14 samples that comprise 4 plasma and 3 urine specimens from 3 individuals. Amplicons were characterized as TOSV genotype A. Investigation of the follow-up samples suggested that virus shedding in urine coincides or follows viremia. Despite conserved sequences observed in paired or sequential plasma-urine specimens, L693S substitution in the viral polymerase was characterized in a urine sample. Conclusions These preliminary findings indicate that urine can be employed as a additional clinical sample for TOSV RNA detection in suspected cases, especially in individuals where specimens for viral diagnostics during the early stages of the infection are not available.

Multifocal acquired demyelinating sensory and motor (MADSAM) neuropathy is characterized by asymmetric multifocal motor and sensory loss and conduction blocks in peripheral nerves. Peripheral demyelinating diseases may be accompanied by demyelination in central nervous system (CNS). In this report, a MADSAM patient with a solitary tumefactive demyelinating lesion in brain is presented. Neuroimaging due to a visual field defect revealed a right parietooccipital lesion, which was initially misdiagnosed as a tumor. Pathological examination showed that it was demyelinating in nature. Peripheral nervous symptoms of the patient developed two years later and she was then diagnosed with MADSAM. There was prominent clinical and electrophysiological response to steroid treatment. Tumefactive brain involvement was not previously reported for MADSAM neuropathy, although it was documented in a single case with typical chronic inflammatory demyelinating polyneuropathy (CIDP). CNS involvement should therefore be considered in MADSAM patients.

BackgroundCombined central and peripheral nervous system demyelination is a rare and poorly described phenomenon. Recently, anti-neurofascin antibodies were reported to be positive in 86% of these patients in a Japanese cohort. Yet, there seems to be a clinical, radiological, and serological heterogeneity among these patients. In this report, our aim is to describe characteristics of our patients with this entity and compare with others in the literature.MethodsWe report clinical, electrophysiological, radiological, and laboratory characteristics of five patients with both multiple sclerosis and chronic inflammatory demyelinating polyradiculoneuropathy from our institutional database containing 1890 MS patients.ResultsThree patients presented with extensive, active demyelination of both central nervous system and peripheral nervous system with hypertrophic peripheral nerves. Plexuses, trunks, division and cords were involved in the process. Oligoclonal band was negative. Conduction block was not detected. Corticosteroid treatment was not adequate. Others had a slowly progressive clinical course. Serum anti-neurofascin antibody was negative. Review of the literature revealed similar cases with active disease, early-onset hypertrophic peripheral nerves, and central demyelination, in addition to other cases with an insidious course.ConclusionsPatients with combined central and peripheral demyelination form a spectrum. Some patients may have an antibody-mediated syndrome with or without anti-neurofascin antibodies and others seem to represent a coincidence.

Amac Primer progresif multipl skleroz (PPMS) ve progresif relapsing multipl skleroz (PRMS) baslangictan beri olan progresyon ile karakterize MS tipleridir. Nadir gorulmelerinden dolayi, literaturde diger MS formlarina gore daha az bilgi bulunmaktadir. Bu calismanin amaci progresif baslangicli MS (PBMS) hastalarinda klinik ve laboratuvar ozelliklerini ortaya koymaktir. Yontem PBMS hastalari 2010-2014 yillari arasinda degerlendirilip demografik, klinik ozellikleri ve beyin omurilik sivisi (BOS) bulgulari belirlendi. Bulgular Otuz iki PBMS hastasi ile ilgili veriler degerlendirildi. Hastalik seyri 24 hastada relaps olmadan (PPMS), sekiz hastada ise relapsli progresifti (PRMS). Kadin/erkek orani tum grupta 1'di. Ortalama baslangic yasi tum grup icin 40 (23-55) yasti. Gruplar arasinda hastalik baslangic yasi ortancasi anlamli farkli bulunmadi (p=0,053). En sik prezantasyon belirtisi motor bozukluklardi. Relapslar tum hastalarda hastaligin ilk 10 yilinda goruldu. BOS analizinde oligoklonal bant pozitifligi ve artmis IgG indeksi acisindan gruplar arasinda fark saptanmadi (p=0,938, p=0,058). Hastalik suresi her iki grupta da benzer oldugu halde, PPMS grubunda degerlendirme sirasinda ortanca EDSS skoru daha yuksek bulundu (p=0,020). Sonuc Calismamiz Turk PBMS hastalarinin klinik seyir ve laboratuvar bulgularina odaklanmis ilk calismadir. Iki grubun klinik ve laboratuvar bulgularinin karsilastirilmasi benzer sonuclar gostermistir. Gruplar arasinda hastalik baslangic yasi ve artmis IgG indeksi acisindan farklilik olup olmadigini netlestirmek icin gelecekte daha genis orneklemli calismalar yapilmasi gerekmektedir.

We, herein, report a 23-year-old male with a rare inherited immunodeficiency disease, hyperimmunoglobulin IgE syndrome (HIES), who developed progressive multifocal leukoencephalopathy (PML) and lymphoma simultaneously. Primary immunodeficiency of the patient has remained undiagnosed until adulthood. PML is a severe demyelinating disease of the central nervous system caused by John Cunningham virus. HIES is a rare, inherited immunodeficiency characterized by high serum levels of IgE, recurrent staphylococcal infection, eczema, and hypereosinophilia. PML may accompany primary immunodeficiency syndromes, but the association with HIES is exceedingly rare. We discuss the imaging findings, medical management, and a review of related literature on primary immunodeficiency cases complicating with PML.

A progressive encephalopathy of unknown etiology has been described in patients with primary immunodeficiency disorders. In this report, we characterize the clinical features of this progressive neurodegenerative dementing disorder in a young man with Bruton agammaglobulinemia, through neuropsychological tests and a video sequence. The clinical course of the encephalopathy seems rather uniform: Cognition, especially frontal lobe function, is affected in the early stages, and some patients develop movement disorders. The syndrome causes severe cognitive and physical disability, and can eventually be fatal. The autoimmunity results from dysregulated immune responses, but the underlying mechanism has not yet been fully explained.

Boz, Cavit/0000-0003-0956-3304; Altintas, Ayse/0000-0002-8524-5087; YUCEYAR, NUR/0000-0003-4590-6423; Sevim, Serhan/0000-0002-0518-3374; Efendi, Husnu/0000-0002-9143-3893, WOS: 000502098900008, PubMed: 31473488, Background: Fingolimod and teriflunomide are commonly used in the treatment of relapsing-remitting multiple sclerosis (RRMS). These have not been compared in controlled trials, but only in observational studies, with inconclusive results. Comparison of their effect on relapse and disability in a real-world setting is therefore needed. Objectives: the objective of this study was to compare the efficacy of fingolimod and teriflunomide in reducing disease activity in RRMS. Methods: This multicenter, retrospective observational study was carried out with prospectively collected data from 15 centers. All consecutive RRMS patients treated with teriflunomide or fingolimod were included. Data for relapses, Expanded Disability Status Scale (EDSS) scores and brain magnetic resonance imaging (MRI) scans were collected. Patients were matched using propensity scores. Annualized relapse rates (ARR), disability accumulation, percentage of patients with active MRI and treatment discontinuation over a median 2.5-year follow-up period were compared. Results: Propensity score matching retained 349 out of 1388 patients in the fingolimod group and 349 out 678 in the teriflunomide group for final analyses. Mean ARR decreased markedly from baseline after 1 and 2 years of treatment in both the fingolimod (0.58-0.17 after 1 year and 0.11 after 2 years, p < 0.001) and teriflunomide (0.56-0.29 after 1 year and 0.31 after 2 years, p < 0.001) groups. Mean ARR was lower in fingolimod-treated patients than in those treated with teriflunomide at years 1 (p = 0.02) and 2 (p = 0.004). Compared to teriflunomide, the fingolimod group exhibited a higher percentage of relapse-free patients and a lower percentage of MRI-active patients after 2.5-year follow-up. Disability worsening was similar between the two groups. Patients were less likely to discontinue fingolimod than teriflunomide (p < 0.001). Conclusion: Fingolimod was associated with a better relapse control and lower discontinuation rate than teriflunomide. the two oral therapies exhibited similar effects on disability outcomes.

Anti-NMDA receptor encephalitis is a severe disorder characterised clinically by seizures, autonomic instability, and severe disturbances of memory, behaviour, and cognition. Due to the severity of symptoms, many patients are admitted to the intensive care unit. For some patients, the presence of various movement disorders and abnormal autonomic signs, as well as a history of seizures, lead to a false impression of status epilepticus, which is reported in 6% of the cases. Here, we present two young female patients, one of whom had ovarian teratoma. Both patients were referred to our neurological intensive care unit with a diagnosis of status epilepticus. However, prolonged video-EEG findings were compatible with encephalopathy. We avoided aggressive treatment with intravenous anaesthetics and both patients recovered after immunotherapy, one of whom received surgery. Physicians should be cautious in interpreting abnormal movements and autonomic signs in such patients and video-EEG monitoring is advised when status epilepticus is suspected. [Published with video sequences].

Th17-related cytokines (IL-17, IL-23, and IL-26) and receptors (IL-17R and IL-23R) were evaluated in MS patients under immunomodulatory IFN-β1 therapy during a 2year follow-up. Before the initiation of treatment, no significant difference was found in cytokine or receptor expression between controls and MS patients. Of the three cytokines evaluated, IL-26 was the highest in the patients' sera. The amount of IL-17 and CD13(+)IL-17R(+) cells was steadily decreased whereas IL-23 and IL-26 levels were gradually increased with IFN-β1 therapy. The patients in progressive phase had very high levels of IL-17. Th17-associated parameters should be considered in the immunomodulatory IFN-β1 therapy of MS.

Background Multiple sclerosis can impair cognition from the early stages and has been shown to be associated with gray matter damage in addition to white matter pathology. Objectives To investigate the profile of cognitive impairment in clinically isolated syndrome (CIS), and the contribution of cortical inflammation, cortical and deep gray matter atrophy, and white matter lesions to cognitive decline. Methods Thirty patients with clinically isolated syndrome and twenty demographically- matched healthy controls underwent neuropsychologic assessment through the Rao Brief Repeatable Battery, and brain magnetic resonance imaging with double inversion recovery using a 3T scanner. Results Patients with clinically isolated syndrome performed significantly worse than healthy controls on tests that evaluated verbal memory, visuospatial learning and memory, and verbal fluency. Significant deep gray matter atrophy was found in the patients but cortical volume was not lower than the controls. Visual memory tests correlated with the volume of the hippocampus, cerebral white matter and deep gray matter structures and with cerebellar cortical atrophy. Cortical or white matter lesion load did not affect cognitive test results. Conclusion In our patients with CIS, it was shown that cognitive impairment was mainly related to cerebral white matter, cerebellar cortical and deep gray matter atrophy, but not with cortical inflammation, at least in the early stage of disease.

Background: The prevalence of MS starting under 18 years of age ranges between 2–10% of the total MS population. Objective: We aimed to examine the clinical and long term follow-up data of pediatric-onset cases in our institutional MS database. Method: We evaluated the clinical data from the MS database of the Departments of Neurology and Pediatric Neurology of Hacettepe University Hospital. Results: The clinical features of 74 patients who had experienced the first attack before age 18 years comprised 3.9% of our MS population. Median age at onset was 15 (3, 5–17, IQR=3.63) years, and female: male ratio was 2.4. The most frequent symptom at onset was brainstem/cerebellar dysfunction (32.4%). Seventy two patients (97.3%) initially had relapsing remitting course and in the follow-up, 17 (23%) of them developed secondary progressive (SP) course. The median interval to develop SPMS course was 10 (5–21, IQR=8) years. At the last visit, median disease duration was 6.67 (0.83–25, IQR=9.06) years, 41 (55.4%) of them had EDSS of ≥4. Conclusion: These findings illustrate the profile of our pediatric MS patients: almost all are relapsing-remitting initially; about one fourth become secondarily progressive in 10 years, and about half acquire disability EDSS ≥4 in mean 8 years.

Kurne A, Guc D, Canpinar H, Aydin OF, Sayat G, Yorubulut M, Esendagli G, Karabudak R. Analysis of BAFF and TRAIL expression levels in multiple sclerosis patients: evaluation of expression under immunomodulatory therapy. Acta Neurol Scand: 2011: 123: 8–12. © 2010 The Authors Journal compilation © 2010 Blackwell Munksgaard. Objectives – Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) and B cell-activating factor (BAFF), the members of tumor necrosis factor superfamily, play essential roles in immune homeostasis and may have potential contributions to the autoimmune process in multiple sclerosis (MS). Material and methods – Thirty-five relapsing remitting MS (RRMS) patients and 19 healthy individuals were enrolled in the study. The expression of TRAIL on peripheral blood lymphocytes was analyzed by flow cytometry. The serum levels of soluble TRAIL (sTRAIL) and soluble BAFF (sBAFF) were determined by ELISA. Further, we evaluated the effect of IFN-β on sTRAIL, sBAFF levels and on TRAIL surface expression in these patients on the third and sixth months following the treatment. Results and conclusion – These preliminary results signify that MS patients are heterogenous in TRAIL expression. Additionally, during the IFN-β treatment, the soluble form of TRAIL increases concomitantly as its surface expression decreases on lymphocytes. The basal sBAFF levels of patients were significantly higher than the control group and no significant change was observed. Thus, the changes in TRAIL expression may be a potential parameter indicating the response to IFN-β1 therapy at individual level.

A more favorable clinical course in early-onset (EO) multiple sclerosis (MS) than adult-onset (AO) disease is reported. Our aim was to assess white matter with/without lesions by magnetization transfer (MT) imaging in EO and AO MS patients matched for duration of the disease. Relapsing-remitting MS patients with disease onset at ageor =18 years and18 years (n = 11 for each) were matched according to sex, age, disease duration, and 22 sex-and age-matched healthy subjects were studied with MT imaging. MT ratios (MTR) of manually outlined ROIs from T1-hypointense, T1-isointense lesions and perilesional normal appearing white matter (NAWM) as well as NAWM of the left frontal lobe of the patients and healthy subjects were calculated. MTR differences between two patient groups and control subjects, and correlation of MTR with EDSS, disease onset age, disease duration and relapse rate were analyzed statistically. In comparison with NAWM of the patients and healthy subjects, the greatest MTR reductions were observed in T1-hypointense lesions followed by T1-isointense lesions and perilesional NAWM, respectively, in EO and AO MS. Both groups' NAWM MTR were reduced; greater and more significantly in EO patients. No correlation was found between MTR of any ROI and EDSS, duration of the disease, disease onset age, or relapse rate. Although normalization does not occur, abnormality of white matter in MS decreases as distance from the lesions increases. Greater NAWM abnormality in EO MS may relate to inherent myelin abnormalities and different repair/reorganization processes in this particular group.

We conducted this study to determine familial Mediterranean fever (FMF)-associated central nervous system involvement including demyelinating lesions, stroke, and posterior reversible leukoencephalopathy syndrome (PRES). Patients with MEFV mutations were systematically reviewed through the Medical Biology Unit database. All samples sent for mutation analysis were screened for 10 common MEFV mutations. Patients with FMF and neurologic disorders according to the clinical records were invited for reevaluation. Lumbar puncture, electroencephalography, and evoked potentials were used to determine the type of neurologic involvement in selected cases. Electrocardiography, transthoracic and/or transesophageal echocardiography, and magnetic resonance imaging and/or angiography were performed to clarify the etiology of cerebrovascular disease. Of 8864 patients in the genetic testing database, 18 with neurologic signs were assessed. The mean age of patients was 31.0 +/- 11.8 years, mean age at first FMF symptom was 12.6 +/- 5.6 years, and mean age at neurologic involvement was 25.8 +/- 12.2 years. Fifty-five percent of patients were women. A homozygote MEFV mutation was detected in 16 of 18 patients (88.8%), and a homozygote M694V mutation was found in 72.2% of patients. We found 7 FMF patients with demyelinating lesions, 7 with cerebrovascular disease, and 4 with PRES. The mean interval between first FMF sign and neurologic involvement was 13.7 +/- 8.9 years in the demyelinating group, and 23.4 +/- 10.3 years in the group with cerebrovascular disease. Mean stroke age was 28.5 +/- 16.4 years. All patients in the PRES group had hypertension. Three different neurologic conditions in FMF patients were noticeable. Demyelinating lesions and cerebrovascular disease were the most common clinical presentations. Approximately 70% of patients had the homozygote M694V mutation. Neurologic involvement is rare but serious in FMF.

Background Optic neuritis in children may be an isolated, usually postinfectious event, or the symptom of a more widespread disorder. Aim To investigate the etiological spectrum of optic neuritis in children in association with diagnostic findings and follow-up results. Methods We retrospectively examined the records of 31 children aged 4–15 (mean 9.7 ± 2.9) years in whom isolated optic neuritis was the presenting neurological symptom. Results Monophasic bilateral optic neuritis was the most common presentation (45%), followed by the unilateral (32%) and recurrent (22%) forms. Initial cranial MRI was abnormal in 12/31 patients. During a mean follow-up of 2.2 years (6 months–15 years), 6/14 bilateral cases, 9/10 unilateral and 5/7 recurrent cases were diagnosed with various disorders including total eight with MS. The MS group tended to start with unilateral optic neuritis, was older (mean 11.6 ± 1.5 vs. 8.8 ± 2.9 years), and included more girls than the other groups. Conclusions Optic neuritis in children is frequently part of a systemic or neurological disorder even in the presence of normal cranial imaging. These patients should be evaluated and followed-up in pediatric neurology clinics.

BACKGROUND AND PURPOSE: Myelin instability and citrullinated myelin basic protein have been demonstrated in the brains of patients with chronic and fulminating forms of multiple sclerosis (MS). Our aim was to trace citrulline in the brains of patients with early-onset MS by using proton MR spectroscopy ( 1 H-MR spectroscopy). MATERIALS AND METHODS: A short-echo single-voxel 1 H-MR spectroscopy by using the point-resolved proton spectroscopy sequence was performed in 27 patients with MS and 23 healthy subjects. Voxels of interest were chronic demyelinating lesions (CDLs, n = 25) and normal-appearing white matter (NAWM, n = 25) on T2-weighted imaging, and when available in patients with MS, enhancing demyelinating lesions (EDLs, n = 8). Frontal white matter (WM) was studied in control subjects. N -acetylaspartate, choline, and myo-inositol (mIns)-creatine (Cr) ratios and the presence of a citrulline peak were noted. RESULTS: Citrulline peaks were more frequently observed in patients with MS than in control subjects ( P = .035), located in the NAWM in 8/25 (32%), in CDLs in 7/25 (28%), and in EDLs of 1/8 (12.5%) patients with MS. The presence of citrulline and measured metabolite/Cr ratios was not related to age at imaging, age at disease onset, duration of disease, or number of relapses. There was no significant metabolic difference between the NAWM of patients with MS and the WM of the control subjects. mIns/Cr was significantly greater in CDLs compared with the NAWM of patients with MS and the WM of healthy subjects. CONCLUSIONS: Citrulline was more frequently identified in the brains of patients with early-onset MS than in healthy subjects by 1 H-MR spectroscopy, suggesting an association of increased citrullination of myelin proteins with demyelinating diseases.

Severe primary central nervous system (CNS) involvement such as vasculitis and pachymeningitis can rarely occur in rheumatoid arthritis (RA) even in the absence of systemic disease activation. The authors illustrate a female patient with well-controlled RA who presented with headaches, encephalopathy, seizures and relapsing focal neurological deficits. Primary rheumatoid cerebral vasculitis and pachymeningitis were diagnosed based on suggestive brain magnetic resonance (MR) imaging, MR angiography, cerebrospinal fluid analysis and cerebral angiography. MR showed abnormal leptomeningeal enhancement and hyperintense FLAIR signal in the cortical subarachnoid spaces consistent with pachymeningitis. Cerebral angiography findings were consistent with vasculitis. Aggressive treatment resulted in significant clinicoradiological resolution. Cerebral vasculitis is a rare but certain manifestation of RA. This complication can be diagnosed in the presence of suggestive angiographic and CSF findings. The condition may be steroid resistant, and needs to be treated more aggressively.

Acute isolated neurological syndromes, such as optic neuropathy or transverse myelopathy, may cause diagnostic problems since they can be the first presentations of a number of diseases such as multiple sclerosis (MS) and collageneous tissue disorders. In the present study, particular systemic lupus erythematosus (SLE) and primary Sjogren syndrome (pSS) patients, who were followed up with the initial diagnosis of possible MS with no evidence of collagen tissue disorders for several years, are described. Five patients with the final diagnosis of SLE and five pSS patients are evaluated with their neurologic, systemic and radiologic findings.Over several years, all developed some systemic symptoms like arthritis, arthralgia, headache, dry mouth and eyes unexpected in MS. During the regular and close follow-up laboratory evaluations of vasculitic markers revealed positivity, leading to the final definite diagnosis of SLE or pSS. Patients with atypical neurological presentation of MS, a relapsing remitting clinical profile, or lack of response to the regular MS treatment should be evaluated for the presence of a connective tissue disease. Various laboratory tests, such as cerebrospinal fluid findings, autoantibodies profile, markers, cranial and spinal magnetic resonance imaging, can be helpful for the differential diagnosis. Lack of response to the regular multiple sclerosis treatment, even increasing rate of relapses can force the clinician for the differential diagnosis. In particular cases an accurate diagnosis can only be made after close follow-up.

Ocular symptoms of patients with myasthenia gravis respond to anticholinesterases favorably but usually incompletely. Here, we report 7 myasthenic patients whose ocular signs rapidly responded to intravenous immunoglobulin (IvIg) therapy. We propose that the IvIg should be considered in myasthenic patients whose ocular findings do not respond to conventional therapies. Future studies may disclose whether all patients with ocular involvement or only a subset of patients considerably respond to the IvIg.

WOS: 000249672600012 PubMed: 17890414 A case of Graves' disease with white matter abnormalities is presented here. The diagnosis as Graves' disease was made when the patient was 5 years old, and a subtotal thyroidectomy was performed when she was 10. Her neurological symptoms began at age 19 with paresthesia of her legs and lower body. Cranial magnetic resonance imaging was normal; thoracic magnetic resonance imaging revealed demyelinating lesions. Intravenous pulse steroid therapy improved her symptoms. Ten months later she described dizziness, lower body paresthesia, and ataxia. Both her cranial and thoracic magnetic resonance imagings revealed demyelinating lesions. After pulse steroid therapy, glatiramer acetate therapy was initiated with diagnosis of an autoimmune multiphasic demyelinating syndrome. Five months later, she presented with right-sided mild optic neuritis followed by rapid spontaneous remission. Antithyroglobulin antibody levels remained normal; antithyroid peroxidase antibody level was high. This presents a rare case of Graves' disease associated with multiphasic demyelinating autoimmune syndrome.

Purpose: Smoking has been associated with an increased risk of developing multiple sclerosis, disease progression and clinical disability. We detected the effects of smoking on regional brain volumes and lesion load in patients with clinically isolated syndrome using quantitative magnetic resonance imaging. Materials and Methods: Smoker patients (n = 16), smoker healthy controls (n = 13), non-smoker patients (n = 17) and non-smoker healthy controls (n = 14) underwent magnetic resonance imaging and neocortical volumes were measured. Lesion load was calculated in terms of number and volume of white matter hyperintensities. Results: Smoking was associated with increased gray matter volumes in several regions of the brain. A tendency towards greater lesion load in smoker patients was found. Smoking duration was significantly negatively correlated with intracranial volume and left hemisphere cortical gray matter volume. There was no relationship between regional brain volumes and clinical disability scores, lesion load duration of the disease and degree of smoking exposure. Conclusions: Clinically isolated syndrome related regional brain atrophy might vary in extent and severity with smoking. Despite increased lesion load, less cortical and deep gray matter damage with a possible neuroprotective effect occurs in smoking. © 2015 Taylor and Francis.

A 22-year-old woman was evaluated after a seizure manifesting as tonic posturing of the left hand, head and eye deviation to the left, and a secondarily generalized tonic-clonic seizure. Brain MRI revealed multiple cystic and nodular lesions, some of which enhanced with gadolinium, and hydrocephalus (figure 1). CSF was notable only for elevated opening pressure of 35 cm CSF. Pathologic evaluation showed superficial cortical involvement by oligodendroglial-like bland cells, positive for S100 protein and negative for neuronal nuclear antigen, synaptophysin, phosphoneurofilament (pNF), glial fibrillary acid protein, CD34, mutations of mutant IDH-1, and p53 with low Ki-67. Alcian blue staining highlighted the myxoid stroma. Morphologic evaluation (figure 2) resembled disseminated oligodendroglial-like leptomeningeal tumor, a rare form of low-grade neoplasm.1

It has been acknowledged that neutrophil granulocytes, the common mediators of immune responses against extracellular bacteria, can also intercede autoimmune reactions such as experimental autoimmune encephalomyelitis (EAE). Formyl-methionyl-leucyl-phenylalanine (fMLP) is a microbial peptide that can be well-tolerated when intravenously administered and can directly lead to activation and accumulation of neutrophils into the blood circulation. Here, this antigenic peptide was injected to the mice at the induction of EAE, and the immunological and pathological outcomes were assessed. As a peripheral immune organ, spleen of the animals that received fMLP contained considerably high percentages of Gr-1(hi)Ly7/4(hi) mature neutrophils. In the sera samples, only a slight difference was determined in Th1/Th2/Th17-related cytokine levels. Expression of CXCR1 or CXCR2 chemokine receptors was not significantly modulated in EAE with or without fMLP which might indicate a direct role for this antigenic peptide on neutrophil accumulation. Even though fMLP administration did not propone the clinical (symptomatic) onset of the disease, the animals showed severe body conditions with higher EAE scores. Accordingly, the expression of TNF-α and CXCL1 inflammatory mediators in the brain was increased in fMLP-EAE group. In conclusion, with its potent capacity to mobilize neutrophils and to stimulate innate immune cells, fMLP peptide can be used to aggravate immune reactions in EAE. This observation may indicate that the strength of innate immune responses particularly at the induction phase of EAE might influence the clinical course of the disease.

We describe an HIV-infected, bilingual patient presenting with Wernicke's aphasia due to partial status epilepticus with periodic lateralized epileptiform discharges, as the first sign of AIDS-toxoplasmosis complex. The localization of the native and secondary language centers in the brain and the possible role of recurrent seizures in the fluctuating course of Wernicke's aphasia in this patient are discussed. The clinical course of this patient supports the belief that a second language area for a second language learned in the later stages of life is located in an area different from that for the native language but still in close proximity to it.

Importance Dural arteriovenous fistula is a very rare cause of myelitis that can only be treated interventionally or surgically. Observations A man in his 30s with paraparesis and urinary incontinence had a long-segment thoracic lesion on spinal magnetic resonance imaging. Transverse myelitis was the initial diagnosis. Although a pulse steroid and intravenous immunoglobulin treatment regimen was given, no definite clinical response was seen. A spinal angiogram was performed in our center demonstrating right T7 to T8 spinal dural arteriovenous fistula. The fistula was occluded with embolization and the patient showed recovery following the endovascular treatment. Conclusions and Relevance Myelitis usually is known to respond well to immunosuppressive treatments. Despite adequate medical treatment, if slow progression is seen in the follow-up clinically and radiologically, dural arteriovenous fistulas should be kept in mind in the etiopathogenesis.

There is emerging evidence that matrix metalloproteinases (MMPs) might be involved in blood brain barrier (BBB) breakdown in multiple sclerosis. A group of natural tissue inhibitors of metalloproteinases (TIMPS) regulates proteolytic activity to prevent tissue damage. TIMP-1 and MMP-9 are known to be secreted as heterodimers and TIMP-1 preferentially functions to inhibit MMP-9 activity. In this present study, the effects of IFNbeta-1a on serum MMP-9 and TIMP-1 were evaluated longitudinally during a one-year period. The MMP-9 levels showed no significant changes while TIMP-1 levels gradually and significantly increased during 3rd and 6th months of therapy compared with pretreatment levels.

Voltage gated calcium channel (VGCC) antibodies are generally associated with Lambert-Eaton myasthenic syndrome. However the presence of this antibody has been associated with paraneoplastic as well as non-paraneoplastic cerebellar degeneration. Most patients with VGCC-antibody-positivity have small cell lung cancer (SCLC). Lambert-Eaton myasthenic syndrome (LEMS) is an autoimmune disease of the presynaptic part of the neuromuscular junction. Its classical clinical triad is proximal muscle weakness, areflexia and autonomic dysfunction. Fifty to sixty percent of LEMS patients have a neoplasia, usually SCLC. The co-occurrence of SCLC and LEMS causes more severe and progressive disease and shorter survival than non-paraneoplastic LEMS. Treatment includes 3,4 diaminopyridine for symptomatic purposes and immunotherapy with prednisolone, azathioprine or intravenous immunoglobulin in patients unresponsive to 3,4 diaminopyridine. Paraneoplastic cerebellar degeneration (PCD) is a syndrome characterized with severe, subacute pancerebellar dysfunction. Serum is positive for VGCC antibody in 41%-44% of patients, usually with the co-occurrence of SCLC. Clinical and electrophysiological features of LEMS are also present in 20%-40% of these patients. Unfortunately, PCD symptoms do not improve with immunotherapy. The role of VGCC antibody in the immunopathogenesis of LEMS is well known whereas its role in PCD is still unclear. All patients presenting with LEMS or PCD must be investigated for SCLC.