Retinal degeneration is associated with brain volume reduction and prognosis in radiologically isolated syndrome.

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.

Progressive multifocal leukoencephalopathy in a patient with lymphoma and presumptive hyper IgE syndrome.

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.

Fulminant Central Plus Peripheral Nervous System Demyelination without Antibodies to Neurofascin.

BACKGROUND: Combined 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. METHODS: We 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. RESULTS: Three 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. CONCLUSIONS: Patients 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.

Assessment of the effect of cigarette smoking on regional brain volumes and lesion load in patients with clinically isolated 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.

White matter involvement beyond the optic nerves in CRION as assessed by diffusion tensor imaging.

BACKGROUND: Chronic relapsing inflammatory optic neuropathy (CRION) is an inflammatory optic neuropathy, characterized by relapses and remissions in patients with normal brain and spinal magnetic resonance imaging (MRI). Discrepancy from other demyelinating diseases is important, and it is still uncertain whether CRION is restricted to the optic pathways or it affects other brain white matter (WM) structures. OBJECTIVE: To assess WM structure in patients with CRION by using diffusion tensor imaging (DTI). METHODS: DTI was performed in six CRION patients and six age- and sex-matched healthy controls on a 3 T scanner. Tract-based spatial statistics (TBSS) was used for voxelwise statistical analysis of DTI data. Fractional anisotropy (FA), mean diffusivity (MD), axial diffusivity (AD), radial diffusivity (RD) measures were obtained. RESULTS: TBSS analysis revealed two different patterns of WM alterations in patients with CRION. The optic chiasm and connected structures had significantly higher FA and lower RD, AD and MD in the patients than in the healthy controls. On the other hand, anterior frontal bundles of inferior fronto-occipital tracts, left uncinate fascicule and internal capsule showed decreased FA and increased RD. No correlation was found between the clinical variables and diffusion measures. CONCLUSION: WM appearing normal on brain MRI shows widespread abnormalities in a cohort of CRION patients as assessed by DTI.

Progressive neurodegenerative syndrome in a patient with X-linked agammaglobulinemia receiving intravenous immunoglobulin therapy.

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.

The course of myasthenia gravis with systemic lupus erythematosus.

BACKGROUND: Systemic lupus erythematosus (SLE) is one of the autoimmune diseases, which is rarely reported with Myasthenia Gravis (MG). In the literature, the clinical features of MG in these patients were not mentioned in detail. Here, we want to present our five patients with MG and SLE. METHODS: Between 2000 and 2010, 132 MG patients were evaluated and have been followed up in our institution. Five patients had MG with SLE and eleven patients had antinuclear antibody (ANA) positivity without SLE symptoms. The clinical, laboratory findings and treatment responses were reviewed. RESULTS: All patients had generalized MG and four of five patients experienced at least one myasthenic crisis. The response to corticosteroid was poor; consequently, they needed immunosuppressive treatments, IVIg or plasmapheresis. Although in the literature thymectomy was accused of the precipitation of SLE, in our series SLE symptoms preceded thymectomy. CONCLUSION: We would like to point out that MG and SLE being two autoimmune diseases may coexist. This coexistence might cause a more severe myasthenic course compared to MG alone; therefore, these patients need a close and frequent follow-up.

Antiepileptic treatment for anti-NMDA receptor encephalitis: the need for video-EEG monitoring.

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].

High frequency of psoriasis in relatives in a Turkish multiple sclerosis cohort.

Psoriasis was recently accepted as an autoimmune T cell-mediated disease. Various autoimmune disease associations for psoriasis have been defined, including multiple sclerosis, a model autoimmune demyelinating neurologic disorder. In this study, the familial frequency of psoriasis in a Turkish multiple sclerosis cohort was investigated, and a higher frequency of psoriasis was found, supporting the presence of a complex background of autoimmunity underlying psoriasis.

Clinical features and disease course of neurological involvement in Behcet's disease: HUVAC experience.

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-Behçet'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.

An unusual central nervous system involvement in rheumatoid arthritis: combination of pachymeningitis and cerebral vasculitis.

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.

Progressive Onset Multiple Sclerosis: Demographic, Clinical and Laboratory Characteristics of Patients With and Without Relapses in the Course.

AMAÇ: Primer progresif multipl skleroz (PPMS) ve progresif relapsing multipl skleroz (PRMS) baslangiçtan beri olan progresyon ile karakterize MS tipleridir. Nadir görülmelerinden dolayi, literatürde diger MS formlarina göre daha az bilgi bulunmaktadir. Bu çalismanin amaci progresif baslangiçli MS (PBMS) hastalarinda klinik ve laboratuvar özelliklerini ortaya koymaktir. YÖNTEM: PBMS hastalari 2010-2014 yillari arasinda degerlendirilip demografik, klinik özellikleri 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 tüm grupta 1'di. Ortalama baslangiç yasi tüm grup için 40 (23-55) yasti. Gruplar arasinda hastalik baslangiç yasi ortancasi anlamli farkli bulunmadi (p=0,053). En sik prezantasyon belirtisi motor bozukluklardi. Relapslar tüm hastalarda hastaligin ilk 10 yilinda görüldü. BOS analizinde oligoklonal bant pozitifligi ve artmis IgG indeksi açisindan gruplar arasinda fark saptanmadi (p=0,938, p=0,058). Hastalik süresi her iki grupta da benzer oldugu halde, PPMS grubunda degerlendirme sirasinda ortanca EDSS skoru daha yüksek bulundu (p=0,020). SONUÇ: Çalismamiz Türk PBMS hastalarinin klinik seyir ve laboratuvar bulgularina odaklanmis ilk çalismadir. Iki grubun klinik ve laboratuvar bulgularinin karsilastirilmasi benzer sonuçlar göstermistir. Gruplar arasinda hastalik baslangiç yasi ve artmis IgG indeksi açisindan farklilik olup olmadigini netlestirmek için gelecekte daha genis örneklemli çalismalar yapilmasi gerekmektedir.

Identification of circulating MOG-specific B cells in patients with MOG antibodies.

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.

The Glycosylation Site of Myelin Oligodendrocyte Glycoprotein Affects Autoantibody Recognition in a Large Proportion of Patients.

Autoantibodies to myelin oligodendrocytes glycoprotein (MOG) are found in a fraction of patients with inflammatory demyelination and are detected with MOG-transfected cells. While the prototype anti-MOG mAb 8-18C5 and polyclonal anti-MOG responses from different mouse strains largely recognize the FG loop of MOG, the human anti-MOG response is more heterogeneous and human MOG-Abs recognizing different epitopes were found to be pathogenic. The aim of this study was to get further insight into details of antigen-recognition by human MOG-Abs focusing on the impact of glycosylation. MOG has one known N-glycosylation site at N31 located in the BC loop linking two beta-sheets. We compared the reactivity to wild type MOG with that toward two different mutants in which the neutral asparagine of N31 was mutated to negatively charged aspartate or to the neutral alanine. We found that around 60% of all patients (16/27) showed an altered reactivity to one or both of the mutations. We noted seven different patterns of recognition of the two glycosylation-deficient mutants by different patients. The introduced negative charge at N31 enhanced recognition in some, but reduced recognition in other patients. In 7/27 patients the neutral glycosylation-deficient mutant was recognized stronger. The folding of the extracellular domain of MOG with the formation of beta-sheets did not depend on its glycosylation as seen by circular dichroism. We determined the glycan structure of MOG produced in HEK cells by mass spectrometry. The most abundant glycoforms of MOG expressed in HEK cells are diantennary, contain a core fucose, an antennary fucose, and are decorated with α2,6 linked Neu5Ac, while details of the glycoforms of MOG in myelin remain to be identified. Together, we (1) increase the knowledge about heterogeneity of human autoantibodies to MOG, (2) show that the BC loop affects recognition in about 60% of the patients, (3) report that all patients recognized the unglycosylated protein backbone, while (4) in about 20% of the patients the attached sugar reduces autoantibody binding presumably via steric hindrance. Thus, a neutral glycosylation-deficient mutant of MOG might enhance the sensitivity to identify MOG-Abs.

Comparative analysis of fingolimod versus teriflunomide in relapsing-remitting multiple sclerosis.

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.

A clinically isolated syndrome: a challenging entity: multiple sclerosis or collagen tissue disorders: clues for differentiation.

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.

Recurrent alien hand syndrome in a multiple sclerosis case.

Alien hand syndrome is the strange feeling of one's hand behaving independently. This syndrome has rarely been reported in multiple sclerosis (MS) patients. Herein, we present a 34-year-old female MS patient who had recurrent symptoms of alien hand syndrome that were evaluated as MS attacks based on cranial magnetic resonance imaging that showed demyelinating lesions in the corpus callosum. Alien hand syndrome is classified according to the location of the lesion and the presenting symptoms. As such, our patient can best be classified as a callosal alien hand case.

Neuroinvasive Listeriosis: Could Petechial Hemorrhages be a Diagnostic Clue?

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.

White matter alteration in a patient with Graves' disease.

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.