Severe disease reactivation in seropositive neuromyelitis optica spectrum disorders patients after stopping eculizumab treatment.

INTRODUCTION: Neuromyelitis optica spectrum disorders (NMOSD) is an autoimmune, inflammatory disease of the central nervous system affecting the optic nerves and spinal cord. Most NMOSD patients have autoantibodies against the astrocyte water channel protein aquaporin-4 (AQP4). Eculizumab treatment is used effectively and safely in AQP4-IgG+ NMOSD. Our study evaluated the prognosis and outcomes of all clinical trial (PREVENT) patients from Turkey who received eculizumab treatment for AQP4-IgG+ NMOSD. METHOD: Clinical and demographic data of all patients enrolled in the PREVENT and OLE clinical trial in Turkey were analyzed during the study period and after the study ended. Clinical follow-up results were recorded in detail in patients who had to discontinue eculizumab treatment. RESULTS: The study included 10 patients who participated in PREVENT and OLE. Seven patients completed the studies, three patients did not continue the study and were switched to other treatments. Only one of the seven patients was able to continue treatment after eculizumab was approved in AQP4-IgG+NMOSD. The other six patients could not continue treatment due to reimbursement conditions. Four of the six patients who could not continue eculizumab treatment experienced early relapse (within the first three months after stopping the drug). All of these patients had high disease activity before eculizumab and had never relapsed under eculizumab treatment over the long term. CONCLUSION: Eculizumab was used effectively and safely in Turkish AQP4-IgG+NMOSD patients with high disease activity. Disease reactivation and relapse may occur after discontinuation of eculizumab treatment in patients with a long-term stable course. In these cases, close monitoring for disease reactivation is recommended.

Laboratory and clinical correlates of brain atrophy in Neuro-Behçet's disease.

Background: Diagnostic evaluation of patients with parenchymal Neuro-Behçet's disease (NBD) requires magnetic resonance imaging (MRI), neuro-ophthalmologic, and neuropsychological evaluation. In this study, we aimed to find out the ideal diagnostic method that most closely reflects the progress in cognitive disability and brain atrophy in NBD. Methods: In this matched case-control study, we included patients with parenchymal NBD, Behçet's disease without neurological involvement (BD), rheumatoid arthritis, and healthy controls. Detailed ophthalmological examination, pattern-reversal visual evoked potentials (prVEP) test, optical coherence tomography (OCT), brain MRI volumetry and cognitive evaluation tests were performed. Disability status was assessed by revised EDSS. Results: Sixty-eight individuals (35 female, 33 male) were recruited. Mean ACE-R scores were significantly lower in the NBD group (NBD vs. healthy, 80±14.4, 93±4.9, p=0.002). prVEP values were similar across groups, but retinal nerve fiber layer thickness (RNFLT) were more frequently abnormal in the NBD group. We found considerable volume reduction in the brainstem, cerebellum, hippocampus, and thalamus in the NBD group. Regarding prVEP, 120 minutes P100 amplitude (p<0.001, r=0.97) and 60 minutes P100 amplitude values (p=0.006, r=0.90) were positively correlated with the total cerebral white matter volume. Conclusion: Our results confirmed previous observations on cognitive dysfunction in patients with NBD. We reported MRI volumetry data of patients with parenchymal neuro-Behçet's disease for the first time and elucidated novel brain regions with atrophy. Clinically determined scores and OCT failed to predict the status of brain atrophy. prVEP P100 amplitude may be used as a surrogate marker of cerebral white matter involvement in NBD.

Characteristics of optic neuropathy in Behçet disease.

OBJECTIVE: We present the clinical profile, features, and neuroimaging findings of 25 patients with Behçet disease (BD), and optic neuropathy (ON), which has been rarely reported in BD. METHODS: Data from 5 university hospitals were retrospectively reviewed, and patients with BD and ON were evaluated. There were 2 groups: (1) those already diagnosed with BD when ON developed (BD→ON group) and (2) those diagnosed with BD during the evaluation of ON (ON→BD group). RESULTS: There were 25 BD patients with ON (13 males). Among these, 13 had ON→BD, and 12 had BD→ON. Seventeen patients had unilateral ON, and 7 patients had recurrent ON. BD→ON patients were older. Disc edema was seen more in ON→BD than in BD→ON patients (10 vs 3). Fourteen patients also had uveitis, 7 with BD→ON and 7 with ON→BD. There was other neurologic involvement in 8 patients; in the BD→ON group, 4/4 had MS-like disease, in the ON→BD group, 3 had typical parenchymal BD, and 1 had MS-like disease. Twenty of 21 patients received immunosuppressive medications, corticosteroids, or both. Prognosis was favorable in most: vision improved in 20 patients, more often in those receiving combined therapies. CONCLUSION: BD may be diagnosed earlier if it is considered and investigated during the assessment of ON, particularly in high-risk regions. Prognosis of ON related to BD seems to be favorable. Immunosuppressants should be given along with corticosteroids. MS-like presentations should also be kept in mind in patients with BD and ON.

Behçet's Disease and Nervous System Involvement.

OPINION STATEMENT: Management of neuro-Behçet's disease can be divided into two stages: treatment of acute attacks and prevention of relapses. Treatment of acute attacks is accomplished by high-dose intravenous corticosteroids followed by maintenance treatment with oral steroids for 6-12 months depending on the type and severity of the neurological involvement. Relapses can be prevented by using immunosuppressants. Oral immunosuppressants such as azathioprine and mycophenolate are the most widely utilized agents for this purpose. Patients who are refractory or who cannot tolerate these medications can be managed by cyclophosphamide, interferon alpha, or anti-TNF-α monoclonal antibodies such as infliximab, etanercept, and adalimumab. Recent reports showed that newer agents such as tocilizumab, canakinumab, and anakinra, which exert their biological activity through IL-1 and IL-6 pathways, are also promising treatment alternatives for progressive or relapsing patients.

Status of diagnostic approaches to AQP4-IgG seronegative NMO and NMO/MS overlap syndromes.

Distinguishing aquaporin-4 IgG(AQP4-IgG)-negative neuromyelitis optica spectrum disorders (NMOSD) from opticospinal predominant multiple sclerosis (MS) is a clinical challenge with important treatment implications. The objective of the study was to examine whether expert clinicians diagnose and treat NMO/MS overlapping patients in a similar way. 12 AQP4-IgG-negative patients were selected to cover the range of clinical scenarios encountered in an NMO clinic. 27 NMO and MS experts reviewed their clinical vignettes, including relevant imaging and laboratory tests. Diagnoses were categorized into four groups (NMO, MS, indeterminate, other) and management into three groups (MS drugs, immunosuppression, no treatment). The mean proportion of agreement for the diagnosis was low (p o = 0.51) and ranged from 0.25 to 0.73 for individual patients. The majority opinion was divided between NMOSD versus: MS (nine cases), monophasic longitudinally extensive transverse myelitis (LETM) (1), acute disseminated encephalomyelitis (ADEM) (1) and recurrent isolated optic neuritis (RION) (1). Typical NMO features (e.g., LETM) influenced the diagnosis more than features more consistent with MS (e.g., short TM). Agreement on the treatment of patients was higher (p o = 0.64) than that on the diagnosis with immunosuppression being the most common choice not only in patients with the diagnosis of NMO (98 %) but also in those indeterminate between NMO and MS (74 %). The diagnosis in AQP4-IgG-negative NMO/MS overlap syndromes is challenging and diverse. The classification of such patients currently requires new diagnostic categories, which incorporate lesser degrees of diagnostic confidence. Long-term follow-up may identify early features or biomarkers, which can more accurately distinguish the underlying disorder.

Behçet's disease patients with multiple sclerosis-like features: discriminative value of Barkhof criteria.

OBJECTIVES: Behçet's disease (BD) is a systemic auto-inflammatory disorder of unknown cause, which may affect the central nervous system in around 5% of the patients [neuro-BD (NBD)], usually causing large lesions encompassing brainstem, diencephalon and basal ganglia regions. Occasionally NBD patients present with white matter lesions necessitating differential diagnosis from multiple sclerosis (MS). In this study, the efficacy of Barkhof criteria was tested in diagnostic differentiation of NBD and MS. METHODS: Charts and MRIs of 84 NBD patients were retrospectively evaluated. Clinical and radiological features of NBD patients fulfilling (Barkhof+) and not fulfilling Barkhof criteria (Barkhof-) were compared. RESULTS: While the Barkhof- patients (n=73) mostly displayed typical large lesions covering brainstem, diencephalon and basal ganglia regions and neurological findings consistent with brainstem involvement, all Barkhof+ (n=11) patients demonstrated MS-like white matter lesions, fulfilled McDonald's criteria and showed reduced frequency of brainstem symptoms and increased frequency of hemiparesis, hemihypesthesia and spinal cord symptoms. Moreover, the Barkhof+ group had more female patients, increased number of attacks, higher rate of oligoclonal band positivity and less patients with cerebrospinal fluid pleocytosis. CONCLUSIONS: A subgroup of BD patients with neurological complaints displays MS-like lesions, fulfills the clinical and radiological criteria of MS and presents with clinical and laboratory features resembling those of MS rather than NBD. These results suggest that Barkhof+ patients are either an overlapping group between NBD and MS, or they represent MS patients with concomitant systemic findings of BD, rather than NBD. Barkhof criteria appear to be effective in discriminating these patients.

Neuro-Behçet's Disease with Chorea.

Behçet's disease (BD) was described as a three-symptom complex comprising uveitis, oral aphthae, and genital ulcerations. It is a multisystemic, recurrent, inflammatory disorder and it is of unknown cause. Neuro-Behçet (NB) is present in 5%-7% of BD. Movement disorders have rarely been reported in NB. Here, we report a case of chronic parenchymal NB presenting with chorea.

Uveitis as a prognostic factor in multiple sclerosis.

Uveitis is occasionally encountered in multiple sclerosis (MS) patients. The objective of this report is to investigate whether uveitis has a prognostic impact on the clinical course of MS. Several clinical and demographic features were compared between 41 MS patients with uveitis and 100 randomly selected MS patients without uveitis. While there were no significant differences by means of gender, age of MS onset, oligoclonal band positivity and disease duration, EDSS and progression index (PI) scores of MS patients with uveitis were significantly lower than those without uveitis (p = 0.004 and <0.001, respectively). Our results suggest that uveitis might be used as a good prognostic factor.

Predictive value of early serum cytokine changes on long-term interferon beta-1a efficacy in multiple sclerosis.

BACKGROUND: In a previous study, we had evaluated short-term effects of interferon beta-1a (IFNB-1a) 44 µg s.c. three times per week treatment on serum levels of IFN-gamma (IFNG), IL-23, IL-17, IL-10, IL-9, IL-4 and TGF-beta (TGFB) and found a reduction only in IL-17 and IL-23 levels after 2 months of treatment. METHODS: Using the same multiple sclerosis (MS) cohort, we assessed the predictive value of early cytokine level changes (difference between 2nd month and baseline levels as measured by ELISA) on the efficacy of long-term IFNB-1a treatment. RESULTS: The alteration in IFNG levels of patients without any relapse was statistically lower than that of patients having one or more relapses (p = 0.019, Student's t-test). When patients with or without expanded disability severity scale (EDSS) progression were compared, none of the cytokine level changes showed a significant difference between groups. IL-17 and IL-23 level changes did not predict relapse and EDSS progression in IFNB-1a-treated MS patients. CONCLUSION: Our results show that the predictive power of early IFNG measurement on relapse occurrence may potentially extend a time span of several years.

Neuro-Behçet syndrome.

Behçet syndrome (BS) is an idiopathic chronic relapsing multisystem vascular-inflammatory disease of unknown origin. As the disease affects many organs and systems and shows a wide range of clinical manifestations and presentations, it is prefereable to call Behçet's a syndrome (BS) rather than a disease. Nervous system involvement, known as "neuro-BS" (NBS), is seen in about 5-10% of all cases. Clinical and imaging evidence suggests that primary neurologic involvement in BS may be subclassified into two major forms: the first, which is seen in the majority of patients, may be characterized as a vascular-inflammatory central nervous system disease with focal or multifocal parenchymal involvement, mostly presenting with a subacute brainstem syndrome and hemiparesis (intra-axial NBS); the other, which has few symptoms and a better neurologic prognosis, may be caused by isolated cerebral venous sinus thrombosis and intracranial hypertension (extra-axial NBS), occurring in 10-20% of the cases. These two types are rarely seen in the same individual, and their pathogenesis is likely to be different. Isolated behavioral syndromes and peripheral nervous system involvement are rare, whereas a vascular type headache is relatively common and independent from neurologic involvement. Neurologic complications secondary to systemic involvement of BS, as well as neurologic complications related to BS treatments are considered as secondary neurologic involvement of the syndrome. The core histopathologic phenomenon seems to be a vasculitic involvement in some cases, and low-grade chronic nonspecific inflammation in others. As the neurologic involvement in this syndrome is so heterogeneous, it is difficult to predict its course and prognosis, and its response to treatment. Currently, treatment options for NBS are limited to attack therapies with high-dose intravenous methylprednisolone followed by a prolonged oral taper, symptomatic management, and generally the use of azathioprine, cyclophosphamide, interferon-α and anti-TNF agents for long-term preventive treatment, although there no evidence for their efficacy.

Diagnosis and management of Neuro-Behçet's disease: international consensus recommendations.

Neuro-Behçet's disease (NBD) is one of the more serious manifestations of Behçet's disease (BD), which is a relapsing inflammatory multisystem disease with an interesting epidemiology. Though NBD is relatively uncommon, being potentially treatable, neurologists need to consider it in the differential diagnosis of inflammatory, infective, or demyelinating CNS disorders. Evidence-based information on key issues of NBD diagnosis and management is scarce, and planning for such studies is challenging. We therefore initiated this project to develop expert consensus recommendations that might be helpful to neurologists and other clinicians, created through an extensive literature review and wide consultations with an international advisory panel, followed by a Delphi exercise. We agreed on consensus criteria for the diagnosis of NBD with two levels of certainty in addition to recommendations on when to consider NBD in a neurological patient, and on the use of various paraclinical tests. The management recommendations included treatment of the parenchymal NBD and cerebral venous thrombosis, the use of disease modifying therapies, prognostic factors, outcome measures, and headache in BD. Future studies are needed to validate the proposed criteria and provide evidence-based treatments.

Glycine receptor and myelin oligodendrocyte glycoprotein antibodies in Turkish patients with neuromyelitis optica.

BACKGROUND: Seronegative NMO is highly prevalent in non-Western countries implying the presence of as yet unknown antibodies (Ab). We investigated potential novel Ab in aquaporin-4 Ab (AQP-4-Ab) positive and negative NMO patients. METHODS: Sera of 20 NMO patients were examined for AQP-4, myelin oligodendrocyte glycoprotein (MOG) and glycine receptor (GlyR) Ab by cell-based assays. RESULTS: AQP-4-Ab was identified in 10 NMO patients, MOG-Ab was detected only in one AQP-4-Ab positive patient and GlyR-Ab was detected in two AQP-4-Ab negative patients. GlyR-Ab positive patients displayed simultaneous optic neuritis and transverse myelitis attacks and relatively low disability, whereas MOG and AQP-4-Ab double positive patient had a significantly increased disability. CONCLUSION: This study showed for the first time the presence of GlyR-Ab in Turkish NMO patients. In contrast with previous reports, MOG Ab does not appear to be a distinctive marker for Turkish AQP-4-Ab negative NMO patients.

Mitochondrial carrier homolog 1 (Mtch1) antibodies in neuro-Behçet's disease.

Efforts for the identification of diagnostic autoantibodies for neuro-Behcet's disease (NBD) have failed. Screening of NBD patients' sera with protein macroarray identified mitochondrial carrier homolog 1 (Mtch1), an apoptosis-related protein, as a potential autoantigen. ELISA studies showed serum Mtch1 antibodies in 68 of 144 BD patients with or without neurological involvement and in 4 of 168 controls corresponding to a sensitivity of 47.2% and specificity of 97.6%. Mtch1 antibody positive NBD patients had more attacks, increased disability and lower serum nucleosome levels. Mtch1 antibody might be involved in pathogenic mechanisms of NBD rather than being a coincidental byproduct of autoinflammation.

Kleptomania in patients with neuro-Behçet's disease.

OBJECTIVE: This study was conducted to characterize the prevalence and clinical features of kleptomania, an impulse control disorder, in patients with Behçet's disease involving the central nervous system. SUBJECTS AND METHODS: Medical records of 350 patients with neuro-Behçet's disease were evaluated, and clinical and neuropsychological features of patients with kleptomania were noted. RESULTS: Of the 350 neuro-Behçet's disease patients 6 (1.7%) had presented with symptoms that fulfilled the criteria of kleptomania according to the revised 4th version of the Diagnostic and Statistical Manual of Mental Disorders. The 6 patients (5 men, 1 woman) had parenchymal lesions and had developed kleptomania during remission. Magnetic resonance imaging done on the 6 patients before the onset of kleptomania mostly revealed brainstem lesions. Psychiatric assessment did not show any comorbid psychiatric disorders and neuropsychological evaluation showed executive dysfunction in all patients. CONCLUSION: The 6 patients with kleptomania had developed a frontal lobe syndrome.

Comparative clinical characteristics of early- and adult-onset multiple sclerosis patients with seizures.

Multiple sclerosis (MS) and epilepsy are common disorders, the co-occurrence of which has been of considerable interest. This study aimed to evaluate the prevalence and clinical features of epileptic seizures in patients with definite MS including those with pediatric onset (≤16 years of age). Out of 2,300 patients with definite MS followed in our outpatient clinic, 36 with epileptic seizures were identified. In this cohort, 8 out of 146 pediatric cases had seizures. The clinical and demographic features of the patients were recorded. Multiple logistic regression model with the occurence of seizures as the dependent variable was performed to identify the risk factors for seizure occurrence in MS patients. The prevalence of epileptic seizures was 1.5% in definite MS patients, 1.3% in adult-onset (comparable to seizure prevalence in the general population) and 5.5% in pediatric MS patients (≤16 years old). Twenty-six of 36 (72%) patients with MS and epilepsy developed recurrent seizures after the first epileptic seizure. Mean annual relapse rate (p ≤ 0.001), mean expanded disability status scale (EDSS) score (p = 0.004) and the ratio of patients with pediatric onset (p = 0.01) were higher in MS patients with seizures. In the multiple logistic regression analysis, age at MS onset and EDSS at the last examination were found to be predictors of seizure occurrence. Occurrence of seizures during the clinical course of MS appears to be associated with early-onset and increased disease severity and might be coincidental in adults.

Intrathecal oligoclonal IgG bands are infrequently found in neuro-Behçet's disease.

OBJECTIVES: Oligoclonal bands (OCB) of immunoglobulins (IgG) in the cerebrospinal fluid (CSF) provides an evidence for the humoral response and have been screened in the CSF and serum of patients revealing 5 different patterns. In this study, patients with Behçet's disease (BD) are screened in a larger sample to potentially provide information about the possible role of CSF oligoclonal immunoglobulins in the diagnosis of this disease. METHODS: Paired CSF and serum samples from 121 consecutive BD patients with neurological complaints (43 women and 78 men) were included in this study. Parenchymal NBD was diagnosed in 74 patients, and 22 patients had cerebral venous sinus thrombosis (CVST); of the remaining patients, 18 had primary headache disorders not directly associated with BD, and 7 had a cerebrovascular event. OCB of IgG were detected by isoelectric focusing on agarose and immunoblotting of matched serum and CSF sample pairs. Intrathecal production of IgG only is considered positive (Pattern 2 or 3). RESULTS: In the whole group, only 8 patients had OCB in the CSF showing pattern 2. All these positive cases had parenchymal neuro-BD (10.8% positive and 78.4% negative in parenchymal neuro-BD group). All other groups were negative. CONCLUSIONS: The rare presence of oligoclonal IgG bands in CSF can be utilized as another laboratory finding in the diagnosis of NBD.

Coexistence of Guillain-Barré syndrome and Behçet's disease.

Behçet's disease (BD) is a multisystemic, recurrent and inflammatory disorder. Neurological involvement is rare and affects mainly the central nervous system (CNS) in the form of brainstem meningoencephalitis or dural sinus thrombosis. Peripheral neuropathy is usually not observed during the course of BD but some reports have shown electrophysiologic evidence of subclinical neuropathy, mononeuritis multiplex and cranial neuropathy in BD patients. The co-occurrence of Guillain-Barré syndrome (GBS), an acute inflammatory demyelinating neuropathy, with other autoimmune or systemic diseases is rare. We present a case of BD with clinical and electrophysiological diagnosis of GBS. The findings of the patient were discussed with reference to literature.

Progressive encephalomyelitis with rigidity and myoclonus: a syndrome with diverse clinical features and antibody responses.

BACKGROUND/AIMS: To better characterize progressive encephalomyelitis with rigidity and myoclonus (PERM) syndrome and identify novel PERM phenotypes. METHODS: The clinical features and antibody status of PERM patients were investigated using immunoblots, cell-based assays, RIA, protein macroarray and ELISA. RESULTS: Two patients with supratentorial involvement showed abnormal PET or EEG findings. One patient was discovered to have renal cell carcinoma, and protein macroarray revealed Ma3-antibodies. Another patient with leucine-rich, glioma-inactivated 1 (LGI1) and glutamic acid decarboxylase (GAD) antibodies showed a good response to immunotherapy. CONCLUSION: The heterogeneity of the immunological features suggests that PERM is caused by diverse pathogenic mechanisms. Seropositivity to well-characterized neuronal cell surface antigens might indicate a good treatment response.