Ayse Altintas

Behçet's disease : diagnostic and prognostic aspects of neurological involvement

Abstract This study was conducted to describe clinical and prognostic aspects of neurological involvement in Behçets disease (BD). Patients referred for neurological evaluation fulfilled the criteria of the International Study Group for Behçets Disease. We analyzed disability and survival by the Kaplan-Meier method, using Kurtzkes Extended Disability Status Scale (modified for BD) and the prognostic effect of demographic and clinical factors by Cox regression analysis. We studied 164 patients; of the 107 diagnostic neuroimaging studies: 72.1% showed parenchymal involvement, 11.7% venous sinus thrombosis (VST) and the others were normal. CSF studies were performed in 47 patients; all with inflammatory CSF findings (n=18) had parenchymal involvement. An isolated increase in pressure was compatible with either VST or normal imaging. The final diagnoses were VST (12.2%), neuro-Behçets syndrome (NBS) (75.6%), isolated optic neuritis (0.6%), psycho-Behçets syndrome (0.6%), and indefinite (11%). VST and NBS were never diagnosed together. Ten years from onset of BD 45.1% (all NBS) reached a disability level of EDSS 6 or higher, and 95.7±2.1% of the patients were still alive. Having accompanying cerebellar symptoms at onset or a progressive course is unfavorable. Onset with headache or a diagnosis of VST is favorable. Two major neurological diagnoses in BD are NBS and VST. These are distinct in clinical, radiological, and prognostic aspects, hence suggesting a difference in pathogenesis.

Behçet’s Syndrome and the Nervous System

Purpose of reviewBehçets syndrome (BS) is a multi-system, vascular-inflammatory disease of unknown origin, involving the nervous system in a subgroup of patients. The syndrome is rare, but as patients with BS are young and frequently present with an acute or subacute brainstem syndrome or hemiparesis, as well as with other various neurological manifestations, the syndrome is often included in the differential diagnosis of multiple sclerosis, stroke of the young adult, and another wide range of neurological disorders. The present review summarizes the neurological involvement in BS, and emphasizes recent clinical concepts and ethiopathogenetic findings. Recent findingsOver the last years the growing clinical and imaging evidence had suggested that neurological involvement in BS may be subclassified into two major forms: one, which is seen in the majority of patients, may be characterized as a vascular-inflammatory CNS disease, with focal or multifocal parenchymal involvement; the other, which has few symptoms and a better neurological prognosis, may be caused by isolated cerebral venous sinus thrombosis and intracranial hypertension. These two types rarely occur in the same individual, and their pathogenesis is likely to be different. A nonstructural vascular type headache is relatively common, whereas isolated behavioral syndromes and peripheral nervous system involvement are rare. SummaryThe involvement of the nervous system in BS is heterogeneous as clinical and imaging data reveal. Currently it is unknown which factors determine or have a role in the development of neurological involvement, but some progress has been achieved in understanding the neurological spectrum of the syndrome, which may lead to a better management of these patients.

Fatigue and sleep disturbance in multiple sclerosis

Considering the association of sleep disturbance and fatigue in multiple sclerosis (MS), we investigated the presence of sleep disturbances that may be related to fatigue by using objective and subjective measures. We included 27 MS patients with fatigue, 10 MS patients without fatigue and 13 controls. The Pittsburgh sleep quality index score showed significant differences between patient groups and controls. Beck depression inventory scores were significantly higher in fatigued than non‐fatigued patients. Comparison of patient groups and controls revealed significant differences for time in bed, sleep efficiency index, sleep continuity index, wake time after sleep onset, total arousal index and periodic limb movement arousal index. Our study confirms that MS causes sleep fragmentation in terms of both macro and microstructure. Fatigue in MS could be partially explained by disruption of sleep microstructure, poor subjective sleep quality and depression.

Consensus definitions and application guidelines for control groups in cerebrospinal fluid biomarker studies in multiple sclerosis.

The choice of appropriate control group(s) is critical in cerebrospinal fluid (CSF) biomarker research in multiple sclerosis (MS). There is a lack of definitions and nomenclature of different control groups and a rationalized application of different control groups. We here propose consensus definitions and nomenclature for the following groups: healthy controls (HCs), spinal anesthesia subjects (SASs), inflammatory neurological disease controls (INDCs), peripheral inflammatory neurological disease controls (PINDCs), non-inflammatory neurological controls (NINDCs), symptomatic controls (SCs). Furthermore, we discuss the application of these control groups in specific study designs, such as for diagnostic biomarker studies, prognostic biomarker studies and therapeutic response studies. Application of these uniform definitions will lead to better comparability of biomarker studies and optimal use of available resources. This will lead to improved quality of CSF biomarker research in MS and related disorders.

Association of APOE polymorphisms with disease severity in MS is limited to women

The authors studied the association of an exon 4 (E4*ε2/3/4) and three promoter polymorphisms of APOE with disease course and severity stratified by gender in 221 patients with multiple sclerosis from two overlapping population-based prevalence cohorts. Women carriers of the E4*ε2 allele took longer to attain an Expanded Disability Status Scale score of 6 (p = 0.015) and had more favorable ranked severity scores than noncarriers (p = 0.009). There was no association in men. Alleles ε3 or ε4 and promoter polymorphisms were not associated with disease course or severity.

Clinical And Radiological Characteristics Of Tumefactive Demyelinating Lesions: Follow-up Study

Background: Demyelinating lesions over 20 mm in size, referred to as tumefactive demyelinating lesions, can be misdiagnosed as being either a tumor or an abscess. Although some radiological characteristics can help make a differential diagnosis easier, a cerebral biopsy may still be necessary. Objective: Our objective was to assess the clinical characteristics of tumefactive lesions, with or without a diagnosis of multiple sclerosis (MS), and present follow-up data for 54 patients with tumefactive lesions. Methods: Demographic, clinical, radiological and laboratory data were gathered and treatment responses were evaluated in a total of 54 patients from five medical centers. Result: Twenty-nine patients were diagnosed with tumefactive lesions at the onset, whereas 25 patients were diagnosed with tumefactive lesions after a diagnosis of MS. Median follow-up was 38.12 months. At final examination, 19 of the patients with a tumefactive lesion diagnosis at the onset eventually developed relapsing–remitting MS, while 10 remained with the condition as a clinically isolated syndrome. The tumefactive lesions studied were mostly focal, with closed-ring enhancement. We found that oligoclonal band positivity was less frequent in the patients with tumefactive onset. Conclusion: Although our demographic data were similar to formerly collected Turkish MS data, we found that the distribution of the patients’ clinical course differed if there was an absence of primary progressive MS and that there was a lower frequency of secondary progressive MS cases in our group of patients. We believe that less frequent oligoclonal band positivity and the difference we witnessed in the clinical course of disease in our study groups suggest that there is a need for further studies to compare all the biological and immunological differences between MS and tumefactive lesion cases, in order to reveal whether there are different pathogenetic mechanisms involved.

Multiple sclerosis risk in radiologically uncovered asymptomatic possible inflammatory-demyelinating disease

Background Natural history of patients with incidentally discovered lesions that fulfill magnetic resonance imaging (MRI) criteria for multiple sclerosis (MS) in the absence of objective clinical symptoms suggestive of central nervous system (CNS) inflammatory-demyelinating disease is not well defined. Objective We evaluated the risk of developing symptomatic MS in patients with radiologically uncovered asymptomatic possible inflammatory-demyelinating disease (RAPIDD). Methods We identified and longitudinally followed a cohort of 22 patients from two tertiary care MS centers: Istanbul University, Cerrahpasa School of Medicine, Istanbul, Turkey, and Mayo Clinic, Rochester, Minnesota, after an initial MRI study fulfilling the Barkhof–Tintore MRI criteria completed for other reasons unrelated to MS. Results Eight of 22 patients developed an objective clinical symptom consistent with a CNS inflammatory-demyelinating syndrome and fulfilled dissemination in space and time criteria for definite MS. Median age at the time of diagnosis of MS was 44.8 years (range 28.3–71.4 years). Time taken for the development of definite MS was studied by survival analysis. Cumulative event rates were; 12 months: 9%, 24 months: 15%, 36 months: 30.4%, and 60 months: 44.6%. Six of 22 patients were followed beyond 60 months. Two of these six patients developed MS later (at 66 and 112 months, respectively). Three patients remained asymptomatic despite follow-up of 10 years. Conclusions Patients with RAPIDD develop MS at a similar rate to treated patients (and less frequently than placebo groups) with clinically isolated syndromes from prior randomized controlled studies. Some patients with RAPIDD continue to have radiological evolution of subclinical disease without MS symptoms despite long follow-up periods.

Headache in Behçet's Syndrome

Objective.—To study the frequencies and characteristics of different headache types seen in patients with Behçets syndrome (BS) in a large cohort of patients.

Multicentre comparison of a diagnostic assay: aquaporin-4 antibodies in neuromyelitis optica

Objective Antibodies to cell surface central nervous system proteins help to diagnose conditions which often respond to immunotherapies. The assessment of antibody assays needs to reflect their clinical utility. We report the results of a multicentre study of aquaporin (AQP) 4 antibody (AQP4-Ab) assays in neuromyelitis optica spectrum disorders (NMOSD). Methods Coded samples from patients with neuromyelitis optica (NMO) or NMOSD (101) and controls (92) were tested at 15 European diagnostic centres using 21 assays including live (n=3) or fixed cell-based assays (n=10), flow cytometry (n=4), immunohistochemistry (n=3) and ELISA (n=1). Results Results of tests on 92 controls identified 12assays as highly specific (0–1 false-positive results). 32 samples from 50 (64%) NMO sera and 34 from 51 (67%) NMOSD sera were positive on at least two of the 12 highly specific assays, leaving 35 patients with seronegative NMO/spectrum disorder (SD). On the basis of a combination of clinical phenotype and the highly specific assays, 66 AQP4-Ab seropositive samples were used to establish the sensitivities (51.5–100%) of all 21 assays. The specificities (85.8–100%) were based on 92 control samples and 35 seronegative NMO/SD patient samples. Conclusions The cell-based assays were most sensitive and specific overall, but immunohistochemistry or flow cytometry could be equally accurate in specialist centres. Since patients with AQP4-Ab negative NMO/SD require different management, the use of both appropriate control samples and defined seronegative NMOSD samples is essential to evaluate these assays in a clinically meaningful way. The process described here can be applied to the evaluation of other antibody assays in the newly evolving field of autoimmune neurology.

Characterization of neuromyelitis optica and neuromyelitis optica spectrum disorder patients with a late onset

Background: Few data are available for patients with a late onset (≥ 50 years) of neuromyelitis optica (LONMO) or neuromyelitis optica spectrum disease (LONMOSD), defined by an optic neuritis/longitudinally extensive transverse myelitis with aquaporin-4 antibodies (AQP4-Ab). Objective: To characterize LONMO and LONMOSD, and to analyze their predictive factors of disability and death. Methods: We identified 430 patients from four cohorts of NMO/NMOSD in France, Germany, Turkey and UK. We extracted the late onset patients and analyzed them for predictive factors of disability and death, using the Cox proportional model. Results: We followed up on 63 patients with LONMO and 45 with LONMOSD during a mean of 4.6 years. This LONMO/LONMOSD cohort was mainly of Caucasian origin (93%), women (80%), seropositive for AQP4-Ab (85%) and from 50 to 82.5 years of age at onset. No progressive course was noted. At last follow-up, the median Expanded Disability Status Scale (EDSS) scores were 5.5 and 6 in the LONMO and LONMOSD groups, respectively. Outcome was mainly characterized by motor disability and relatively good visual function. At last follow-up, 14 patients had died, including seven (50%) due to acute myelitis and six (43%) because of opportunistic infections. The EDSS 4 score was independently predicted by an older age at onset, as a continuous variable after 50 years of age. Death was predicted by two independent factors: an older age at onset and a high annualized relapse rate. Conclusion: LONMO/LONMOSD is particularly severe, with a high rate of motor impairment and death.