Arzu Çoban

Epigenetics of Multiple Sclerosis: An Updated Review

Multiple sclerosis (MS) is an inflammatory and neurodegenerative disease characterized with autoimmune response against myelin proteins and progressive axonal loss. The heterogeneity of the clinical course and low concordance rates in monozygotic twins have indicated the involvement of complex heritable and environmental factors in MS pathogenesis. MS is more often transmitted to the next generation by mothers than fathers suggesting an epigenetic influence. One of the possible reasons of this parent-of-origin effect might be the human leukocyte antigen-DRB1*15 allele, which is the major risk factor for MS and regulated by epigenetic mechanisms such as DNA methylation and histone deacetylation. Moreover, major environmental risk factors for MS, vitamin D deficiency, smoking and Ebstein–Barr virus are all known to exert epigenetic changes. In the last few decades, compelling evidence implicating the role of epigenetics in MS has accumulated. Increased or decreased acetylation, methylation and citrullination of genes regulating the expression of inflammation and myelination factors appear to be particularly involved in the epigenetics of MS. Although much less is known about epigenetic factors causing neurodegeneration, epigenetic mechanisms regulating axonal loss, apoptosis and mitochondrial dysfunction in MS are in the process of identification. Additionally, expression levels of several microRNAs (miRNAs) (e.g., miR-155 and miR-326) are increased in MS brains and potential mechanisms by which these factors might influence MS pathogenesis have been described. Certain miRNAs may also be potentially used as diagnostic biomarkers in MS. Several reagents, especially histone deacetylase inhibitors have been shown to ameliorate the symptoms of experimental allergic encephalomyelitis. Ongoing efforts in this field are expected to result in characterization of epigenetic factors that can be used in prediction of treatment responsive MS patients, diagnostic screening panels and treatment methods with specific mechanism of action.

Iatrogenic botulism after botulinum toxin type A injections.

Therapeutic use of botulinum toxin type A (BT/A) is well known, effective, and safe. Iatrogenic botulism that presents with generalized weakness, dysphagia, and respiratory distress is a rare but significant complication in BT/A treatment. In this study, we report 4 patients who developed iatrogenic botulism after receiving therapeutic doses of BT/A for spasticity and blepharospasm. One patient was placed in intensive care unit, but consequently, every patient recovered fully. The cause of BT/A as an adverse effect is most likely hematological spread of the toxin.

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.

Reduced orexin-A levels in frontotemporal dementia: possible association with sleep disturbance.

Sleep disturbances including excessive daytime sleepiness (EDS) are encountered in frontotemporal dementia (FTD). To investigate the relationship between the plasma orexin-A levels and sleep disturbance patterns, we measured the plasma orexin-A levels and performed sleep studies in patients with FTD. The orexin-A levels were measured in 10 consecutive patients with FTD and controls by enzyme-linked immunosorbent assay. Nocturnal polysomnography (PSG) and Multiple Sleep Latency Test (MSLT) were performed in 2 patients with FTD. The orexin-A levels were significantly lower in patients with FTD compared to controls. The PSG revealed increased rapid eye movement (REM) latency in patients, whether or not they reported EDS. Mean sleep latency in MSLT was less than 10 minutes in both the patients, being shorter in patient without EDS, but none of them had REM sleep onset. Some patients with FTD may develop narcolepsy-like involuntary sleep attacks, even without complaining of EDS. Involvement of hypothalamus and a subsequent alteration in the orexin levels might be one of the determining factors in this sleep disturbance.

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.

Sporadic Multiple Cerebral Cavernomatosis Report of a Case and Review of Literature

Objective:Cerebral cavernous malformations (CCM) are vascular malformations causing seizures and cerebral hemorrhages. They occur in sporadic and familial forms. Familial cases are associated with a high frequency of multiple lesions, which are less frequently associated with sporadic cases. Case Report:We report a 46-year-old woman presenting with epilepsy with multiple cerebral cavernomatosis on MRI. Because she had had a previous liver transplantation operation, and received immunosuppressants, she was not advised to have a brain operation. However, she had to be operated as a result of a bleeding in one of her cerebral cavernomas. The histologic diagnosis was cavernoma. She has been seizure free after the operation with levetiracetam therapy for the last 17 months. She had no positive family history for both epilepsy and cavernomatosis. Conclusion:When multiple cerebral cavernomatosis are identified in a patient, a detailed neurologic family history should be sought despite the possibility of its being a sporadic case. Our main intention is to present a patient who is surgically controversial and to point out the importance of genetic heredity.

Evaluation of incidence and clinical features of antibody-associated autoimmune encephalitis mimicking dementia.

Background. Anti-neuronal autoimmunity may cause cognitive impairment that meets the criteria for dementia. Objective. Our aim was to detect the incidence and clinical features of autoimmune encephalitis imitating clinical findings of primary dementia disorders and to delineate the validity of anti-neuronal antibody screening in dementia patients. Methods. Fifty consecutive patients fulfilling the clinical criteria for primary dementia, 130 control patients, and 50 healthy controls were included. Their sera were investigated for several ion channel and glutamic acid decarboxylase (GAD) antibodies by a cell-based assay, radioimmunoassay, and ELISA, as required. Results. Sixteen patients satisfying dementia criteria had atypical findings or findings suggestive of autoimmune encephalitis. N-methyl-D-aspartate receptor (NMDAR) antibody was detected in a patient with dementia, Parkinsonism, and REM sleep behavior disorder (RBD) fulfilling the criteria for dementia with Lewy bodies (DLB). One control patient with bipolar disease displayed low anti-GAD antibody levels. Conclusions. Our study showed for the first time the presence of parkinsonism and RBD in an anti-NMDAR encephalitis patient mimicking DLB. Although autoimmune encephalitis patients may occasionally present with cognitive decline, most dementia patients do not exhibit anti-neuronal antibodies, suggesting that routine analysis of these antibodies in dementia is not mandatory, even though they display atypical features.

Multiple sclerosis-like clinical and magnetic resonance imaging findings in human immunodeficiency virus positive-case.

Objective:Neurologic complications may develop during the course of acquired immunodeficiency syndrome. Differential diagnosis of the chronic progressive myelopathy related to human immunodeficiency virus must include multiple sclerosis. Case Report:We report a human immunodeficiency virus–positive case with progressive myelopathy who showed multiple sclerosis–like white matter lesions on cranial magnetic resonance imaging. Viral screening revealed positive serology for human immunodeficiency virus. Conclusion:This case suggests that in a patient who presents with a multiple sclerosis–like clinical course and cerebral white matter lesions, a human immunodeficiency virus–related clinical picture should be taken into consideration in the differential diagnosis.

Aquaporin-1 Antibody in Neuromyelitis Optica Patients

Background/Methods: To find out the prevalence of aquaporin-antibody (Aqp-Ab) and characterize Aqp-Ab associated clinical features in NMO, Aqp-1 and Aqp-4-Abs were examined using radioimmunoprecipitation and cell-based assays, respectively. Results: Aqp-4 and Aqp-1-Abs were detected in 20/30 and 8/30 NMO patients, respectively. One patient was Aqp-1-Ab single-positive, 13 patients were Aqp-4-Ab single-positive, 7 patients were Aqp-4/Aqp-1-Ab double-positive and 9 patients were seronegative. All double-positive patients had optic neuritis during the first attack. Only 2/29 MS patients and none of the control idiopathic intracranial hypertension patients were Aqp-1-Ab positive. Conclusion: Aqp-1-Ab is usually detected in Aqp-4-Ab positive NMO patients and might be involved in optic neuritis pathogenesis.

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, Students 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.