HLA associations in South Asian multiple sclerosis.

BACKGROUND: Previous efforts to identify Human Leukocyte Antigen (HLA) gene associations with multiple sclerosis (MS) in the South Asian population have been underpowered. AIM: To identify the primary HLA class II alleles associated with MS in Indians. METHODS: We typed HLA-DRB1, -DQA1 and -DQB1 in 419 patients and 451 unrelated controls by polymerase chain reaction using sequence specific oligonucleotide probes (PCR-SSOP). RESULTS: At the gene level DRB1 showed significant evidence of association (p=0.0000012), DQA1 showed only marginal evidence of association (p=0.04) and there was no evidence for association at DQB1 (p=0.26). At the DRB1 locus association is confirmed with the *15:01 (p=0.00002) and the *03 (p=0.00005) alleles. CONCLUSION: Our study confirms that the risk effects attributable to the HLA- DRB1*15:01and DRB1*03 alleles seen in Europeans are also seen in Indians. The absence of any evidence of association with DQB1 alleles reflects the lower linkage disequilibrium between DQB1 alleles and DRB1 risk alleles present in this population, and illustrates the potential value of fine mapping signals of association in different ethnic groups.

Approach to diagnosis and management of optic neuropathy.

Visual loss consequent to anterior visual pathway involvement can occur in a variety of clinical settings. In a tropical country like India, apart from the usual suspects, nutritional, infective, and toxic amblyopia have to be considered in the differential diagnosis. The mode of onset (acute/chronic), unilateral versus bilateral involvement, accompanying occular pain or the lack of it, and pattern of visual loss are some of the pointers which help to differentiate optic neuropathy clinically. The presence of concurrent neurological deficits, evidence of other systemic illnesses, and the results of serological and radiological investigations help to confirm the diagnosis. This article briefly describes the important causes of optic neuropathy in the Indian context and outlines a practical approach to management.

Mycophenolate mofetil in the treatment of multiple sclerosis: a preliminary report.

BACKGROUND: Mycophenolate mofetil (MMF) is an affordable and tolerable drug reported to be beneficial in the treatment of multiple sclerosis (MS). AIM: To determine efficacy of MMF as first line disease modifying drug (DMD) in 40 patients with MS seen in our demyelinating disease registry. MATERIALS AND METHODS: The annualized relapse rate (ARR) for 1 year prior to starting MMF therapy and 1 year post treatment was calculated. Pre- and post-treatment expanded disability status scores (EDSS), age at onset of treatment, disease duration, and type of MS were recorded. Wilcoxon rank sum test was used for comparison of ARRs and EDSS before and after treatment. RESULTS: Forty patients included 27 females and 13 males. Mean duration of MMF therapy was 24 months (range 14-33 months). Pre-treatment mean ARR of 0.95 was significantly different from post treatment mean ARR of 0.11 (P=0.0001). Pre-treatment mean EDSS 3.80 (inter quartile range [IQR] 3.5-4.5) was significantly different from post-treatment mean EDSS 2.66 (IQR 1.5-3.0, P=0.0001). No adverse effects were reported that required stopping of medication. Five patients discontinued treatment 6-11 months after starting therapy, two of whom relapsed subsequently. CONCLUSION: Our preliminary results support the use of MMF, a cheap and well-tolerated drug, as first line disease modifying drug in MS. Long-term results in a larger patient cohort is required for validating our preliminary conclusions.

Determining Effectiveness of "Off-Label Therapies" for Multiple Sclerosis in a Real-World Setting.

OBJECTIVE: To determine the factors, if any, that are associated with the efficacy of "off-label therapies" (OLTs) for multiple sclerosis (MS). METHODS: Consecutive patients (N = 174) with relapsing-remitting MS (RRMS) or secondary progressive MS (SPMS) with relapses, on OLTs with a generic formulation of azathioprine, mycophenolate mofetil, or rituximab biosimilar for ≥2 years were included. Annualized relapse rate (ARR) and expanded disability status score (EDSS) 1 year before and ≥2 years after starting OLTs were recorded. Optical coherence tomography (OCT) was done at baseline and at the end of the study. RESULTS: During a median period of 4.1 years (2.4-24), ARR reduced in all (P < 0.0001) and EDSS improved in RRMS (P < 0.0001) patients but not in SPMS (P < 0.31) patients. Good responders were those who had RRMS (P = 0.001, odds ratio [OR] 0.04, 95% confidence interval [CI] 0.01-0.15), female gender (P 0.008, OR 6.67, 95% CI 1.7-26.8), and had early access to OLT (P = 0.006, OR 1.2, 95% CI 1.05-1.40). Baseline peripapillary retinal nerve fiber layer thickness identified the risk of conversion to SPMS (P < 0.01, OR 1.03; 95% CI 1.01-1.06). CONCLUSIONS: This limited prospective study suggests that early identification of patients who could potentially respond to unconventional but accessible therapies may be valuable in the treatment of MS, particularly in resource-poor regions.

MOG-IgG-associated disease has a stereotypical clinical course, asymptomatic visual impairment and good treatment response.

OBJECTIVES: We investigated the clinical characteristics and treatment response in myelin oligodendrocyte glycoprotein antibody (MOG-IgG)-associated disease and looked for evidence of subclinical disease. METHODS: We prospectively evaluated the frequency and pattern of relapse, tested afferent visual function and monitored treatment response in 42 south Asian patients from a single centre. RESULTS: Eighteen patients (42.9%) had monophasic and 24 (57.1%) a relapsing course. Disease duration was longer (P<0.02) in those with a relapsing course. Median time to the second attack was prolonged (P<0.04) in patients with recurrent transverse myelitis when compared with neuromyelitis optica spectrum disorder and recurrent optic neuritis. Thirteen out of 17 patients (76.5%) initially presenting with optic neuritis developed recurrent optic neuritis later. After the first attack of transverse myelitis, 17 out of 22 (77.3%) had disease confined to the spinal cord. Optical coherence tomography detected peripapillary retinal nerve fibre layer thickness (P<0.05) and macular ganglion cell complex volume (P<0.005) abnormalities in seven out of 10 (70.0%) patients without clinical optic neuritis. Immunosuppressants induced remission in 17 out of 22 (77.3%) patients during a median follow-up of 48 months and the median Expanded Disability Status Score was 1 (range 1-10). CONCLUSION: Our study highlighted the tendency for stereotypical attacks in MOG-IgG-associated disease, heterogeneity in clinical course among subtypes, subclinical visual impairment and the need for early and sustained immunosuppressive therapy.

Anti Myelin Oligodendrocyte Glycoprotein associated Immunoglobulin G (AntiMOG-IgG)-associated Neuromyelitis Optica Spectrum Disorder with Persistent Disease Activity and Residual Cognitive Impairment.

Antibodies targeting myelin oligodendrocyte glycoprotein (MOG) have been recently reported in association with idiopathic inflammatory central nervous system disorders. Initially believed to be a benign disorder, anti MOG-IgG was noted to cause steroid responsive recurrent optic neuritis and isolated longitudinally extensive myelitis. However, there is growing evidence that the disease may be predominantly relapsing, often producing severe visual loss and involving regions other than the spinal cord and optic nerve. We report an adolescent male with an aggressive disease course previously undescribed in anti MOG-IgG-associated disease that left him with residual cognitive dysfunction.

Serological markers associated with neuromyelitis optica spectrum disorders in South India.

BACKGROUND: Neuromyelitis optica spectrum disorders (NMOSDs) represent 20% of all demyelinating disorders in South India. No studies have determined the seroprevalence to both antibodies against aquaporin-4* and antimyelin oligodendrocyte glycoprotein antibody (anti-MOG+) in this population. OBJECTIVE: To identify and characterize seropositive patients for anti-aquaporin-4 antibody (anti-AQP4+) and anti-MOG+ in South India. MATERIALS AND METHODS: We included 125 consecutive patients (15 children) who were serologically characterized using live transfected cells to human M23-AQP4 or full-length MOG. RESULTS: Among a total of 125 patients, 30.4% of patients were anti-AQP4+, 20% were anti-MOG+, and 49.6% were seronegative. No patient was positive for both. Anti-MOG+ patients represented 28.7% (25/87) of seronegative NMOSD. In comparison to anti-AQP4+ patients, anti-MOG+ patients were commonly male, had less frequent attacks and milder disability on expanded disability status score scale. Seronegative patients were also predominantly male, 36% (9/25) had monophasic longitudinally extensive transverse myelitis and disability was comparable with anti-AQP4+ patients. Lumbar cord involvement was common in anti-MOG+ and seronegatives, whereas anti-AQP4+ patients had more cervical lesions. CONCLUSION: Anti-AQP4+/anti-MOG + patients accounted for nearly half of the patients suspected of having NMOSD in South India, indicating that antibody testing may be useful on the management of subgroups with different prognosis.

Relapsing optic neuritis and isolated transverse myelitis are the predominant clinical phenotypes for patients with antibodies to myelin oligodendrocyte glycoprotein in India.

BACKGROUND: Clinical phenotypes of patients with antibodies to myelin oligodendrocyte glycoprotein (anti-MOG+) are unknown in India. OBJECTIVES: Retrospectively to characterise anti-MOG+ patients with inflammatory central nervous system disorders in India. METHOD: A total of 87 patients with non-multiple sclerosis demyelinating disorders (excluding acute disseminated encephalomyelitis) who were seronegative for anti-aquaporin 4 antibody were retrospectively analysed using a cell-based assay for anti-MOG+ status. RESULTS: Twenty-five patients were anti-MOG+ in this cohort. They represented 28.7% (25/87) of patients who tested negative for anti-AQP4+. Sixty-four per cent (16/25) of anti-MOG+ patients were men and had a relapsing course. Patients with recurrent optic neuritis and those with a single attack of acute longitudinally extensive transverse myelitis were the most common phenotypes. CONCLUSION: Relapsing optic neuritis was the most common phenotype, contrasting with a lower risk of relapses in transverse myelitis.

Environmental factors related to multiple sclerosis in Indian population.

BACKGROUND: Multiple sclerosis (MS) is less prevalent among Indians when compared to white populations. Genetic susceptibility remaining the same it is possible that environmental associations may have a role in determining disease prevalence. AIMS: To determine whether childhood infections, vaccination status, past infection with Helicobacter pylori (H.pylori), diet, socioeconomic and educational status were associated with MS. MATERIAL AND METHODS: 139 patients and 278 matched control subjects were selected. A validated environmental exposure questionnaire was administered. Estimation of serum H.pylori IgG antibody was done by ELISA. Patients and controls were genotyped for HLA-DRB1*15:01. RESULTS: In our cohort a significant association was seen with measles (p < 0.007), vegetarian diet (p < 0.001, higher educational status (p < 0.0001) and urban living (p < 0.0001). An inverse relationship was seen with H.Pylori infection and MS (p < 0.001). Measles infection (OR 6.479, CI 1.21-34.668, p < 0.029) and high educational status (OR 3.088, CI 1.212-7.872, p < 0.018) were significant risk factors associated with MS. H.pylori infection was inversely related to MS (OR 0. 319, CI 0.144- 0.706, p < 0.005). CONCLUSIONS: Environmental influences may be important in determining MS prevalence.

Optimizing the management of neuromyelitis optica and spectrum disorders in resource poor settings: Experience from the Mangalore demyelinating disease registry.

BACKGROUND: In resource-poor settings, the management of neuromyelitis optica (NMO) and NMO spectrum (NMOS) disorders is limited because of delayed diagnosis and financial constraints. AIM: To device a cost-effective strategy for the management of NMO and related disorders in India. MATERIALS AND METHODS: A cost-effective and disease-specific protocol was used for evaluating the course and treatment outcome of 70 consecutive patients. RESULTS: Forty-five patients (65%) had a relapse from the onset and included NMO (n = 20), recurrent transverse myelitis (RTM; n = 10), and recurrent optic neuritis (ROPN; n = 15). In 38 (84.4%) patients presenting after multiple attacks, the diagnosis was made clinically. Only 7 patients with a relapsing course were seen at the onset and included ROPN (n = 5), NMO (n = 1), and RTM (n = 1). They had a second attack after a median interval of 1 ± 0.9 years, which was captured through our dedicated review process. Twenty-five patients had isolated longitudinally extensive transverse myelitis (LETM), of which 20 (80%) remained ambulant at follow-up of 3 ± 1.9 years. Twelve patients (17%) with median expanded disability status scale (EDSS) of 8.5 at entry had a fatal outcome. Serum NMO-IgG testing was done in selected patients, and it was positive in 7 of 18 patients (39%). Irrespective of the NMO-IgG status, the treatment compliant patients (44.4%) showed significant improvement in EDSS (P ≤ 0.001). CONCLUSIONS: Early clinical diagnosis and treatment compliance were important for good outcome. Isolated LETM was most likely a post-infectious demyelinating disorder in our set-up. NMO and NMOS disorders contributed to 14.9% (45/303) of all demyelinating disorders in our registry.

Lymhomatosis cerebri--a rare cause of leukoencephalopathy.

BACKGROUND: Lymphomatosis cerebri is a rare variant of primary central nervous system lymphoma. Clinically it presents usually as rapidly progressive dementia and is accompanied by extensive white matter changes in magnetic resonance imaging (MRI). CASE DESCRIPTION: A 49-year-old immuno-competent male who complained of dull diffuse headache, rapidly deteriorated in higher functions over a 6 month period. On examination he was globally declined in cognitive functions and had papilledema. MRI showed extensive white matter lesions. He became temporarily alert, and attentive after a course of parenteral steroids. However within three weeks he relapsed and a wedge biopsy of the brain revealed histopathology consistent with lymphomatosis cerebri. CONCLUSION: The differential diagnosis of diffuse white matter diseases is constantly expanding. In the background of a rapidly progressing subcortical dementia and extensive white matter disease, neoplastic disorders of the brain especially lymphomatosis cerebri should be considered. Early tissue diagnosis is important for specific treatment and interventions.