Publications by authors named "Bhim Singhal"

24 Publications

  • Page 1 of 1

Effect of Disease-Modifying Therapy on Disability in Relapsing-Remitting Multiple Sclerosis Over 15 Years.

Neurology 2021 02 28;96(5):e783-e797. Epub 2020 Dec 28.

From CORe (T.K., I.D., S.S., C.M.), Department of Medicine, University of Melbourne; MS Centre (T.K., I.D., S.S., C.M.), Department of Neurology, Royal Melbourne Hospital, Australia; Karolinska Institute (T.S.), Stockholm, Sweden; Department of Neuroscience (T.S., V.J., A.v.d.W., O.S., H.B.), Central Clinical School, Monash University, Melbourne; Burnet Institute (T.S.), Melbourne, Australia; Department of Neurology and Center of Clinical Neuroscience (D.H., E.K.H.), General University Hospital and Charles University in Prague, Czech Republic; Department of Basic Medical Sciences, Neuroscience and Sense Organs (M. Trojano), University of Bari, Italy; Hospital Universitario Virgen Macarena (G.I.), Sevilla, Spain; Department of Neuroscience, Imaging and Clinical Sciences (A.L.), University "G. d'Annunzio," Chieti; Department of Biomedical and Neuromotor Sciences (A.L.), University of Bologna, IRCCS Istituto delle Scienze Neurologiche di Bologna, Italy; Hopital Notre Dame (A.P., M.G., P.D.), Montreal; CHUM and Universite de Montreal (A.P., M.G., P.D.); CISSS Chaudière-Appalache (P.G.), Levis, Canada; Department of Neurology (V.J., A.v.d.W., O.S., H.B.), Alfred Hospital, Melbourne, Australia; Neuro Rive-Sud (F. Grand'Maison), Quebec, Canada; Department of Neuroscience (P.S., D.F.), Azienda Ospedaliera Universitaria, Modena, Italy; Isfahan University of Medical Sciences (V.S.), Isfahan, Iran; Amiri Hospital (R. Alroughani), Kuwait City, Kuwait; Zuyderland Ziekenhuis (R.H.), Sittard, the Netherlands; Medical Faculty (M. Terzi), 19 Mayis University, Samsun; KTU Medical Faculty Farabi Hospital (C.B.), Karadeniz Technical University, Trabzon, Turkey; School of Medicine and Public Health (J.L.-S.), University Newcastle; Department of Neurology (J.L.-S.), John Hunter Hospital, Newcastle, Australia; UOC Neurologia (E.P.), Azienda Sanitaria Unica Regionale Marche-AV3, Macerata, Italy; Cliniques Universitaires Saint-Luc (V.V.P.), Brussels, Belgium; University of Parma (F. Granella); C. Mondino National Neurological Institute (R.B.), Pavia; Azienda Ospedaliera di Rilievo Nazionale San Giuseppe Moscati Avellino (D.S.), Italy; Flinders University (M. Slee), Adelaide; Westmead Hospital (S.V.), Sydney, Australia; Nemocnice Jihlava (R. Ampapa), Czech Republic; University of Queensland (P.M.), Brisbane; Royal Brisbane and Women's Hospital (P.M.), Brisbane, Australia; Hospital Germans Trias i Pujol (C.R.-T.), Badalona, Spain; CSSS Saint-Jérôme (J.P.), Canada; Hospital Universitario Donostia (J.O.), Paseo de Begiristain, San Sebastián, Spain; Hospital Italiano (E.C.), Buenos Aires, Argentina; Brain and Mind Centre (M.B.), University of Sydney, Australia; INEBA-Institute of Neuroscience Buenos Aires (M.L.S.), Argentina; Hospital de Galdakao-Usansolo (J.L.S.-M.), Galdakao, Spain; Liverpool Hospital (S. Hodgkinson), Sydney, Australia; Jahn Ferenc Teaching Hospital (C.R.), Budapest, Hungary; Craigavon Area Hospital (S. Hughes), UK; Jewish General Hospital (F.M.), Montreal, Canada; Deakin University (C.S.), Geelong; Monash Medical Centre (E.B.), Melbourne, Australia; South East Trust (O.G.), Belfast, UK; Perron Institute (A.K.), University of Western Australia, Nedlands; Institute of Immunology and Infectious Diseases (A.K.), Murdoch University; Sir Charles Gairdner Hospital (A.K.), Perth, Australia; Department of Neurology (T.C.), Faculty of Medicine, University of Debrecen, Hungary; Bombay Hospital Institute of Medical Sciences (B.S.), Mumbai, India; St Vincents Hospital (N.S.), Fitzroy, Melbourne, Australia; Veszprém Megyei Csolnoky Ferenc Kórház zrt (I.P.), Veszprem, Hungary; Royal Hobart Hospital (B.T.), Australia; Semmelweis University Budapest (M. Simo), Hungary; Central Military Emergency University Hospital (C.-A.S.), Bucharest; Titu Maiorescu University (C.-A.S.), Bucharest, Romania; BAZ County Hospital (A.S.), Miskolc, Hungary; and Box Hill Hospital (H.B.), Melbourne, Australia.

Objective: To test the hypothesis that immunotherapy prevents long-term disability in relapsing-remitting multiple sclerosis (MS), we modeled disability outcomes in 14,717 patients.

Methods: We studied patients from MSBase followed for ≥1 year, with ≥3 visits, ≥1 visit per year, and exposed to MS therapy, and a subset of patients with ≥15-year follow-up. Marginal structural models were used to compare the cumulative hazards of 12-month confirmed increase and decrease in disability, Expanded Disability Status Scale (EDSS) step 6, and the incidence of relapses between treated and untreated periods. Marginal structural models were continuously readjusted for patient age, sex, pregnancy, date, disease course, time from first symptom, prior relapse history, disability, and MRI activity.

Results: A total of 14,717 patients were studied. During the treated periods, patients were less likely to experience relapses (hazard ratio 0.60, 95% confidence interval [CI] 0.43-0.82, = 0.0016), worsening of disability (0.56, 0.38-0.82, = 0.0026), and progress to EDSS step 6 (0.33, 0.19-0.59, = 0.00019). Among 1,085 patients with ≥15-year follow-up, the treated patients were less likely to experience relapses (0.59, 0.50-0.70, = 10) and worsening of disability (0.81, 0.67-0.99, = 0.043).

Conclusion: Continued treatment with MS immunotherapies reduces disability accrual by 19%-44% (95% CI 1%-62%), the risk of need of a walking aid by 67% (95% CI 41%-81%), and the frequency of relapses by 40-41% (95% CI 18%-57%) over 15 years. This study provides evidence that disease-modifying therapies are effective in improving disability outcomes in relapsing-remitting MS over the long term.

Classification Of Evidence: This study provides Class IV evidence that, for patients with relapsing-remitting MS, long-term exposure to immunotherapy prevents neurologic disability.
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http://dx.doi.org/10.1212/WNL.0000000000011242DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7884998PMC
February 2021

Consensus Statement On Immune Modulation in Multiple Sclerosis and Related Disorders During the COVID-19 Pandemic: Expert Group on Behalf of the Indian Academy of Neurology.

Ann Indian Acad Neurol 2020 Apr 13;23(Suppl 1):S5-S14. Epub 2020 Apr 13.

Department of Neurology, Bombay Hospital, Mumbai, Maharashtra, India.

Knowledge related to SARS-CoV-2 or 2019 novel coronavirus (2019-nCoV) is still emerging and rapidly evolving. We know little about the effects of this novel coronavirus on various body systems and its behaviour among patients with underlying neurological conditions, especially those on immunomodulatory medications. The aim of the present consensus expert opinion document is to appraise the potential concerns when managing our patients with underlying CNS autoimmune demyelinating disorders during the current COVID-19 pandemic.
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http://dx.doi.org/10.4103/0972-2327.282442DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7213028PMC
April 2020

Clinical and therapeutic predictors of disease outcomes in AQP4-IgG+ neuromyelitis optica spectrum disorder.

Mult Scler Relat Disord 2020 Feb 25;38:101868. Epub 2019 Nov 25.

CORe, Department of Medicine, University of Melbourne, Melbourne, Australia; Department of Neurology, Royal Melbourne Hospital, Melbourne, Australia; Department of Neurology, Royal Melbourne Hospital, Melbourne, Australia. Electronic address:

Background: Aquaporin-4-IgG positive (AQP4-IgG+) Neuromyelitis Optica Spectrum Disorder (NMOSD) is an uncommon central nervous system autoimmune disorder. Disease outcomes in AQP4-IgG+NMOSD are typically measured by relapse rate and disability. Using the MSBase, a multi-centre international registry, we aimed to examine the impact immunosuppressive therapies and patient characteristics as predictors of disease outcome measures in AQP4-IgG+NMOSD.

Method: This MSBase cohort study of AQP4-IgG+NMOSD patients examined modifiers of relapse in a multivariable proportional hazards model and expanded disability status score (EDSS) using a mixed effects model.

Results: 206 AQP4-IgG+ patients were included (median follow-up 3.7 years). Age (hazard ratio [HR] = 0.82 per decade, p = 0.001), brainstem onset (HR = 0.45, p = 0.009), azathioprine (HR = 0.46, p<0.001) and mycophenolate mofetil (HR = 0.09, p = 0.012) were associated with a reduced risk of relapse. A greater EDSS was associated with age (β = 0.45 (per decade), p<0.001) and disease duration (β = 0.07 per year, p<0.001). A slower increase in EDSS was associated with azathioprine (β = -0.48, p<0.001), mycophenolate mofetil (β = -0.69, p = 0.04) and rituximab (β = -0.35, p = 0.024).

Interpretation: This study has demonstrated that azathioprine and mycophenolate mofetil reduce the risk of relapses and disability progression is modified by azathioprine, mycophenolate mofetil and rituximab. Age and disease duration were the only patient characteristics that modified the risk of relapse and disability in our cohort.
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http://dx.doi.org/10.1016/j.msard.2019.101868DOI Listing
February 2020

Risk of secondary progressive multiple sclerosis: A longitudinal study.

Mult Scler 2020 01 9;26(1):79-90. Epub 2019 Aug 9.

CORe, Department of Medicine, The University of Melbourne, Melbourne, VIC, Australia/Department of Neurology, Royal Melbourne Hospital, Melbourne, VIC, Australia/L4 Centre, Melbourne Brain Centre at Royal Melbourne Hospital, Parkville, VIC, Australia.

Background: The risk factors for conversion from relapsing-remitting to secondary progressive multiple sclerosis remain highly contested.

Objective: The aim of this study was to determine the demographic, clinical and paraclinical features that influence the risk of conversion to secondary progressive multiple sclerosis.

Methods: Patients with adult-onset relapsing-remitting multiple sclerosis and at least four recorded disability scores were selected from MSBase, a global observational cohort. The risk of conversion to objectively defined secondary progressive multiple sclerosis was evaluated at multiple time points per patient using multivariable marginal Cox regression models. Sensitivity analyses were performed.

Results: A total of 15,717 patients were included in the primary analysis. Older age (hazard ratio (HR) = 1.02,  < 0.001), longer disease duration (HR = 1.01,  = 0.038), a higher Expanded Disability Status Scale score (HR = 1.30,  < 0.001), more rapid disability trajectory (HR = 2.82,  < 0.001) and greater number of relapses in the previous year (HR = 1.07,  = 0.010) were independently associated with an increased risk of secondary progressive multiple sclerosis. Improving disability (HR = 0.62,  = 0.039) and disease-modifying therapy exposure (HR = 0.71,  = 0.007) were associated with a lower risk. Recent cerebral magnetic resonance imaging activity, evidence of spinal cord lesions and oligoclonal bands in the cerebrospinal fluid were not associated with the risk of conversion.

Conclusion: Risk of secondary progressive multiple sclerosis increases with age, duration of illness and worsening disability and decreases with improving disability. Therapy may delay the onset of secondary progression.
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http://dx.doi.org/10.1177/1352458519868990DOI Listing
January 2020

Rituximab in Neuromyelitis Optica Spectrum Disorders: Our Experience.

Ann Indian Acad Neurol 2017 Jul-Sep;20(3):229-232

Department of Neurology, Bombay Hospital Institute of Medical Sciences, Mumbai, Maharashtra, India.

Background: Neuromyelitis optica (NMO) is an inflammatory demyelinating central nervous system disease, with recurrent attacks of severe bilateral optic neuritis and longitudinally extensive transverse myelitis. Aggressive immunosuppression is essential to prevent clinical relapses and permanent disability. Rituximab, a monoclonal antibody to CD20, has been found effective in several reports and small uncontrolled studies. There is a paucity of data regarding its use in Indian patients.

Objectives: The aim of this study was to report the results of rituximab treatment in NMO spectrum disorders (NMOSDs) in the Indian scenario.

Methods: This study is a retrospective, observational study including 13 NMOSD patients treated with rituximab. After initial therapy in the acute episode with IV methylprednisolone and if needed plasma exchange, therapy was initiated as a cycle of intravenous rituximab, two doses 2 weeks apart of 1 g each. Subsequent cycles were advised at intervals of every 6 months. The primary outcome measure was annualized relapse rate (ARR), defined as a number of clinical attacks per year. Clinical adverse events were recorded throughout the study.

Results: In the study, mean ARR reduced from 2.61 to 0.09 after therapy ( = 0.000685). Of 13 patients, 8 (61.54%) were completely relapse free after starting treatment with rituximab. Treatment was well tolerated and no serious adverse events were noted.

Conclusions: The treatment of NMOSDs with rituximab in Indian patients reduces the frequency of relapses and is well tolerated.
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http://dx.doi.org/10.4103/aian.AIAN_499_16DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5586117PMC
September 2017

Long-term disability trajectories in primary progressive MS patients: A latent class growth analysis.

Mult Scler 2018 04 6;24(5):642-652. Epub 2017 Apr 6.

Department of Basic Medical Sciences, Neuroscience and Sense Organs, University of Bari, Bari, Italy.

Background: Several natural history studies on primary progressive multiple sclerosis (PPMS) patients detected a consistent heterogeneity in the rate of disability accumulation.

Objectives: To identify subgroups of PPMS patients with similar longitudinal trajectories of Expanded Disability Status Scale (EDSS) over time.

Methods: All PPMS patients collected within the MSBase registry, who had their first EDSS assessment within 5 years from onset, were included in the analysis. Longitudinal EDSS scores were modeled by a latent class mixed model (LCMM), using a nonlinear function of time from onset. LCMM is an advanced statistical approach that models heterogeneity between patients by classifying them into unobserved groups showing similar characteristics.

Results: A total of 853 PPMS (51.7% females) from 24 countries with a mean age at onset of 42.4 years (standard deviation (SD): 10.8 years), a median baseline EDSS of 4 (interquartile range (IQR): 2.5-5.5), and 2.4 years of disease duration (SD: 1.5 years) were included. LCMM detected three different subgroups of patients with a mild ( n = 143; 16.8%), moderate ( n = 378; 44.3%), or severe ( n = 332; 38.9%) disability trajectory. The probability of reaching EDSS 6 at 10 years was 0%, 46.4%, and 81.9% respectively.

Conclusion: Applying an LCMM modeling approach to long-term EDSS data, it is possible to identify groups of PPMS patients with different prognosis.
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http://dx.doi.org/10.1177/1352458517703800DOI Listing
April 2018

Higher latitude is significantly associated with an earlier age of disease onset in multiple sclerosis.

J Neurol Neurosurg Psychiatry 2016 Dec 3;87(12):1343-1349. Epub 2016 Nov 3.

Menzies Institute for Medical Research, University of Tasmania, Hobart, Tasmania, Australia.

Background: Age at onset (AAO) in multiple sclerosis (MS) is an important marker of disease severity and may have prognostic significance. Understanding what factors can influence AAO may shed light on the aetiology of this complex disease, and have applications in the diagnostic process.

Methods: The study cohort of 22 162 eligible patients from 21 countries was extracted from the MSBase registry. Only patients with MS aged ≥16 years were included. To reduce heterogeneity, only centres of largely European descent were included for analysis. AAO was defined as the year of the first symptom suggestive of inflammatory central nervous system demyelination. Predictors of AAO were evaluated by linear regression.

Results: Compared with those living in lower latitudes (19.0-39.9°), onset of symptoms was 1.9 years earlier for those at higher latitudes (50.0-56.0°) (p=3.83×10). A reciprocal relationship was seen for ambient ultraviolet radiation (UVR), with a significantly increasing AAO for patients with MS per each quartile increment of ambient UVR (p=1.56×10). We found that the AAO of female patients was ∼5 months earlier than male patients (p=0.002). AAO of progressive-onset patients with MS were ∼9 years later than relapsing-onset patients (p=1.40×10).

Conclusions: An earlier AAO in higher latitude regions was found in this worldwide European-descent cohort and correlated inversely with variation in latitudinal UVR. These results suggest that environmental factors which act at the population level may significantly influence disease severity characteristics in genetically susceptible populations.
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http://dx.doi.org/10.1136/jnnp-2016-314013DOI Listing
December 2016

Contribution of different relapse phenotypes to disability in multiple sclerosis.

Mult Scler 2017 Feb 11;23(2):266-276. Epub 2016 Jul 11.

Department of Medicine, The University of Melbourne, Melbourne, VIC, Australia/Department of Neurology, Melbourne Brain Centre at Royal Melbourne Hospital, Parkville, VIC, Australia.

Objective: This study evaluated the effect of relapse phenotype on disability accumulation in multiple sclerosis.

Methods: Analysis of prospectively collected data was conducted in 19,504 patients with relapse-onset multiple sclerosis and minimum 1-year prospective follow-up from the MSBase cohort study. Multivariable linear regression models assessed associations between relapse incidence, phenotype and changes in disability (quantified with Expanded Disability Status Scale and its Functional System scores). Sensitivity analyses were conducted.

Results: In 34,858 relapses recorded during 136,462 patient-years (median follow-up 5.9 years), higher relapse incidence was associated with greater disability accumulation (β = 0.16, p < 0.001). Relapses of all phenotypes promoted disability accumulation, with the most pronounced increase associated with pyramidal (β = 0.27 (0.25-0.29)), cerebellar (β = 0.35 (0.30-0.39)) and bowel/bladder (β = 0.42 (0.35-0.49)) phenotypes (mean (95% confidence interval)). Higher incidence of each relapse phenotype was associated with an increase in disability in the corresponding neurological domain, as well as anatomically related domains.

Conclusion: Relapses are associated with accumulation of neurological disability. Relapses in pyramidal, cerebellar and bowel/bladder systems have the greatest association with disability change. Therefore, prevention of these relapses is an important objective of disease-modifying therapy. The differential impact of relapse phenotypes on disability outcomes could influence management of treatment failure in multiple sclerosis.
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http://dx.doi.org/10.1177/1352458516643392DOI Listing
February 2017

Multiple sclerosis-Indian perspective.

Authors:
Bhim Singhal

Neurol India 2015 Nov-Dec;63(6):824-5

Department of Neurology, Bombay Hospital Institute of Medical Sciences, Mumbai, Maharashtra, India.

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http://dx.doi.org/10.4103/0028-3886.170065DOI Listing
November 2015

Multiple sclerosis in India: An overview.

Ann Indian Acad Neurol 2015 Sep;18(Suppl 1):S2-5

Department of Neurology, Bombay Hospital Institute of Medical Sciences, Marine Lines, Mumbai, Maharashtra, India.

Multiple sclerosis (MS) is being increasingly diagnosed in India mainly due to increase in the number of practicing neurologists and easy and affordable availability of magnetic resonance imaging (MRI). The clinical features and course are largely similar to those seen in the West. The term optico-spinal MS (Asian MS) was coined in the pre-MRI days. Many such patients turn out to be cases of neuromyelitis optica - a distinct disorder and not a variant of MS. Others have shown the classical features of MS on MRI scan. Several of the disease-modifying agents, not all, are now available in India. Their use, however, has been limited in view of the high cost.
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http://dx.doi.org/10.4103/0972-2327.164812DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4604693PMC
September 2015

HLA associations in South Asian multiple sclerosis.

Mult Scler 2016 Jan 28;22(1):19-24. Epub 2015 Apr 28.

Center for Advanced Neurological Research, KS Hegde Medical College, Nitte University, Mangalore, Karnataka, India.

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.
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http://dx.doi.org/10.1177/1352458515581439DOI Listing
January 2016

Risk of relapse phenotype recurrence in multiple sclerosis.

Mult Scler 2014 Oct 28;20(11):1511-22. Epub 2014 Apr 28.

Royal Melbourne Hospital, AustraliaUniversity of Melbourne, Australia.

Objectives: The aim was to analyse risk of relapse phenotype recurrence in multiple sclerosis and to characterise the effect of demographic and clinical features on this phenotype.

Methods: Information about relapses was collected using MSBase, an international observational registry. Associations between relapse phenotypes and history of similar relapses or patient characteristics were tested with multivariable logistic regression models. Tendency of relapse phenotypes to recur sequentially was assessed with principal component analysis.

Results: Among 14,969 eligible patients (89,949 patient-years), 49,279 phenotypically characterised relapses were recorded. Visual and brainstem relapses occurred more frequently in early disease and in younger patients. Sensory relapses were more frequent in early or non-progressive disease. Pyramidal, sphincter and cerebellar relapses were more common in older patients and in progressive disease. Women presented more often with sensory or visual symptoms. Men were more prone to pyramidal, brainstem and cerebellar relapses. Importantly, relapse phenotype was predicted by the phenotypes of previous relapses. (OR = 1.8-5, p = 10(-14)). Sensory, visual and brainstem relapses showed better recovery than other relapse phenotypes. Relapse severity increased and the ability to recover decreased with age or more advanced disease.

Conclusion: Relapse phenotype was associated with demographic and clinical characteristics, with phenotypic recurrence significantly more common than expected by chance.
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http://dx.doi.org/10.1177/1352458514528762DOI Listing
October 2014

A clinical and radiological profile of neuromyelitis optica and spectrum disorders in an Indian cohort.

Ann Indian Acad Neurol 2014 Jan;17(1):77-81

Department of Neurology, Bombay Hospital Institute of Medical Sciences, Mumbai, Maharashtra, India.

Background: There is insufficient data on the clinical and radiological features of neuromyelitis optica (NMO) and neuromyelitis optica spectrum disorders (NMOSD) from India.

Objective: The objective of the following study is to examine the clinico-radiological features of NMO and NMOSD in an Indian cohort.

Materials And Methods: This retrospective study included 44 consecutive patients who (1) satisfied the 2006 Wingerchuk criteria for NMO (16 seropositive and 7 seronegative); or (2) had isolated or recurrent optic neuritis (ON) with seropositivity (n = 4); or (3) had isolated or recurrent myelitis with seropositivity (n = 17).

Results: The female:male ratio was 7.8:1 with median age of onset 26.5 (range 8-72). Annualized relapse rate (ARR) was comparable across all groups (F [3, 40] = 0.938 and P = 0.431). Various presentations other than ON and myelitis were noted. All 40 patients with myelitis had spinal cord lesions involving ≥3 vertebral segments during the course of the disease. Cervicomedullary involvement was seen in 32.5% (13/40) patients. Brain magnetic resonance imaging was available for 40 patients; eight of these (20%) had brain lesions in locations described in multiple sclerosis (MS), 27.5% (11/40) had lesions at sites unusual for MS and 52.5% (21/40) had normal brain imaging.

Conclusion: NMO and NMOSD patients in this cohort have comparable ARR regardless of clinical presentation, supporting the emerging trend of treating all patients with immunotherapeutic agents at an early stage. Varied presentations seen in NMO and NMOSD highlight the need for a high index of suspicion for NMO in demyelinating episodes not classical for MS.
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http://dx.doi.org/10.4103/0972-2327.128559DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3992776PMC
January 2014

Sex as a determinant of relapse incidence and progressive course of multiple sclerosis.

Brain 2013 Dec 18;136(Pt 12):3609-17. Epub 2013 Oct 18.

1 Department of Medicine, University of Melbourne, Melbourne, Australia.

The aim of this work was to evaluate sex differences in the incidence of multiple sclerosis relapses; assess the relationship between sex and primary progressive disease course; and compare effects of age and disease duration on relapse incidence. Annualized relapse rates were calculated using the MSBase registry. Patients with incomplete data or <1 year of follow-up were excluded. Patients with primary progressive multiple sclerosis were only included in the sex ratio analysis. Relapse incidences over 40 years of multiple sclerosis or 70 years of age were compared between females and males with Andersen-Gill and Tweedie models. Female-to-male ratios stratified by annual relapse count were evaluated across disease duration and patient age and compared between relapse-onset and primary progressive multiple sclerosis. The study cohort consisted of 11 570 eligible patients with relapse-onset and 881 patients with primary progressive multiple sclerosis. Among the relapse-onset patients (82 552 patient-years), 48,362 relapses were recorded. Relapse frequency was 17.7% higher in females compared with males. Within the initial 5 years, the female-to-male ratio increased from 2.3:1 to 3.3:1 in patients with 0 versus ≥4 relapses per year, respectively. The magnitude of this sex effect increased at longer disease duration and older age (P < 10(-12)). However, the female-to-male ratio in patients with relapse-onset multiple sclerosis and zero relapses in any given year was double that of the patients with primary progressive multiple sclerosis. Patient age was a more important determinant of decline in relapse incidence than disease duration (P < 10(-12)). Females are predisposed to higher relapse activity than males. However, this difference does not explain the markedly lower female-to-male sex ratio in primary progressive multiple sclerosis. Decline in relapse activity over time is more closely related to patient age than disease duration.
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http://dx.doi.org/10.1093/brain/awt281DOI Listing
December 2013

Neuromyelitis optica-IgG testing in an Indian cohort with neuromyelitis optica and related demyelinating disorders: Our experience.

Ann Indian Acad Neurol 2013 Jul;16(3):376-9

Department of Neurology, Daya General Hospital, Trichur, India.

Background: Neuromyelitis optica (NMO) is an immune-mediated inflammatory demyelinating disorder of the central nervous system with a predilection for the optic nerves and the spinal cord. Immunopathological evidence suggests that the target antigen of the disease is aquaporin-4. An IgG antibody against this protein has been explored as a molecular marker for the disease and as a diagnostic tool due to its high sensitivity and specificity in various populations.

Objective: To assess the value of NMO-IgG testing in Indian patients with clinical and magnetic resonance imaging features consistent with NMO and longitudinally extensive transverse myelitis (LETM).

Materials And Methods: Forty-five patients with clinical and magnetic resonance imaging features consistent with NMO, LETM, and MS were tested for serum NMO-IgG. Of these patients, 22 patients satisfied revised (2006) Wingerchuk criteria for NMO (excluding NMO-IgG status) and 11 patients had LETM. Twelve patients satisfied the revised (2010) McDonald criteria for multiple sclerosis (MS).

Results: Of the 21 patients, satisfying the criteria for NMO and for whom the test results were available, 17 were positive for NMO-IgG (80.9%), and of the 11 patients having LETM, 6 (54.5%) were positive for NMO-IgG. In one patient with NMO, the test result was not available. None of the 12 patients satisfying McDonald criteria for MS showed NMO-IgG seropositivity.

Conclusion: Our study suggests that it is worthwhile to pursue NMO-IgG testing as a diagnostic tool for patients with clinical and Magnetic Resonance Imaging (MRI) features consistent with NMO and LETM in the Indian population.
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http://dx.doi.org/10.4103/0972-2327.116945DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3788284PMC
July 2013

Persistence on therapy and propensity matched outcome comparison of two subcutaneous interferon beta 1a dosages for multiple sclerosis.

PLoS One 2013 21;8(5):e63480. Epub 2013 May 21.

Departments of Medicine and Neurology, University of Melbourne and Royal Melbourne Hospital, Melbourne, Australia.

Objectives: To compare treatment persistence between two dosages of interferon β-1a in a large observational multiple sclerosis registry and assess disease outcomes of first line MS treatment at these dosages using propensity scoring to adjust for baseline imbalance in disease characteristics.

Methods: Treatment discontinuations were evaluated in all patients within the MSBase registry who commenced interferon β-1a SC thrice weekly (n = 4678). Furthermore, we assessed 2-year clinical outcomes in 1220 patients treated with interferon β-1a in either dosage (22 µg or 44 µg) as their first disease modifying agent, matched on propensity score calculated from pre-treatment demographic and clinical variables. A subgroup analysis was performed on 456 matched patients who also had baseline MRI variables recorded.

Results: Overall, 4054 treatment discontinuations were recorded in 3059 patients. The patients receiving the lower interferon dosage were more likely to discontinue treatment than those with the higher dosage (25% vs. 20% annual probability of discontinuation, respectively). This was seen in discontinuations with reasons recorded as "lack of efficacy" (3.3% vs. 1.7%), "scheduled stop" (2.2% vs. 1.3%) or without the reason recorded (16.7% vs. 13.3% annual discontinuation rate, 22 µg vs. 44 µg dosage, respectively). Propensity score was determined by treating centre and disability (score without MRI parameters) or centre, sex and number of contrast-enhancing lesions (score including MRI parameters). No differences in clinical outcomes at two years (relapse rate, time relapse-free and disability) were observed between the matched patients treated with either of the interferon dosages.

Conclusions: Treatment discontinuations were more common in interferon β-1a 22 µg SC thrice weekly. However, 2-year clinical outcomes did not differ between patients receiving the different dosages, thus replicating in a registry dataset derived from "real-world" database the results of the pivotal randomised trial. Propensity score matching effectively minimised baseline covariate imbalance between two directly compared sub-populations from a large observational registry.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0063480PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3660604PMC
December 2013

Association of Epstein-Barr virus infection with multiple sclerosis in India.

J Neurol Sci 2013 Feb 9;325(1-2):86-9. Epub 2013 Jan 9.

Center for Advanced Neurological Research, Nitte University, Mangalore, Karnataka, India.

Objectives: Epstein-Barr virus (EBV) seroprevalence is high from early childhood in Indian populations, though multiple sclerosis (MS) is uncommon. The present study aims to evaluate the association of EBV infection with MS in Indian patients.

Method: In this study 140 MS patients and equal number of matched controls were included. Estimation of serum Immunoglobin G (IgG) for EBV Nuclear antigen 1 (EBNA1), viral capsid antigen (EBV-VCA) and early antigen (EB-EA) were obtained by quantitative enzyme linked immunosorbent assay (ELISA). Patients and controls were genotyped for the human leukocyte antigen (HLA) DRB1*1501 allele.

Results: A modest difference was observed for EBNA1 (p=0.02) and EBV-VCA (p=0.03) titres in MS patients as compared to healthy controls. There was no association between EBNA1 titres and MS. High EBNA1 titre (>99.75U/l) was significantly associated with HLA DRBI*15:01 (OR=4.92. CI=1.07-22.57) status in MS patients but not in healthy controls (OR=1.19, CI=0.53-2.63).

Conclusion: Evidence for a strong association with remote EBV infection was lacking in this study of Indian patients with MS. Patients who are carriers of HLA DR15 allele may have high EBNA1 titres. These preliminary results need to be reproduced in an independent and larger dataset.
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http://dx.doi.org/10.1016/j.jns.2012.12.004DOI Listing
February 2013

Asian adaptation and validation of an English version of the multiple sclerosis international quality of life questionnaire (MusiQoL).

Ann Acad Med Singap 2011 Feb;40(2):67-73

Department of Rheumatology, Singapore General Hospital, Singapore.

Introduction: The Multiple Sclerosis International Quality of Life questionnaire (MusiQoL) is a self-administered, multi-dimensional, patient-based health-related quality of life (HRQoL) instrument. With increasing prevalence of multiple sclerosis (MS) in Asian countries, a valid tool to assess HRQoL in those patients is needed. The aim of this study was to evaluate patient acceptability, content validity and psychometric properties of an Asian version of the English MusiQoL in Singapore, Malaysia and India.

Materials And Methods: English speaking patients older than 18 years of age with a defi nite diagnosis of MS were included. The self-administered survey material included the adapted HRQoL questionnaire, a validated generic HRQoL questionnaire: the short-form 36 (SF-36), as well as a checklist of 14 symptoms. We assessed the internal and external validity of the adapted MusiQoL.

Results: A total of 81 patients with MS were included in the study. The questionnaire was generally well accepted. In the samples from Malaysia and Singapore, all scales exhibited good internal consistency (Cronbach's alpha >0.70). Correlation to SF-36 was generally good, demonstrating high construct validity (P <0.001) in some aspects of the MusiQoL.

Conclusion: The Asian adaptation of the English version of the MusiQoL in evaluating HRQoL seems to be a valid, reliable tool with adequate patient acceptability and internal consistency.
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February 2011

Evaluation of the established non-MHC multiple sclerosis loci in an Indian population.

Mult Scler 2011 Feb 15;17(2):139-43. Epub 2010 Oct 15.

Department of Neurology, KS Hegde Medical Academy, Mangalore, India.

Background: Multiple sclerosis (MS) is a chronic demyelinating neurodegenerative disorder with a strong genetic component.

Objective: The prevalence of MS in India is low compared with white populations of Northern European descent.

Methods: In order to ascertain whether disease susceptibility genes are the same across different populations, we completed the first investigation in the Indian MS population of 15 MS loci outside of the major histocompatibility (MHC) region that were previously identified and validated with MS susceptibility through genome-wide association and replication studies in white populations.

Results: In total, 197 Indian patients and 197 unrelated controls were analyzed. The most associated single nucleotide polymorphism (SNP) within this study was rs6897932 in the IL7R gene, which showed a strong protective effect in this data set (rs 6897932, OR = 0.5543, 95% CI = 0.37-0.78, p = 0.0009727). Two other SNPs were nominally associated with MS in this dataset, namely CLEC16A rs 12708716 (p = 0.0082, OR = 1.478, 95% CI = 1.106-1.975) and CD226 rs763361 (p = 0.03971, OR = 1.353, CI = 1.014-1.805). For the majority of the remaining SNPs (7/14), the trend for association was in the same direction as in previous studies in the white population.

Conclusions: Although the power of this study was limited, our preliminary data suggest that disease susceptibility genes in MS in the Indian population may be similar to those of western populations.
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http://dx.doi.org/10.1177/1352458510384011DOI Listing
February 2011

Genetic and clinical heterogeneity in eIF2B-related disorder.

J Child Neurol 2008 Feb;23(2):205-15

Children's National Medical Center, Children's Research Institute, Center for Genetic Medicine, Washington, DC 20010, USA.

Eukaryotic initiation factor 2B (eIF2B)-related disorders are heritable white matter disorders with a variable clinical phenotype (including vanishing white matter disease and ovarioleukodystrophy) and an equally heterogeneous genotype. We report 9 novel mutations in the EIF2B genes in our subject population, increasing the number of known mutations to more than 120. Using homology modeling, we have analyzed the impact of novel mutations on the 5 subunits of the eIF2B protein. Although recurrent mutations have been found at CpG dinucleotides in the EIF2B genes, the high incidence of private or low frequency mutations increases the challenge of providing rapid genetic confirmation of this disorder, and limits the application of EIF2B screening in cases of undiagnosed leukodystrophy.
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http://dx.doi.org/10.1177/0883073807308705DOI Listing
February 2008

Progressive cavitating leukoencephalopathy: a novel childhood disease.

Ann Neurol 2005 Dec;58(6):929-38

Neurogenetics Department, Kennedy Krieger Institute and the Johns Hopkins Medical Institutions, 707 N. Broadway, 5th Floor Tower, Baltimore, MD 21205, USA.

We report 19 patients with a previously undelineated neurodegenerative syndrome characterized by episodic acute onset of irritability or neurological deficits between 2 months and 3.5 years of age, followed by steady or intermittent clinical deterioration. Seven children died between 11 months and 14 years of age. Cranial magnetic resonance imaging (MRI) shows patchy leukoencephalopathy with cavities, and vascular permeability, in actively affected regions. Early lesions affect corpus callosum and centrum semiovale, with or without cerebellar or cord involvement. After repeated episodes, areas of tissue loss coalesce with older lesions to become larger cystic regions in brain or spinal cord. Diffuse spasticity, dementia, vegetative state, or death ensues. Gray matter is spared until late in the course. In some, incomplete clinical or MRI recovery occurs after episodes. The clinical course varies from rapid deterioration to prolonged periods of stability that are unpredictable by clinical or MRI changes. Elevated levels of lactate in brain, blood, and cerebrospinal fluid, abnormal urine organic acids, and changes in muscle respiratory chain enzymes are present but inconsistent, without identifiable mitochondrial DNA mutations or deletions. Pathological studies show severe loss of myelin sparing U-fibers, axonal disruption, and cavitary lesions without inflammation. Familial occurrence and consanguinity suggest autosomal recessive inheritance of this distinct entity.
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http://dx.doi.org/10.1002/ana.20671DOI Listing
December 2005

Megalencephalic leukoencephalopathy with subcortical cysts.

J Child Neurol 2003 Sep;18(9):646-52

Department of Neurology, Bombay Hospital Institute of Medical Sciences, Medical Research Center, Mumbai, India.

Megalencephalic leukoencephalopathy with subcortical cysts is one of the newly described white-matter disorders for which recognition has been brought about by advances in imaging technology. The essential diagnostic features include megalencephaly noted in infancy, motor disability in the form of spasticity, ataxia, occasional seizures, mild cognitive decline, and slow progression. Magnetic resonance imaging (MRI) shows bilateral extensive white-matter changes with cysts in the temporal regions. Based on the clinical and MRI features, megalencephalic leukoencephalopathy with subcortical cysts can be distinguished from other conditions (ie, Alexander's disease, Canavan's disease, glutaricaciduria type I) that present in infancy with megalencephaly. Megalencephalic leukoencephalopathy with subcortical cysts is an autosomal recessive disorder, and mutations in the MLC1 gene have now been shown to cause this condition. Several genotypic and phenotypic variations have been described. In India, megalencephalic leukoencephalopathy with subcortical cysts occurs predominantly in the Agarwal community. A common mutation in the MLC1 gene has been seen in 31 Agarwal patients, which suggests a founder effect.
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http://dx.doi.org/10.1177/08830738030180091201DOI Listing
September 2003

Epidemiology and treatment of Parkinson's disease in India.

Parkinsonism Relat Disord 2003 Aug;9 Suppl 2:S105-9

Medical Research Center, Bombay Hospital 12, Marine Lines, Mumbai 400 020, India.

Parkinson's disease (PD) has a low prevalence in India except in the small Parsi community where Bharucha et al. found a high prevalence. Although early onset PD and familial cases have been described from India, no genetic mutations have as yet been identified. PD has been known in India since ancient days and the powder of Mucuna Pruriens seeds was used for its treatment. The present day management of PD in India is similar to that in the other countries. Unfortunately, lack of awareness, limitation of human resources and cost factors deny the benefits of therapy to many patients.
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http://dx.doi.org/10.1016/s1353-8020(03)00024-5DOI Listing
August 2003

Modulation of age at onset in Huntington's disease and spinocerebellar ataxia type 2 patients originated from eastern India.

Neurosci Lett 2003 Jul;345(2):93-6

Crystallography and Molecular Biology Division, Saha Institute of Nuclear Physics, 1/AF Bidhan Nagar, Kolkata 700 064, India.

To identify the genetic modifier(s) that might alter the age at onset in Huntington's disease (HD) we have analyzed variations in GluR6 kainate receptor (GluR6), CA150 gene, Delta2642 and polymorphic CCG repeat variation in huntingtin (htt) gene in 77 HD patients and normal individuals. In addition, variation in the RAI1 gene was analyzed in 30 spinocerebellar ataxia (SCA2) patients and normal individuals to show the possible influence on the age at onset. Multiple regression analysis indicated that variation in GluR6 and CCG repeat genotype might explain 6.2% and 3.1%, respectively, of the variability in the age at onset in HD. Similar analysis with SCA2 patients indicated that RAI1 might explain about 13% of the variability in the age at onset. Specific alleles in GluR6 and CA150 locus were only observed in HD patients.
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http://dx.doi.org/10.1016/s0304-3940(03)00436-1DOI Listing
July 2003