Virender Bhan

Clinical features and viral serologies in children with multiple sclerosis: a multinational observational study

BACKGROUND The full spectrum of clinical manifestations and outcome, and the potential importance of regional or demographic features or viral triggers in paediatric multiple sclerosis (MS), has yet to be fully characterised. Our aim was to determine some of these characteristics in children with MS. METHODS 137 children with MS and 96 control participants matched by age and geographical region were recruited in a multinational study. They underwent structured clinical-demographic interviews, review of academic performance, physical examination, disability assessment (MS patients only), and standardised assays for IgG antibodies directed against Epstein-Barr virus, cytomegalovirus, parvovirus B19, varicella zoster virus, and herpes simplex virus. FINDINGS MS was relapsing-remitting at diagnosis in 136 (99%) children. The first MS attack resembled acute disseminated encephalomyelitis (ADEM) in 22 (16%) of the children, most under 10 years old (mean age 7.4 [SD 4.2] years). Children with ADEM-like presentations were significantly younger than were children with polyfocal (11.2 [4.5] years; p<0.0001) or monofocal (12.0 [3.8] years; p=0.0005) presentations. Permanent physical disability (EDSS>or=4.0) developed within 5 years in 15 (13%) of the 120 children for whom EDSS score was available. 23 (17%) had impaired academic performance, which was associated with increasing disease duration (p=0.02). Over 108 (86%) of the children with MS, irrespective of geographical residence, were seropositive for remote EBV infection, compared with only 61 (64%) of matched controls (p=0.025, adjusted for multiple comparisons). Children with MS did not differ from controls in seroprevalence of the other childhood viruses studied, nor with respect to month of birth, sibling number, sibling rank, or exposure to young siblings. INTERPRETATION Paediatric MS is a relapsing-remitting disease, with presenting features that vary by age at onset. MS in children might be associated with exposure to EBV, suggesting a possible role for EBV in MS pathobiology.

Clinical, environmental, and genetic determinants of multiple sclerosis in children with acute demyelination: a prospective national cohort study

BACKGROUND HLA-DRB1*15 genotype, previous infection with Epstein-Barr virus, and vitamin D insufficiency are susceptibility factors for multiple sclerosis, but whether they act synergistically to increase risk is unknown. We aimed to assess the contributions of these risk factors and the effect of established precursors of multiple sclerosis, such as brain lesions on MRI and oligoclonal bands in CSF at the time of incident demyelination, on development of multiple sclerosis in children. METHODS In our prospective national cohort study, we assessed children who presented with incident CNS demyelination to any of the 16 paediatric health-care facilities or seven regional health-care facilities in Canada. We did univariate and multivariable analyses to assess contributions of HLA-DRB1*15, Epstein-Barr virus, vitamin D status, MRI evidence of brain lesions, and CSF oligoclonal bands as determinants of multiple sclerosis. We used classification and regression tree analyses to generate a risk stratification algorithm for clinical use. FINDINGS Between Sept 1, 2004, and June 30, 2010, we screened 332 children of whom 302 (91%) were eligible and followed-up for a median of 3·14 years (IQR 1·61-4·51). 63 (21%) children were diagnosed with multiple sclerosis after a median of 127 days (99-222). Although the risk of multiple sclerosis was increased with presence of one or more HLA-DRB1*15 alleles (hazard ratio [HR] 2·32, 95% CI 1·25-4·30), reduced serum 25-hydroxyvitamin D concentration (HR per 10 nmol/L decrease 1·11, 1·00-1·25), and previous Epstein-Barr-virus infection (HR 2·04, 0·99-4·20), no interactions between these variables were detected on multivariate analysis. Multiple sclerosis was strongly associated with baseline MRI evidence of one or more brain lesion (HR 37·9, 5·26-273·85) or CSF oligoclonal bands (6·33, 3·35-11·96), suggesting established disease. One patient diagnosed with multiple sclerosis had a normal MRI scan, and therefore sensitivity of an abnormal MRI scan for multiple sclerosis diagnosis was 98·4%. INTERPRETATION Risk of multiple sclerosis in children can be stratified by presence of HLA-DRB1*15 alleles, remote Epstein-Barr virus infection, and low serum 25-hydroxyvitamin D concentrations. Similar to previous studies in adults, brain lesions detected on MRI and CSF oligoclonal bands in children are probable precursors to the clinical onset of multiple sclerosis. Children with a normal MRI are very likely to have a monophasic illness. FUNDING Canadian Multiple Sclerosis Scientific Research Foundation.

Incidence of acquired demyelination of the CNS in Canadian children

Background: The incidence of acquired demyelination of the CNS (acquired demyelinating syndromes [ADS]) in children is unknown. It is important that physicians recognize the features of ADS to facilitate care and to appreciate the future risk of multiple sclerosis (MS). Objective: To determine the incidence, clinical features, familial autoimmune history, and acute management of Canadian children with ADS. Methods: Incidence and case-specific data were obtained through the Canadian Pediatric Surveillance Program from April 1, 2004, to March 31, 2007. Before study initiation, a survey was sent to all pediatric health care providers to determine awareness of MS as a potential outcome of ADS in children. Results: Two hundred nineteen children with ADS (mean age 10.5 years, range 0.66–18.0 years; female to male ratio 1.09:1) were reported. The most common presentations were optic neuritis (ON; n = 51, 23%), acute disseminated encephalomyelitis (ADEM; n = 49, 22%), and transverse myelitis (TM; n = 48, 22%). Children with ADEM were more likely to be younger than 10 years, whereas children with monolesional ADS (ON, TM, other) were more likely to be older than 10 years (p < 0.001). There were 73 incident cases per year, leading to an annual incidence of 0.9 per 100,000 Canadian children. A family history of MS was reported in 8%. Before study initiation, 65% of physicians indicated that they considered MS as a possible outcome of ADS in children. This increased to 74% in year 1, 81% in year 2, and 87% in year 3. Conclusion: The incidence of pediatric acquired demyelinating syndromes (ADS) is 0.9 per 100,000 Canadian children. ADS presentations are influenced by age.

Elevated ATG5 expression in autoimmune demyelination and multiple sclerosis.

Multiple sclerosis (MS) is an inflammatory central nervous system (CNS) disorder characterized by T cell mediated demyelination. In MS, prolonged T cell survival and increased T cell proliferation have been linked to disease relapse and progression. Recently, the autophagy related gene 5 (Atg5) has been shown to modulate T cell survival. In this study, we examined the expression of Atg5 using both a mouse model of autoimmune demyelination as well as blood and brain tissues from MS cases. Quantitative real-time PCR analysis of RNA isolated from blood samples of experimental autoimmune encephalomyelitis (EAE) mice revealed a strong correlation between Atg5 expression and clinical disability. Analysis of protein extracted from these cells confirmed both upregulation and post-translational modification of Atg5 the latter of which was positively correlated with EAE severity. Analysis of RNA extracted from T cells isolated by negative selection, indicated that Atg5 expression was significantly elevated in individuals with active relapsing-remitting MS compared to non-diseased controls. Brain tissue sections from relapsing-remitting MS cases examined by immunofluorescent histochemistry suggested that encephalitogenic T cells are a source of Atg5 expression in MS brain samples. Together these data suggest that increased T cell expression of Atg5 may contribute to inflammatory demyelination in MS.

Diagnostic accuracy of neurological problems in the emergency department.

BACKGROUND Previous studies describe significant rates of misdiagnosis of stroke, seizure and other neurological problems, but there are few studies examining diagnostic accuracy of all emergency referrals to a neurology service. This information could be useful in focusing the neurological education of physicians who assess and refer patients with neurological complaints in emergency departments. METHODS All neurological consultations in the emergency department at a tertiary-care teaching hospital were recorded for six months. The initial diagnosis of the requesting physician was recorded for each patient. This was compared to the initial diagnosis of the consulting neurologist and to the final diagnosis, as determined by retrospective chart review. RESULTS Over a six-month period, 493 neurological consultations were requested. The initial diagnosis of the requesting physician agreed with the final diagnosis in 60.4% (298/493) of cases, and disagreed or was uncertain in 35.7% of cases (19.1% and 16.6% respectively). In 3.9% of cases, the initial diagnosis of both the referring physician and the neurologist disagreed with the final diagnosis. Common misdiagnoses included neurocardiogenic syncope, peripheral vertigo, primary headache and psychogenic syndromes. Often, these were initially diagnosed as stroke or seizure. CONCLUSIONS Our data indicate that misdiagnosis or diagnostic uncertainty occurred in over one-third of all neurological consultations in the emergency department setting. Benign neurological conditions, such as migraine, syncope and peripheral vertigo are frequently mislabeled as seizure or stroke. Educational strategies that emphasize emergent evaluation of these common conditions could improve diagnostic accuracy, and may result in better patient care.

Anti-myelin antibodies modulate clinical expression of childhood multiple sclerosis

Anti-myelin basic protein (MBP) antibodies in pediatric-onset MS and controls were characterized. Serum samples were obtained from 94 children with MS and 106 controls. Paired CSF and serum were obtained from 25 children with MS at time of their initial episode of acute demyelinating syndrome (ADS). Complementary assays were applied across samples to evaluate the presence, and the physical binding properties, of anti-MBP antibodies. While the prevalence and titers of serum anti-MBP antibodies against both immature and mature forms of MBP were similar in children with MS and in controls, binding characteristics and formal Surface Plasmon Resonance (SPR) studies indicated surprisingly high binding affinities of all pediatric anti-MBP antibodies. Serum levels of anti-MBP antibodies correlated significantly with their CSF levels, and their presence in children with MS was associated with significantly increased risk of an acute disseminated encephalomyelitis-like initial clinical presentation. While antibodies to both immature and mature forms of MBP can be present as part of the normal pediatric humoral repertoire, these anti-myelin antibodies are of surprisingly high affinity, can access the CNS during inflammation, and have the capacity to modulate disease expression. Our findings identify an immune mechanism that could contribute to the observed heterogeneity in spectrum of clinical presentations in early-onset MS.

Social anxiety in a multiple sclerosis clinic population

Background Little is known about social anxiety in MS. Objective We estimated the prevalence of social anxiety symptoms and their association with demographic and clinical features in a clinic-attending sample of patients with MS. Methods Patients attending the Dalhousie MS Research Unit for regularly scheduled visits completed the Social Phobia Inventory (SPIN), the Hospital Anxiety and Depression Scale (HADS), and the Health Utilities Index (HUI). Neurological disability was determined by ratings on the Expanded Disability Status Scale (EDSS). Results A total of 251 patients completed self-report scales of anxiety and depression symptoms. In all, 245 (98%) provided sufficient data for analysis. In all, 30.6% (n = 75) had clinically significant social anxiety symptoms as defined by a SPIN threshold score of 19. Half of those with social anxiety had general anxiety (HADSA ≥ 11) and a quarter had depression (HADSD ≥ 11). Severity of social anxiety symptoms was associated with reduced health-related quality of life and not related to neurological disability. Conclusions Social anxiety symptoms are common in persons with MS, contribute to overall morbidity, but are unrelated to the overall severity of neurologic disability. Greater awareness and routine systematic inquiry of social anxiety symptoms is an important component of comprehensive care for persons with MS.

Trial of Minocycline in a Clinically Isolated Syndrome of Multiple Sclerosis

BACKGROUND On the basis of encouraging preliminary results, we conducted a randomized, controlled trial to determine whether minocycline reduces the risk of conversion from a first demyelinating event (also known as a clinically isolated syndrome) to multiple sclerosis. METHODS During the period from January 2009 through July 2013, we randomly assigned participants who had had their first demyelinating symptoms within the previous 180 days to receive either 100 mg of minocycline, administered orally twice daily, or placebo. Administration of minocycline or placebo was continued until a diagnosis of multiple sclerosis was established or until 24 months after randomization, whichever came first. The primary outcome was conversion to multiple sclerosis (diagnosed on the basis of the 2005 McDonald criteria) within 6 months after randomization. Secondary outcomes included conversion to multiple sclerosis within 24 months after randomization and changes on magnetic resonance imaging (MRI) at 6 months and 24 months (change in lesion volume on T2‐weighted MRI, cumulative number of new lesions enhanced on T1‐weighted MRI [“enhancing lesions”], and cumulative combined number of unique lesions [new enhancing lesions on T1‐weighted MRI plus new and newly enlarged lesions on T2‐weighted MRI]). RESULTS A total of 142 eligible participants underwent randomization at 12 Canadian multiple sclerosis clinics; 72 participants were assigned to the minocycline group and 70 to the placebo group. The mean age of the participants was 35.8 years, and 68.3% were women. The unadjusted risk of conversion to multiple sclerosis within 6 months after randomization was 61.0% in the placebo group and 33.4% in the minocycline group, a difference of 27.6 percentage points (95% confidence interval [CI], 11.4 to 43.9; P=0.001). After adjustment for the number of enhancing lesions at baseline, the difference in the risk of conversion to multiple sclerosis within 6 months after randomization was 18.5 percentage points (95% CI, 3.7 to 33.3; P=0.01); the unadjusted risk difference was not significant at the 24‐month secondary outcome time point (P=0.06). All secondary MRI outcomes favored minocycline over placebo at 6 months but not at 24 months. Trial withdrawals and adverse events of rash, dizziness, and dental discoloration were more frequent among participants who received minocycline than among those who received placebo. CONCLUSIONS The risk of conversion from a clinically isolated syndrome to multiple sclerosis was significantly lower with minocycline than with placebo over 6 months but not over 24 months. (Funded by the Multiple Sclerosis Society of Canada; ClinicalTrials.gov number, NCT00666887.)

The incidence and prevalence of multiple sclerosis in Nova Scotia, Canada.

BACKGROUND Estimates of incidence and prevalence are needed to determine disease risk and to plan for health service needs. Although the province of Nova Scotia, Canada is located in a region considered to have a high prevalence of multiple sclerosis (MS), epidemiologic data are limited. OBJECTIVE We aimed to validate an administrative case definition for MS and to use this to estimate the incidence and prevalence of MS in Nova Scotia. METHODS We used provincial administrative claims data to identify persons with MS. We validated administrative case definitions using the clinical database of the provinces only MS Clinic; agreement between data sources was expressed using a kappa statistic. We then applied these definitions to estimate the incidence and prevalence of MS from 1990 to 2010. RESULTS We selected the case definition using ≥7 hospital or physician claims when >3 years of data were available, and ≥3 claims where less data were available. Agreement between data sources was moderate (kappa = 0.56), while the positive predictive value was high (89%). In 2010, the age-standardized prevalence of MS per 100,000 population was 266.9 (95% CI: 257.1- 277.1) and incidence was 5.17 (95% CI: 3.78-6.56) per 100,000 persons/year. From 1990-2010 the prevalence of MS rose steadily but incidence remained stable. CONCLUSIONS Administrative data provide a valid and readily available means of estimating MS incidence and prevalence. MS prevalence in Nova Scotia is among the highest in the world, similar to recent prevalence estimates elsewhere in Canada. Incidence et prévalence de la sclérose en plaques en Nouvelle-Écosse, Canada.

Expression of the inhibitor of apoptosis protein family in multiple sclerosis reveals a potential immunomodulatory role during autoimmune mediated demyelination.

A failure of autoreactive T cells to undergo apoptosis may contribute to the pathogenesis of multiple sclerosis (MS). The role of the inhibitor of apoptosis (IAP) family of anti-apoptotic proteins such as X-linked IAP (XIAP), human inhibitor of apoptosis-1 (HIAP-1), human inhibitor of apoptosis-2 (HIAP-2), neuronal apoptosis inhibitory protein (NAIP) and Survivin in relapsing–remitting, secondary-progressive, primary-progressive or benign forms of MS is unclear. We report here that expression of the IAP family of genes in peripheral blood samples and brain tissues from MS cases support a role for differential regulation of these potent anti-apoptotic proteins in the pathology of MS. XIAP mRNA and protein levels were elevated in peripheral blood mononuclear cells from patients with active disease relative to normal subjects. In patients with active MS, HIAP-1 and HIAP-2 mRNA levels were elevated in resting T cells while NAIP mRNA was increased in whole blood. In post-mortem MS brain tissue, XIAP and HIAP-1 in myelin lesions were co-localized with microglia and T cells, respectively. Only in primary-progressive patients was Survivin expression elevated suggestive of a distinct pathological basis for this subtype of MS. Taken together, these results suggest that patterns of inhibitor of apoptosis expression in immune cells may have value in distinguishing between MS subtypes and offer insight into the mechanisms responsible for their distinct clinical courses.