Comparison of Muscle Biopsy Features with Myositis Autoantibodies in Inflammatory Myopathies: A Pilot Experience.

Background: Idiopathic inflammatory myopathies (IIM), also called autoimmune myositis, are heterogeneous. These include dermatomyositis (DM), inclusion body myositis, immune mediated necrotizing myopathy (IMNM), anti-synthetase syndrome (ASS), and overlap polymyositis. Classification of IIM has evolved from clinical to clinico-pathologic to the recent clinico-sero-pathologic with the discovery of myositis-specific antibodies (MSA) and myositis-associated antibodies. The various antibodies have shown association with specific phenotypes. Objective: To analyze muscle biopsy features with respect to each MSA and MAA to understand the frequency of findings in each entity. Materials and Methods: Biopsy-proven cases of IIM where myositis profile was available were included in the study after obtaining Institutional Ethics Committee (IEC) approval. In addition to the stains and enzyme histochemistry, immunohistochemistry with MHC class I and II and MxA was performed. Features like perifascicular atrophy, perifascicular necrosis, scattered necrosis, inflammation, etc. were analyzed. Myositis profile was performed by line-blot technique using a 16-antigen panel. Cases were divided into different autoantibody subgroups. Various clinical, demographic, and muscle biopsy features were studied with respect to each MSA and MAA. Results: There were a total of 64 cases. Mi2 (N = 18) was the most common autoantibody. Some of the salient observations included PFA with perivascular inflammation in Mi2; pediatric cases and microinfarcts in NXP2; no PFA or inflammation in MDA5; perifascicular necrosis in JO1; extensive necrosis with sparse inflammation in SRP; more inflammation in overlap myositis; MxA positivity in DM; and absent in ASS. Conclusion: This is a pilot study documenting differences in biopsy phenotype with each MSA and MAA which is comparable to the literature. These findings can be used to characterize IIM in seronegative biopsies.

Neurocognitive Profile and 18 F-Fluorodeoxyglucose Positron Emission Tomography Brain Imaging Correlation in Children with Electrical Status Epilepticus during Sleep.

Objective Electrical status epilepticus in sleep (ESES) is defined by near-continuous epileptiform discharges during sleep along with cognitive, behavioral, and/or imaging abnormalities. We studied the neurocognitive profile and their correlation with 18 F fluorodeoxyglucose positron emission tomography (FDG PET) brain abnormalities in children with ESES. Methods Fourteen children with ESES with normal magnetic resonance imaging (MRI) from March to December 2019 were included. The intelligence quotient (IQ) and child behavior checklist (CBCL) scores were estimated using validated scales, and FDG PET brain was done at the same point of time to look for cerebral metabolic defects which was compared with a control group. Results Fourteen patients with a mean age of 8.2 ± 2.7 years were analyzed. The average duration of epilepsy was 6 ± 2.8 years. The mean IQ was 72.4 ± 18.2 and mean CBCL score was 37.3 ± 11.8. There was negative correlation between IQ and CBCL ( r = -0.55, p < 0.001). The duration of epilepsy also showed negative correlation with IQ ( r = -4.75, p < 0.001). FDG PET scan showed predominant thalamic hypometabolism in 12 of 14 patients (85.7%) on visual analysis with multiple other hypometabolic cortical and subcortical regions in the brain. The quantitative analysis showed significant difference in metabolism of basal ganglion when compared with control group. The total number of hypometabolic regions seen in the brain showed moderate positive correlation with CBCL score but no significant correlation with the IQ of cases. Conclusion This study demonstrates functional impairment of cerebral cortical, basal ganglia, and thalamic hypometabolism in a cohort of ESES patients with normal structural MRI brain study. There was a moderate correlation of extent and pattern of cerebral hypometabolism with the neuropsychological status of the child and duration of epilepsy.

Muscle spasms as presenting feature of Nivelon-Nivelon-Mabile syndrome.

Hedgehog acyltransferase gene (HHAT)-associated Nivelon-Nivelon-Mabile syndrome (NNMS) is a rare genetic disorder of multiple system involvement with microcephaly, central nervous system malformations, skeletal dysplasia, and 46,XY sex reversal. Other variable and inconsistent features reported in this disorder are muscle spasms, facial dysmorphism, prenatal onset growth restriction, microphthalmia, and holoprosencephaly. This is the sixth postnatal reported patient with biallelic variants in HHAT gene, who presented with microcephaly, short stature, muscle hypertrophy, muscle spasms, and facial dysmorphism. The most prominent and presenting finding in this patient were muscle hypertrophy and muscle spasms which had a clinical response to phenytoin and acetazolamide treatment. Our report emphasizes the phenotypic variability of NNMS and further reiterates muscle spasms as an important clinical manifestation of this extremely rare condition.

Impact of Thymectomy on Crisis Incidence and Quality of Life amongst Generalised Myasthenia Gravis Patients.

Background: Thymectomy, combined with corticosteroids, immunosuppressive agents, and cholinesterase inhibitors, has been accepted as the standard treatment for myasthenia gravis (MG) patients. Data on the effect of thymectomy on occurrence of myasthenic crisis are few. Objectives: To assess the long-term impact of thymectomy in patients with generalized Myasthenia gravis (GMG) in terms of occurrence of myasthenia crisis and quality of life. Methods: A retrospective analysis of 274 clinical records of patients diagnosed with myasthenia gravis (MG) in Nizam's institute of medical sciences (NIMS), a tertiary level teaching hospital between January 2000 and December 2015 was done. Severity of the disease was assessed using Myasthenia Gravis Foundation of America (MGFA) classification and quantitative myasthenia gravis (QMG) score. Myasthenia crisis was diagnosed in our patients when they required ventilator assistance due to respiratory failure caused by muscle weakness (MGFA class V). Quality of life (QoL) was assessed. Results: Of 230 cases included in the final analysis, 108 (46.9%) underwent thymectomy. Posttreatment crisis occurred in 53.3% of the nonthymectomy subjects, and 25.9% of thymectomy group (P < 0.001). In multivariate logistic regression analysis, after controlling for the effect of gender, age at diagnosis and grade of the disease, the odds ratio of myasthenic crisis in people with thymectomy was 0.186.(95% CI 0.087 to 0.387, P = 0.001). No statistically significant differences were observed in quality of life scores between thymectomy and nonthymectomy groups, either before (P = 0.86) or after surgery (P = 0.939). Conclusions: The odds of myasthenia crisis was lesser in people, who underwent thymectomy even after controlling for MGFA grade and other potential confounders but no significant differences in quality of life were found with thymectomy.

Association of HLA DRB1-DQB1 Haplotypes with the Risk for Neuromyelitis Optica among South Indians.

Background: Neuromyelitis optica (NMO) is an autoimmune demyelinating disorder, mainly characterized by severe optic neuritis, transverse myelitis and the high levels of antibodies against NMO-immunoglobulin G (IgG) or aquaporin-4 (AQP4). HLA-DR and HLA-DQ alleles within the HLA class II region on chromosome 6p21 are known to play a significant role in several autoimmune diseases including NMO. The rationale of the current case-control study is to explore the association of HLA-DRB1 and HLA-DQB1 alleles with the risk of NMO and its association with the clinical and serological markers. Methods: A total of 158 samples (38 NMO cases and 120-age and ethnicity matched controls) were genotyped for the HLA-DRB1 and HLA-DQB1 alleles by using PCR-SSP method. Results: Our analysis showed significant association of HLA-DRB1*10 allele (OR 2.63, 95% CI: 1.18-5.83, p=0.02) with NMO whereas DRB1*14 showed protective role against NMO (OR 0.33: 95% CI: 0.11-0.94, p=0.043). HLA-DRB1*10 allele also showed significant association in patients with NMO-IgG positive antibody (OR 3.28: 95% CI: 1.42-7.5, p=0.006). There was no association of HLA DQB1 alleles with NMO and also with NMO-IgG antibody. Among the haplotypes groups, HLA-DRB1*10-DQB1*05 (OR 2.61, 95% CI: 1.11-6.1, p=0.03), HLA-DRB1*15-DQB1*03 (OR 4.5, 95% CI: 1.81-11.5, p=0.001) were strongly associated with the risk of NMO, whereas DRB1*14-DQB1*05 (OR 0.20, 95% CI: 0.060-0.721, p=0.008) showed negative association with NMO. Conclusion: From this study, it is concluded that the HLA-DRB1*10 and DRB1*10-DQB1*05 and HLA-DRB1*15-DQB1*03 haplotypes may influence the susceptibility to NMO among the South Indians. Additionally we found DRB1*14 allele and DRB1*14-DQB1*05 haplotype showed protective role for NMO.

A real world multi center study on efficacy and safety of natalizumab in Indian patients with multiple sclerosis.

BACKGROUND: Natalizumab (NTZ) is increasingly being used in Indian multiple sclerosis (MS) patients. There are no reports on its safety and efficacy, especially with respect to the occurrence of progressive multifocal leukoencephalopathy (PML). OBJECTIVES: To describe the patient characteristics, treatment outcomes, and adverse events, especially the occurrence of PML in NTZ-treated patients. METHODS: A multicentre ambispective study was conducted across 18 centres, from Jan 2012 to Dec 2021. Patients at and above the age of 18 years treated with NTZ were included. Descriptive and comparative statistics were applied to analyze data. RESULTS: During the study period of 9 years, 116 patients were treated with NTZ. Mean age of the cohort was 35.6 ± 9.7 years; 83/116 (71.6%) were females. Relapse rate for the entire cohort in the year before NTZ was 3.1 ± 1.51 while one year after was 0.20±0.57 (p = 0.001; CI 2.45 -3.35). EDSS of the entire cohort in the year before NTZ was 4.5 ± 1.94 and one year after was 3.8 ± 2.7 (p = 0.013; CI 0.16-1.36). At last follow up (38.3 ± 22.78 months) there were no cases of PML identified. CONCLUSIONS: Natalizumab is highly effective and safe in Indian MS patients, with no cases of PML identified at last follow up.

Clinical and Molecular Spectrum of Degenerative Cerebellar Ataxia: A Single Centre Study.

Background: Cerebellar ataxia is a disabling neurological symptom with extreme clinical and etiological heterogeneity. Objective: To study the clinical and molecular characteristics in patients with degenerative cerebellar ataxia. Materials and Methods: In this study, 150 South-Indian patients with degenerative cerebellar ataxia underwent a phenotype guided, sequential tiered testing. Phenotypic features studied included cerebellar symptoms, pyramidal and extrapyramidal features, and ophthalmic and systemic findings. Tier one included conventional tests such as short PCR/fragment analysis for spinocerebellar ataxia (SCA) subtypes 1, 2, 3, 6, 7, 8, 12, 17, and 36 and TP-PCR for Friedreich ataxia (FA). Tier two testing comprised next-generation sequencing (NGS)-based strategies reserved for select undiagnosed cases. Results: The clinical features were highly overlapping and had limited specificity, except in autosomal recessive ataxias and SCA 34. The overall diagnostic yield of our study was 49.3%. SCA 1, 2, and 3 were noted in 13 (12.6%), 12 (11.6%) and 14 (13.5%), respectively, out of the 103 tested, and FA was noted in 17/55 (30.9%) patients. SCA subtypes 6, 7, 8, 12, 17, and 36 were absent in the cohort studied. Targeted Sanger sequencing and NGS revealed some rare diagnoses in 17 among the 18 patients tested. Whole exome sequencing uncovered a novel genotype-phenotype association in a sibling-pair with ataxia, dysmorphism, and retinopathy. Conclusion: SCA 1, 2, 3 and FRDA were the most common causes of ataxia. SCA 6, 7, 8, 12, 17, and 36 were absent in the cohort studied. NGS testing revealed several rare forms of ataxia. Clinical features based testing is cost-effective, achieves good genotype-phenotype correlation, and prioritizes variants for further studies.

Predictors of Intracerebral Hemorrhage in Acute Stroke Patients Receiving Intravenous Recombinant Tissue Plasminogen Activator.

BACKGROUND: Symptomatic Intracerebral hemorrhage (sICH) is a serious complication of recombinant tissue-plasminogen activator (rt-PA) therapy for acute ischemic stroke (AIS). OBJECTIVE: To estimate the prevalence and predictors of sICH in patients after receiving IV rt-PA for AIS. MATERIAL AND METHODS: Consecutive patients of AIS thrombolysed between January 2010 and June 2016 in a University hospital in Hyderabad (India) were studied prospectively for sICH and it's various variables compared with the control group without sICH to determine any sigificantant difference. RESULTS: Out of 113 patients , sICH was detected in 12 (10.61%) whose mean age(58±12.0 years) and gender ratio ( 2:1 ) was not statistically significant from controls. In s ICH group mean NIHSS score was 16.53± 5.81 vs 10.19± 5.06 in controls (p<0.001), gap between stroke onset and thrombolysis was 227.50±46.15 min vs 178.50± 69.20 min in controls(p=0.018). At presentation mean blood sugar was 208.75±90.97 mg/dl in sICH group vs 146.83±70.21 mg/dl in controls (p=0.002). Prior diabetes was in 7(53.30%) vs 23 (22.8%) in controls (p= 0.014)and hypertension in 11 (91.7%) vs (56(55.4%) in controls (p= 0.026) The mortality in sICH was 7 (58.30%)vs 4 (4.94%) in controls (p<.0.001). At 3 months mean mRS ofsICH patients was 5.57± 0.54 vs 2.17± 1.69 in controls (p<.05). CONCLUSION: High NIHSS score, increased stroke onset to thrombolysis time , high blood sugar at presentation ,prior diabetes and hypertension increase the chances of sICH. None of these contraindicate thrombolysing strokes but should caution the physician.

Comparative Effects of Education and Bilingualism on the Onset of Mild Cognitive Impairment.

BACKGROUND: Increasing evidence suggests that life course factors such as education and bilingualism may have a protective role against dementia due to Alzheimer disease. This study aimed to compare the effects of education and bilingualism on the onset of cognitive decline at the stage of mild cognitive impairment (MCI). METHODS: A total of 115 patients with MCI evaluated in a specialty memory clinic in Hyderabad, India, formed the cohort. MCI was diagnosed according to Petersen's criteria following clinical evaluation and brain imaging. Age at onset of MCI was compared between bilinguals and monolinguals, and across subjects with high and low levels of education, adjusting for possible confounding variables. RESULTS: The bilingual MCI patients were found to have a clinical onset of cognitive complaints 7.4 years later than monolinguals (65.2 vs. 58.1 years; p = 0.004), while years of education was not associated with delayed onset (1-10 years of education, 59.1 years; 11-15 years of education, 62.6 years; >15 years of education, 62.2 years; p = 0.426). CONCLUSION: The effect of bilingualism is protective against cognitive decline, and lies along a continuum from normal to pathological states. In comparison, the role of years of education is less robust.

Worsening Guillain-Barré syndrome: harbinger of IRIS in HIV?

We report an HIV patient aged 38 years with acute inflammatory demyelinating polyradiculoneuropathy subtype of Guillain-Barré syndrome (GBS) as the only manifestation of seroconversion and worsening of GBS being the harbinger of immune reconstitution inflammatory syndrome (IRIS). To date, only 5 cases of GBS during IRIS are reported. They manifested either during the third week or later after starting highly active antiretroviral therapy (HAART). Our patient witnessed worsening weakness by fifth day after starting HAART, even before the occurrence of Pneumocystis jirovecii pneumonia, cautioning one of the impending serious complications of IRIS and helped us initiate steroids at an early date.

Development of global rating instruments for pediatric patients with ataxia telangiectasia.

INTRODUCTION: Ataxia telangiectasia (AT) is a neurodegenerative disorder with cerebellar and extrapyramidal features. Interventional and epidemiological studies in AT should rely on specific scales which encompass the specific neurological features, as well the early progressive course and the subsequent plateau. The aim of this study was to build a scale of the CGI type (Clinical Global Impression) which is disease specific, as well as to check the feasibility of the ICARS scale for ataxia in this population. METHODS: We recruited 63 patients with ataxia, aged 10.76 ± 3.2 years, followed at 6 international AT centers, 49 of them (77.8%) with classical AT. All patients were evaluated for ataxia with ICARS scale. In patients with AT, two CGI scales were scored, unstructured as structured for which separate anchors were provided. RESULTS: Mean ICARS score was 44.7 ± 20.52, and it's severity positively correlated with age (Spearman correlation, r = 0.46, p < 0.01). Mean CGI score was 2 (moderately involved). There was a high correlation between the structured and unstructured CGIs (Spearman correlation, r = 0.87, p < 0.01). Both CGI scales showed positive correlation between severity and increasing age (Spearman correlation r = 0.59, p < 0.01 for structured CGI and r = 0.61, p < 0.01 for unstructured). DISCUSSION: We succeeded to build two CGI scales: structured and unstructured, which are disease specific for AT. The unstructured scale showed better connection to disease course; the sensitivity of the unstructured scale could be improved by adding anchors related to extrapyramidal features. In addition we showed that ataxia can be reliably measured in children with AT by using ICARS.