Spectrum of Auto-antibodies in NMO and MOG Associated CNS Demyelination- The SANMAD Study.

This observational study explored coexisting organ-specific and non-organ-specific autoantibodies in Neuromyelitis optica spectrum disorder(NMOSD) and Myelin oligodendrocyte glycoprotein-IgG-1(MOG-IgG1) associated central nervous system demyelination(MOGAD) in a South Asian cohort from March 2017-2023. Of the 250 cases, 148 were MOGAD(82pediatric) and 102 were NMOSD(15 pediatric). 17.6 % tested positive for ≥1 antibody, with NMOSD showing a higher positivity rate (25.5 %) than MOGAD(12.2 %,p = 0.011). Double antibody positivity occurred more in NMOSD (5.9 %vs.MOGAD,1.4 %,p = 0.045). Three NMOSD cases had Sjogren syndrome with higher Anti-Ro-52 prevalence(12.7 %vs.4.1 %,p = 0.014). NMOSD patients with ≥1 antibody positivity had more constitutional symptoms (45.5 %vs.23.1 %,p = 0.045). Significant associations were found between NMOSD and female gender, having ≥1 antibody-positive status, and testing positive for Anti-Ro-52 and SS-A antibodies (p < 0.05).

The Clinical, Radiological and Genetic Spectrum of PLA2G6-Associated Neurodegeneration: An Experience From a Tertiary Center.

Background: Despite being the second most common type of neurodegeneration with brain iron accumulation, there is limited literature on PLA2G6-associated neurodegeneration (PLAN) within the Asian ethnicity, particularly in the Indian context. Methods: We conducted a retrospective observational study on patients with pathogenic/likely pathogenic PLA2G6 variants based on exome sequencing. Results: We identified 26 patients (22 families, 15 males) of genetically-confirmed PLAN with a median age of 22.5 years and age at onset of 13.0 years, encompassing various subtypes: infantile neuroaxonal dystrophy (5/26;19.2%), atypical neuroaxonal dystrophy (3/26;11.5%), dystonia-parkinsonism (5/26;19.2%), dystonia-parkinsonism-myoclonus (n = 4, 15.38%), early-onset Parkinson's disease (2/26;7.7%), complex dystonia (2/26;7.7%), and complicated hereditary spastic paraparesis (cHSP; 5/26;19.2%). The common initial symptoms included walking difficulty (7/26;26.9%), developmental regression (6/26;23.1%), and slowness (4/26;15.4%). Dystonia (14/26;53.8%), followed by parkinsonism (11/26; 42.3%), was the most common motor symptom. Non-motor symptoms included cognitive decline (12/26;46.2%) and behavioral changes (6/26;23.1%). Neuroimaging revealed cerebellar atrophy in 23/26 (88.5%) patients and claval hypertrophy in 80% (4/5) of INAD patients. Levodopa responsiveness was noted in 12 of 14 patients with parkinsonism/dystonia who received levodopa, and dyskinesia was noted in 10/11 patients. Genetic analysis revealed a total of 19 unique variants in PLA2G6 gene, of which 11 were novel. Twelve patients harbored the c.2222G>A variant, which is predominantly seen in Asian subpopulations. Conclusions: The study introduces 26 new patients of PLAN and 12 patients associated with the c.2222G>A variant, potentially forming the most extensive single center series to date. It also expands the phenotypic, neuroimaging, and genotypic spectrum of PLAN.

Islands and Neurology: An Exploration into a Unique Association.

The current study investigates the intricate connection between neurology and islands shedding light on the historical, epidemiological, and genetic aspects. Based on an elaborate literature review, we identified neurological conditions having a significant clustering in an island(s), confined to a particular island(s), named after an island, and described first in an island. The genetic factors played a crucial role, uncovering disorders like Cayman ataxia, Machado Joseph disease, SGCE-mediated dystonia-myoclonus syndrome, X-linked dystonia parkinsonism, hereditary transthyretinrelated amyloidosis, Charcot Marie Tooth 4F, and progressive myoclonic epilepsy syndromes, that exhibited remarkable clustering in diverse islands. Local customs also left enduring imprints. Practices such as cannibalism in Papua New Guinea led to Kuru, while cycad seed consumption in Guam triggered Lytico-Bodig disease. Toxin-mediated neurologic disorders exhibited intricate island connections, exemplified by Minamata disease in Kyushu islands and atypical parkinsonism in French Caribbean islands. Additionally, the Cuban epidemic of amblyopia and neuropathy was associated with severe nutritional deficiencies. This study pioneers a comprehensive review narrating the genetic, environmental, and cultural factors highlighting the spectrum of neurological disorders in island settings. It enriches the medical literature with a unique understanding of the diverse influences shaping neurological health in island environments.

Expanding the phenotypic and genotypic spectrum of DYT-TUBB4A with seven patients from India.

BACKGROUND: Variants in the TUBB4A gene are associated with dystonia (DYT-TUBB4A), Hypomyelination with Atrophy of the Basal Ganglia and Cerebellum (H-ABC) and spastic paraplegia. Phenotypes intermediate to these three broad phenotypes are also observed. These are rare disorders, and data from diverse populations remains limited. We report seven Indian cases with dystonia phenotype related to TUBB4A mutation. CASES: Among these seven patients, age at onset ranged from 5 to 48 years. Five patients had cranio-cervical onset of dystonia. One patient had prominent parkinsonism with dystonia. Patients responded well to botulinum toxin injected for laryngeal, cervical and jaw dystonia. The patient with parkinsonism responded well to levodopa, albeit with development of dyskinesias. Apart from the common p.Arg2Gly variant in three patients with DYT-TUBB4A, other variants included p.Arg262Pro, p.Arg39Cys and p.Asp245Asn. CONCLUSIONS: We report the first collection of cases with TUBB4A mutation from India. We expand the phenotype to include levodopa-responsive parkinsonism. Indian patients, consistent with global literature, harbor prominent adductor dysphonia, cervical and jaw dystonia, which responds well to botulinum treatment.

Clinical and genetic profile of patients with dystonia: An experience from a tertiary neurology center from India.

BACKGROUND: The genetics of dystonia have varied across different ethnicities worldwide. Its significance has become more apparent with the advent of deep brain stimulation. OBJECTIVE: To study the clinico-genetic profile of patients with probable genetic dystonia using whole exome sequencing (WES). METHODS: A prospective, cross-sectional study was conducted from May 2021 to September 2022, enrolling patients with dystonia of presumed genetic etiology for WES. The study compared genetically-determined cases harboring pathogenic/likely-pathogenic variants (P/LP subgroup) with the presumed idiopathic or unsolved cases. RESULTS: We recruited 65 patients (males, 69.2%) whose mean age of onset (AAO) and assessment were 25.0 ± 16.6 and 31.7 ± 15.2 years, respectively. Fifteen had pathogenic/likely-pathogenic variants (yield = 23.1%), 16 (24.6%) had variants of uncertain significance (VUS), 2 were heterozygous carriers while the remaining 32 cases tested negative (presumed idiopathic group). The P/LP subgroup had a significantly younger AAO (16.8 ± 12.3 vs 31.3 ± 17.0 years, p = 0.009), longer duration of illness (10.9 ± 10.3 vs 4.8 ± 4.3 years, p = 0.006), higher prevalence of generalized dystonia (n = 12, 80.0% vs n = 10, 31.3%, p = 0.004), lower-limb onset (n = 5, 33.3% vs n = 1, 3.1%, p = 0.009), higher motor (p = 0.035) and disability scores (p = 0.042). The classical DYT genes with pathogenic/likely pathogenic variants included 3 cases each of TOR1A, and KMT2B, and single cases each of SGCE, EIF2AK2, and VPS16. Non-DYT pathogenic/likely-pathogenic cases included PINK1, PANK2, CTSF, POLG, MICU1, and TSPOAP1. CONCLUSIONS: The yield of WES was 23.1% among cases of probable genetic dystonia. Pathogenic or likely pathogenic variants in TOR1A, KMT2B, and SGCE genes were commoner. The absence of family history emphasizes the importance of accurate assessment of clinical predictors before genetic testing.

KMT2B-Related Dystonia in Indian Patients With Literature Review and Emphasis on Asian Cohort.

OBJECTIVE: aaMutations in the KMT2B gene have been identified in patients previously diagnosed with idiopathic dystonia. Literature on KMT2B-related dystonia is sparse in the Indian and Asian populations. METHODS: aaWe report seven patients with KMT2B-related dystonia studied prospectively from May 2021 to September 2022. Patients underwent deep clinical phenotyping and genetic testing by whole-exome sequencing (WES). A systematic literature search was performed to identify the spectrum of previously published KMT2B-related disorders in the Asian subcontinent. RESULTS: aaThe seven identified patients with KMT2B-related dystonia had a median age at onset of four years. The majority experienced onset in the lower limbs (n = 5, 71.4%), with generalization at a median duration of 2 years. All patients except one had complex phenotypes manifesting as facial dysmorphism (n = 4), microcephaly (n = 3), developmental delay (n = 3), and short stature (n = 1). Magnetic resonance imaging (MRI) abnormalities were present in four cases. WES revealed novel mutations in the KMT2B gene in all patients except one. Compared to the largest cohort of patients with KMT2B-related disorders, the Asian cohort, comprising 42 patients, had a lower prevalence of female patients, facial dysmorphism, microcephaly, intellectual disability, and MRI abnormalities. Protein-truncating variants were more prevalent than missense variants. While microcephaly and short stature were more common in patients with missense mutations, facial dysmorphism was more common in patients with truncating variants. Deep brain stimulation, performed in 17 patients, had satisfactory outcomes. CONCLUSION: aaThis is the largest series of patients with KMT2B-related disorders from India, further expanding the clinico-genotypic spectrum. The extended Asian cohort emphasizes the unique attributes of this part of the world.

Co-VAN study: COVID-19 vaccine associated neurological diseases- an experience from an apex neurosciences centre and review of the literature.

BACKGROUND: Recent studies have shown various neurological adverse events associated with COVID-19 vaccine. OBJECTIVE: We aimed to retrospectively review and report the neurological diseases temporally associated with COVID-19 vaccine. METHODS: We performed a retrospective chart review of admitted patients from 1st February 2021 to 30th June 2022. A total of 4672 medical records were reviewed of which 51 cases were identified to have neurological illness temporally associated with COVID-19 vaccination. RESULTS: Out of 51 cases, 48 had probable association with COVID-19 vaccination while three had possible association. Neurological spectrum included CNS demyelination (n = 39, 76.5 %), Guillain-Barré-syndrome (n = 3, 5.9 %), stroke (n = 6, 11.8 %), encephalitis (n = 2, 3.9 %) and myositis (n = 1, 2.0 %). Female gender had a greater predisposition (F:M, 1.13:1). Neurological events were more commonly encountered after the first-dose (n = 37, 72.5%). The mean latency to onset of symptoms was 13.2 ± 10.7 days after the last dose of vaccination. COVIShield (ChAdOx1) was the most commonly administered vaccine (n = 43, 84.3 %). Majority of the cases with demyelination were seronegative (n = 23, 59.0 %) which was followed by anti-Myelin oligodendrocyte-glycoprotein associated demyelination (MOGAD) (n = 11, 28.2 %) and Neuromyelitis optica (NMOSD) (n = 5, 12.8 %). Out of 6 Stroke cases, 2 cases (33.3 %) had thrombocytopenia and coagulopathy. At discharge, 25/51 (49.0 %) of the cases had favourable outcome (mRS 0 to 1). Among six patients of stroke, only one of them had favourable outcome. CONCLUSION: In this series, we describe the wide variety of neurological syndromes temporally associated with COVID-19 vaccination. Further studies with larger sample size and longer duration of follow-up are needed to prove or disprove causality association of these syndromes with COVID-19 vaccination.

Long Latency Reflexes in Clinical Neurology: A Systematic Review.

BACKGROUND: Long latency reflexes (LLRs) are impaired in a wide array of clinical conditions. We aimed to illustrate the clinical applications and recent advances of LLR in various neurological disorders from a systematic review of published literature. METHODS: We reviewed the literature using appropriately chosen MeSH terms on the database platforms of MEDLINE, Web of Sciences, and Google Scholar for all the articles from 1st January 1975 to 2nd February 2021 using the search terms "long loop reflex", "long latency reflex" and "C-reflex". The included articles were analyzed and reported using synthesis without meta-analysis (SWiM) guidelines. RESULTS: Based on our selection criteria, 40 articles were selected for the systematic review. The various diseases included parkinsonian syndromes (11 studies, 217 patients), Huntington's disease (10 studies, 209 patients), myoclonus of varied etiologies (13 studies, 127 patients) including progressive myoclonic epilepsy (5 studies, 63 patients) and multiple sclerosis (6 studies, 200 patients). Patients with parkinsonian syndromes showed large amplitude LLR II response. Enlarged LLR II was also found in myoclonus of various etiologies. LLR II response was delayed or absent in Huntington's disease. Delayed LLR II response was present in multiple sclerosis. Among the other diseases, LLR response varied according to the location of cerebellar lesions while the results were equivocal in patients with essential tremor. CONCLUSIONS: Abnormal LLR is observed in many neurological disorders. However, larger systematic studies are required in many neurological disorders in order to establish its role in diagnosis and management.

CoRe study: COVID-19 and remdesivir: An insight into the current health planning and policy.

Introduction: The ongoing coronavirus disease-2019 (COVID-19) pandemic has witnessed rampant use of the repurposed drug, remdesivir, despite its conflicting evidence and rapidly changing guidelines. Methods: A cross-sectional, country-wide, questionnaire-based, electronic survey was conducted among the healthcare professionals involved in COVID-19 management from April 18 to May 18, 2021. Results: Out of 231 responses, 185 were included. Significantly, greater knowledge of trials was reported by the frontline healthcare professionals compared to those who are not involved in COVID-19 care. Medicine practitioners and pulmonologists expressed greater willingness to continue remdesivir (Odds ratio (OR) 5.329, 95% Confidence interval (CI) 2.31-12.291 and 5.063, 95% CI 1.414-18.129, respectively). The rationale attributed was personal experience, current guidelines, non-availability of any alternate antiviral drug, expert recommendations, and local hospital policy either alone (20%, 8.1%, 5.9%, 2.7%, and 2.2%, respectively) or in combination (46.5%, 39.5%, 29.2%, 21.1%, and 15.7%, respectively). Awareness of evidence and knowledge of landmark studies made no statistically significant impact on clinical decision-making. Improved clinical outcomes were reported by 10/22 (45.4%) practitioners who used remdesivir for unconventional indications. Conclusion: The study throws critical insights into the current perspectives of doctors on remdesivir in clinical management and its potential impact on current health planning strategies.

AI-CoV Study: Autoimmune Encephalitis Associated With COVID-19 and Its Vaccines-A Systematic Review.

BACKGROUND AND PURPOSE: Autoimmune encephalitis (AIE) following coronavirus disease 2019 (COVID-19) is an underexplored condition. This study aims to systematically review the clinico-investigational and pathophysiologic aspects of COVID-19 and its vaccines in association with AIE, and identify the factors predicting neurological severity and outcomes. METHODS: Relevant data sources were searched using appropriate search terms on January 15, 2022. Studies meeting the criteria for AIE having a temporal association with COVID-19 or its vaccines were included. RESULTS: Out of 1,894 citations, we included 61 articles comprising 88 cases: 71 of COVID-19-associated AIE, 3 of possible Bickerstaff encephalitis, and 14 of vaccine-associated AIE.There were 23 definite and 48 possible seronegative AIE cases. Anti-NMDAR (N-methyl-D-aspartate receptor; n=12, 16.9%) was the most common definite AIE. Males were more commonly affected (sex ratio=1.63) in the AIE subgroup. The neurological symptoms included alteredmental state (n=53, 74.6%), movement disorders (n=28, 39.4%), seizures (n=24, 33.8%), behavioural (n=25, 35.2%), and speech disturbances (n=17, 23.9%). The median latency to AIE diagnosis was 14 days (interquartile range=4-22 days). Female sex and ICU admission had higherrisks of sequelae, with odds ratio (OR) of 2.925 (95% confidence interval [CI]=1.005-8.516)and 3.515 (95% CI=1.160-10.650), respectively. Good immunotherapy response was seen in42/48 (87.5%) and 13/13 (100%) of COVID-19-associated and vaccine-associated AIE patients, respectively. Sequelae were reported in 22/60 (36.7%) COVID-19 associated and 10/13 (76.9%) vaccine-associated cases. CONCLUSIONS: The study has revealed diagnostic, therapeutic, and pathophysiological aspects of AIE associated with COVID-19 and its vaccines, and its differences from postinfectious AIE. SYSTEMATIC REVIEW REGISTRATION: PROSPERO registration number CRD42021299215.

Surgical Outcomes in Rare Movement Disorders: A Report of Seventeen Patients from India and Review of Literature.

Background: Rare movement disorders (RMDs) throw remarkable challenges to their appropriate management particularly when they are medically refractory. We studied the outcome of functional neurosurgery among patients with RMDs. Methods: Retrospective chart-review from 2006 to 2021 of patients with RMDs who underwent either Deep brain Stimulation (DBS) or lesional surgeries in the department of Neurology and Neurosurgery at a tertiary care centre. Results: Seventeen patients were included. Generalized dystonia (11 patients, 64.7%) and tremor (5 patients, 29.4%) were the most common indication for surgery whereas, Wilson's disease (8 patients, 47.1%) and Neurodegeneration with brain iron accumulation (5 patients, 29.4%) were the most common aetiology. Sixteen patients (94.1%) had objective clinical improvement. Significant improvement was noted in the dystonia motor scores both at 6-months and 12-months follow-up (n = 11, p-value of <0.01 and 0.01 respectively). Comparison between DBS and lesional surgery showed no significant difference in the outcomes (p = 0.95 at 6-months and p = 0.53 at 12-months), with slight worsening of scores in the DBS arm at 12-months. Among five patients of refractory tremor with Wilson's disease, there was remarkable improvement in the tremor scores by 85.0 ± 7.8% at the last follow-up. Speech impairment was the main complication observed with most of the other adverse events either transient or reversible. Discussion: Surgical options should be contemplated among patients with disabling medically refractory RMDs irrespective of the aetiology. Key to success lies in appropriate patient selection. In situations when DBS is not feasible, lesional surgeries can offer an excellent alternative with comparable efficacy and safety.

Disorders of Tetrahydrobiopterin Metabolism: Experience from South India.

BACKGROUND: Disorders of tetrahydrobiopterin metabolism represent a rare group of inherited neurotransmitter disorders that manifests mainly in infancy or childhood with developmental delay, neuroregression, epilepsy, movement disorders, and autonomic symptoms. METHODOLOGY: A retrospective review of genetically confirmed cases of disorders of tetrahydrobiopterin metabolism over a period of three years (Jan 2018 to Jan 2021) was performed across two paediatric neurology centres from South India. RESULTS: A total of nine patients(M:F=4:5) fulfilled the eligibility criteria. The genetic variants detected include homozygous mutations in the QDPR(n=6), GCH1(n=2), and PTS(n=1) genes. The median age at onset of symptoms was 6-months(range 3-78 months), while that at diagnosis was 15-months (8-120 months), resulting in a median delay in diagnosis of 9-months. The main clinical manifestations included neuroregression (89%), developmental delay(78%), dystonia(78%) and seizures(55%). Management strategies included a phenylalanine restricted diet, levodopa/carbidopa, 5-Hydroxytryphtophan, and folinic acid. Only, Patient-2 afforded and received BH4 supplementation at a sub-optimal dose later in the disease course. We had a median duration of follow up of 15 months (range 2-48 months). Though the biochemical response has been marked; except for patients with GTPCH deficiency, only mild clinical improvement was noted with regards to developmental milestones, seizures, or dystonia in others. CONCLUSION: Tetrahydrobiopterin deficiencies represent a rare yet potentially treatable cause for non-phenylketonuria hyperphenylalaninemia with better outcomes when treated early in life. Screening for disorders of biopterin metabolism in patients with hyperphenylalaninemia prevents delayed diagnosis. This study expands the genotype-phenotype spectrum of patients with disorders of tetrahydrobiopterin metabolism from South India.

Pediatric neurobrucellosis: a systematic review with case report.

Pediatric neurobrucellosis represents a common anthropozoonosis in endemic areas but only anecdotal reports are available till date. Using appropriate search terms in the database platforms of MEDLINE, SCOPUS and Web of Sciences, we performed a systematic review of all the cases of pediatric neurobrucellosis published in the medical literature till date, in the light of a case report. The protocol was registered under PROSPERO (CRD42022333907). Our search strategy yielded 187 citations of which 51 citations were included. A total of 119 cases were reviewed. Of these cases, eight of them had insufficient data. The most common presentation was meningitis with or without encephalitis (n = 79, 71.2%). A high prevalence of cranial neuropathies (n = 22, 20.7%) was observed in the pediatric population in which abducens palsy was the most common (n = 9, 8.1%). Diagnosis was based on multimodal investigations including standard agglutination test (n = 44, 39.6%), Rose Bengal test (n = 37, 33.3%), blood culture (n = 23, 20.7%), serology (n = 20, 18.0%) and cerebrospinal fluid (CSF) culture (n = 11, 9.9%). Rifampicin-based triple drug regimen was the most commonly employed (83/102, 81.4%). Pediatric neurobrucellosis was associated with greater frequency of sequalae (5.4%), deafness (2.7%) and mortality (2.7%), when compared to that of general population. Neurobrucellosis mimics neuro-tuberculosis in various aspects. The review highlights several unique aspects of this entity in children. A high index of suspicion can ensure prompt diagnosis, timely initiation of management and favorable outcomes.

Pediatric neurobrucellosis represents a common zoonosis in endemic areas but only anecdotal reports are available till date. Using appropriate search terms in the database platforms of MEDLINE, SCOPUS and Web of Sciences, we performed a systematic review of all the cases of pediatric neurobrucellosis published in the medical literature till date, in the light of a case report. Our search strategy yielded 187 citations of which 51 citations were included. A total of 119 cases were reviewed. When compared to the largest series in neurobrucellosis, a higher frequency of meningitis was observed in the pediatric age group (71.2% vs. 37%). A high prevalence of cranial neuropathies (n = 22, 20.7%) was observed in the pediatric population in which abducens palsy was the most common (n = 9, 8.1%). Diagnosis was based on multimodal investigations including standard agglutination test (n = 44, 39.6%), Rose Bengal test (n = 37, 33.3%), blood culture (n = 23, 20.7%), serology (n = 20, 18.0%) and CSF culture (n = 11, 9.9%). Rifampicin-based triple drug regimen was the most commonly employed (83/102, 81.4%). Our systematic review highlighted the wide and heterogeneous spectrum of manifestations of neurobrucellosis in the pediatric population. A high index of suspicion can ensure prompt diagnosis, timely initiation of management and favorable outcomes.