Phenotypic features of epilepsy due to sodium channelopathies - A single center experience from India.

Objectives: Nearly 40% of pediatric epilepsies have a genetic basis. There is significant phenotypic and genotypic heterogeneity, especially in epilepsy syndromes caused by sodium channelopathies. Sodium channel subunit 1A (SCN1A)-related epilepsy represents the archetypical channel-associated gene that has been linked to a wide spectrum of epilepsies of varying severity. Subsequently, other sodium channels have also been implicated in epilepsy and other neurodevelopmental disorders. This study aims to describe the phenotypes in children with sodium channelopathies from a center in Southern India. Materials and Methods: This is a retrospective, descriptive, and single-center study. Out of 112 children presenting with epilepsy who underwent genetic testing between 2017 and 2021, 23 probands (M: F = 12:11) were identified to have clinically significant sodium channel mutations. Clinical presentation, electroencephalography, and imaging features of these patients were recorded. The utility of genetic test results (e.g., in planning another child, withdrawal of medications, or change in treatment) was also recorded. Results: Age at onset of seizures ranged from day 4 of life to 3.5 years. Clinical epilepsy syndromes included generalized epilepsy with febrile seizures plus (n = 3), Dravet syndrome (n = 5), early infantile epileptic encephalopathy (n = 7), drug-resistant epilepsy (n = 5), and epilepsy with associated movement disorders (n = 3). The most common type of seizure was focal with impaired awareness (n = 18, 78.2%), followed by myoclonic jerks (n = 8, 34.78%), epileptic spasms (n = 7, 30.4%), bilateral tonic-clonic seizures/generalized tonic-clonic seizures (n = 3, 13%), and atonic seizures (n = 5, 23.8%). In addition to epilepsy, other phenotypic features that were discerned were microcephaly (n = 1), cerebellar ataxia (n = 2), and chorea and dystonia (n = 1). Conclusion: Sodium channelopathies may present with seizure phenotypes that vary in severity. In addition to epilepsy, patients may also have other clinical features such as movement disorders. Early clinical diagnosis may aid in tailoring treatment for the given patient.

Characterisation of Patients with SH3TC2 Associated Neuropathy in an Indian Cohort.

Background: SH3TC2 variations lead to demyelinating recessive Charcot-Marie-Tooth (CMT) disease, which is commonly associated with early-onset scoliosis and cranial neuropathy. Data from Indian ethnicity is limited. Objective: We aim to report the characteristics of patients with SH3TC2-associated neuropathy from an Indian cohort. Patients and Methods: Data of five unrelated subjects with SH3TC2 variations were analyzed. Results: Clinical features included female predominance (n = 4), early-onset neuropathy (n = 2), pes cavus and hammer toes (n = 4), kyphoscoliosis (n = 1), impaired vision and hearing (n = 1), facial muscle weakness (n = 1), impaired kinaesthetic sense (n = 3), tremor (n = 2), and ataxia (n = 1). Four patients had the "CMT" phenotype, while one patient had Roussy-Levy syndrome. All had demyelinating electrophysiology with conduction velocities being "very slow" in one, "slow" in one, "mildly slow" in two, and "intermediate" in one patient. Brain stem auditory evoked potentials were universally abnormal though only one patient had symptomatic deafness. Seven variants were identified in SH3TC2 [homozygous = 3 (c.1412del, c.69del, c.3152G>A), heterozygous = 4 (c.1105C>T, c.3511C>T, c.2028G>C, c.254A>T)]. Except for c.3511C>T variant, the rest were novel. Three patients had additional variations in genes having pathobiological relevance in other CMTs or amyotrophic lateral sclerosis. Conclusion: We provide data on a cohort of patients of Indian origin with SH3TC2 variations and highlight differences from other cohorts. Though the majority were not symptomatic for hearing impairment, evoked potentials disclosed abnormalities in all. Further studies are required to establish the functional consequences of novel variants and their interacting molecular partners identified in the present study to strengthen their association with the phenotype.

Surgical Management of Vision Loss in Cerebral Venous Thrombosis: Case Series from a Tertiary Care Stroke Center.

Background and Purpose: Cerebral venous thrombosis (CVT) presenting as vision loss is uncommon. Raised intracranial tension in CVT is proposed as one of the mechanisms (13.2%). There are still unknown underlying mechanisms to explain vision loss in CVT. The safety and outcome of the surgery (optic nerve sheath fenestration [ONSF] or theco-peritoneal shunt [TPS]) to reduce intracranial hypertension and prevent vision loss has not been studied. Methods: A retrospective case record review of CVT patients with impending vision loss who underwent ONSF/TPS from 2007 to 2019 was performed from the stroke registry. All patients had formal neuro-ophthalmological evaluation and documentation of visual acuity, supplemented by visual field assessments by perimetry in a subset of patients. Safety and outcomes were assessed based on vision improvement and adverse effects after the surgery. Results: Among approximately 1400 patients with CVT admitted in the stroke ward over 12 years, surgery for rescuing vision was done in 18. Among these, the males were 6, and the females were 12. The mean age of presentation was 24 (range 18-52 years). All of them had headaches and progressive blurring of vision with papilledema. The number of patients who underwent TPS was 13, ONSF was 1, and both were 4. In the TPS group (26 eyes), vision improved in 15 eyes (57.7%), remained status-quo in 8 eyes (30.7%), and worsened in 3 eyes (11.5%). Four patients underwent both surgeries; three eyes improved, two remained status quo, and three worsened. One patient underwent ONSF, and his vision remained status quo (no perception of light). Three patients (17.6%) of the TPS group had minor complications (low-pressure headache, subdural hygroma), and five (29.4%) had major complications like subdural hemorrhage, abdominal wound infection, and meningitis. Conclusion and Implications: In patients with CVT, adequate vision monitoring is mandatory. Shunt surgeries (especially TPS) may help in stabilizing/improving vision in CVT patients with impending vision loss, despite adequate anti-edema measures (53.8% improved). Early diagnosis and precise decisions in referring for surgery are crucial.

Rituximab in Myasthenia Gravis- Experience from a Low- and Middle-Income Country (LMIC) Setting.

Background: Myasthenia gravis (MG) is an immune-mediated disorder of the neuromuscular junction. About 10% are refractory to immunosuppressive therapy. Aims: To analyze the response of patients with generalized MG to rituximab. Methods and Materials: A retrospective review of patients with MG who received rituximab was carried out (n = 13, M:F = 6:7, mean age: 44.84 ± 15.73 years). Myasthenia Gravis Foundation of America (MGFA), MGFA post-intervention status (MGFA-PIS), and Myasthenia Gravis Status and Treatment Intensity (MGSTI) were assessed before and after rituximab. Results: The duration of MG was 104.07 ± 92.25 months. Before rituximab, the MGFA was IIA/IIB/IIIA/IIIB/IVB/V in 1/1/2/6/2/1 patients and MGSTI was four in eight patients and six in three patients. The mean duration of follow up was 20.92 ± 14.06 months (range, 4 to 42 months). Dose reduction or discontinuation of cholinesterase inhibitors could be achieved 12 patients. Complete stable remission (CSR) and pharmacologic remission (PR) were achieved in one and four patients respectively and five patients had minimal manifestations. Most patients attained level 0, 1 or 2 MGSTI at last follow up. No rituximab infusion-related adverse events were noted. Three patients had exacerbation of MG between one to five weeks after rituximab administration. Three patients died, one each due to a cardiac event unrelated to MG or treatment, complications related to myasthenic crisis, and coronavirus disease. Conclusions: Rituximab was effective in bringing about remission in MG and can be considered as a first-line agent. However, it has to be administered under close supervision as some patients develop exacerbation of MG akin to steroid-induced worsening.

Impact of Antecedent Infections on the Antibodies against Gangliosides and Ganglioside Complexes in Guillain-Barré Syndrome: A Correlative Study.

Background and Aims: Guillain-Barré Syndrome (GBS), an immune-mediated neuropathy, is characterized by antibodies against gangliosides/ganglioside complexes (GSCs) of peripheral nerves. Antecedent infections have been reported to induce antibodies that cross-react with the host gangliosides and thereby have a pivotal role in conferring an increased risk for developing GBS. Data pertaining to the impact of various antecedent infections, particularly those prevalent in tropical countries like India on the ganglioside/GSC antibodies is sparse. We aimed at exploring the association between six antecedent infections and the profile of ganglioside/GSC antibodies in GBS. Methods: Patients with GBS (n = 150) and healthy controls (n = 50) were examined for the serum profile of antibodies against GM1, GM2, GD1a, GD1b, GT1b, and GQ1b and their GSCs by ELISA. These antibodies were correlated with immunoreactivities against Campylobacter jejuni, Japanese encephalitis (JE), dengue, influenza, zika, and chikungunya infections. Results: The frequencies of antibodies against six single gangliosides (P < 0.001) and their GSCs (P = 0.039) were significantly higher in patients as compared to controls. Except for GT1b-antibody which was more frequent in axonal GBS, none of the other ganglioside/GSC antibodies correlated with the electrophysiological subtypes of GBS. Antecedent JE infection was significantly associated with increased frequency of antibodies against GD1a, GD1b, GT1b, and GQ1b. Antibodies against GSCs were not influenced by the antecedent infections. Interpretation: This study for the first time shows an association between antecedent JE infection and ganglioside antibodies in GBS. This finding reinforces the determining role of antecedent infections on ganglioside antibody responses and the subsequent immunological processes in GBS.

Genetic Spectrum of Inherited Neuropathies in India.

Background and Objectives: Charcot-Marie-Tooth (CMT) disease is the commonest inherited neuromuscular disorder and has heterogeneous manifestations. Data regarding genetic basis of CMT from India is limited. This study aims to report the variations by using high throughput sequencing in Indian CMT cohort. Methods: Fifty-five probands (M:F 29:26) with suspected inherited neuropathy underwent genetic testing (whole exome: 31, clinical exome: 17 and targeted panel: 7). Their clinical and genetic data were analysed. Results: Age at onset ranged from infancy to 54 years. Clinical features included early-onset neuropathy (n=23), skeletal deformities (n=45), impaired vision (n=8), impaired hearing (n=6), facial palsy (n=8), thickened nerves (n=4), impaired cognition (n=5), seizures (n=5), pyramidal signs (n=7), ataxia (n=8) and vocal cord palsy, slow tongue movements and psychosis in one patient each. Twenty-eight patients had demyelinating electrophysiology. Abnormal visual and auditory evoked potentials were noted in 60.60% and 37.5% respectively. Sixty two variants were identified in 37 genes including variants of uncertain significance (n=34) and novel variants (n=45). Eleven patients had additional variations in genes implicated in CMTs/ other neurological disorders. Ten patients did not have variations in neuropathy associated genes, but had variations in genes implicated in other neurological disorders. In seven patients, no variations were detected. Conclusion: In this single centre cohort study from India, genetic diagnosis could be established in 87% of patients with inherited neuropathy. The identified spectrum of genetic variations adds to the pool of existing data and provides a platform for validation studies in cell culture or animal model systems.

The Spectrum of Neuro-COVID: A Study of a Comprehensively Investigated Large Cohort from India.

Background: Though reports of neurological manifestations of COVID-19 have emerged from various parts of the world, the cohorts reported are from the West and mostly derived from electronic databases. Much remains unknown regarding neuro-COVID in developing countries. India is the second-worst affected country, and this study reports the neurological manifestations of COVID-19 in a comprehensively evaluated cohort. Objective: The aim of this study was to describe the range of neurological manifestations of COVID-19 in India with an emphasis on the risk factors, laboratory and imaging findings and short-term outcome. Methods: Retrospective review of hospital records of all confirmed COVID-19 patients with neurological manifestations, receiving inpatient care in two neurology referral hospitals were done. All demographic, clinical details, investigations, and treatment were analysed. Results: A total of 120 confirmed COVID-19 cases presenting with neurological symptoms were included. The mean age of illness and duration of illness was 48.03 ± 17.3 years and 10.9 ± 17.3 days respectively. New onset of neurological symptoms occurred in 100 cases while 20 patients had worsening of pre-existing neurological illness. Stroke was the commonest neurological disorder (43%), followed by encephalopathy (23%) and Guillain-Barre syndrome (10%). Other unusual neurological manifestations included new-onset headache (7%), seizures including denovo status epilepticus (5%) and meningo-encephalitis (5%). Nearly half of the patients had preceding COVID-19 symptoms. Poor outcome at discharge was seen in 40% and mortality occurred in 15%. Conclusion: Stroke and encephalopathy constitute the most common neurological manifestations. The absence of preceding COVID-19 symptoms in nearly half the cases is striking. Poor outcome was seen in nearly 50% despite early recognition and management.

Novel insights into the genetic profile of hereditary spastic paraplegia in India.

The Hereditary Spastic Paraplegias (HSPs) are a group of clinically and genetically heterogeneous disorders characterized by length dependent degeneration of the corticospinal tracts. Genetic data related to HSPs are limited from India. We aimed to comprehensively analyse the phenotypic characteristics and genetic basis of a large cohort of HSP from India. Patients with HSP phenotype were evaluated for their clinical features, electrophysiological and radiological abnormalities. Genetic analyses were carried out by clinical exome sequencing (n = 52) and targeted sequencing (n = 5). The cohort comprised of 57 probands (M:F 40:17, age: 3.5-49 years). Based on the phenotype, the cohort could be categorized as 'pure' (n = 15, 26.3%) and 'complicated' (n = 42, 73.7%) HSP. Brain MRI showed thin corpus callosum (n = 10), periventricular hyperintensities (n = 20), cerebral atrophy (n = 3), cerebellar atrophy (n = 3) and diffuse atrophy (n = 4). Sixty-seven variants representing 40 genes were identified including 47 novel variants. Forty-eight patients (84.2%) had variants in genes previously implicated in HSP and other spastic paraplegia syndromes (SPG genes = 24, non-SPG genes = 24); among these 13 had variations in more than one gene and 12 patients (21.0%) had variations in genes implicated in potentially treatable/modifiable metabolic disorders (MTHFR = 8, MTRR = 1, ARG1 = 2 and ABCD1 = 1). In nine patients, no genetic variants implicated in spastic paraplegia phenotype were identified. Thus, the present study from India highlights the phenotypic complexities and spectrum of genetic variations in patients with HSP including those implicated in metabolically modifiable disorders. It sets a platform for carrying out functional studies to validate the causal role of the novel variants and variants of uncertain significance.

Role of altered IL-33/ST2 immune axis in the immunobiology of Guillain-Barré syndrome.

BACKGROUND: The IL-33/ST2 immune axis plays crucial roles in infection and immunity. A dysregulated IL-33/ST2 axis can induce autoimmune reaction and inflammatory responses. Guillain-Barré syndrome (GBS) is an acute peripheral neuropathy, mostly caused by post-infection autoimmunity. The role of IL-33/ST2 axis is not known in GBS. This study aimed to explore the role of IL-33/ST2 axis in GBS. METHODS: Three single nucleotide polymorphisms (SNPs) of Il33 gene (rs16924159, rs7044343, rs1342336) and three SNPs of Il1rl1 gene (rs10192157, rs1041973, rs10206753) coding for suppressor of tumorigenicity 2 (ST2) were genotyped in 179 GBS patients and 186 healthy controls by TaqMan Allelic Discrimination Assay. Plasma levels of IL-33 and sST2 were measured in a subset of GBS patients (n = 80) and healthy controls (n = 80) by ELISA. RESULTS: The frequencies of CC genotype of rs10192157 (p = 0.043) and TT genotype of rs10206753 (p = 0.036) SNPs of Il1rl1 gene differed significantly between GBS patients and healthy controls. Gene-gene interaction between Il33 and Il1rl1 genes also conferred significant risk for GBS. In addition, the plasma sST2 levels were significantly elevated in GBS patients compared to healthy subjects (24,934.31 ± 1.81 pg/ml vs. 12,518.97 ± 1.51 pg/ml, p < 0.001). Plasma sST2 levels showed a significant correlation with the disability scores at the peak of neurological deficit in GBS patients. CONCLUSIONS: The IL-33/ST2 axis is suggested to influence the immunopathogenesis of GBS. Genetic variants of Il1rl1 gene might serve as a risk determinant of GBS and plasma sST2 levels might emerge as a biomarker of severity of GBS, if replicated further by other studies.

Vogt-Koyanagi-Harada Syndrome - A Neurologist's Perspective.

Vogt-Koyanagi-Harada (VKH) syndrome is an immune-mediated granulomatous disease which affects melanin-rich organs like eyes, skin, nervous system, and ears. Neurological and auditory manifestations usually precede the involvement of other sites. Patients may manifest with "complete" or "incomplete" syndrome. We report two patients who presented with acute headache and impaired vision. Fundus examination revealed optic disc hyperemia and exudative retinal detachment which provided a clue for the diagnosis at the bedside. Fundus fluorescein angiogram (FFA) revealed abnormal dye leakage, whereas B scan showed choroid thickening. Cerebrospinal fluid (CSF) pleocytosis contrasted with unremarkable brain magnetic resonance imaging and lack of meningeal signs. Melanophagocytosis was evidenced by melanin-laden macrophages in CSF and skin biopsy. This finding is specific for VKH syndrome and helps to clinch the diagnosis even when the complete syndrome is not present cross-sectionally. VKH syndrome should be suspected in patients with aseptic meningitis if tests for common infectious and immune-mediated diseases are negative.

Clinical Profile and Treatment Response in Patients with CASPR2 Antibody-Associated Neurological Disease.

BACKGROUND: The clinical spectrum of contactin-associated protein-like 2 (CASPR2) antibody-associated disease is wide and includes Morvan syndrome. Studies describing treatment and long-term outcome are limited. AIMS: We report the clinical profile and emphasize response to treatment and long-term outcome in eight patients with CASPR2-antibody-associated disease. METHODS: Clinical, radiological, electrophysiological, treatment, follow-up, and outcome data were collected by retrospective chart review. RESULTS: Clinical manifestations included Morvan syndrome (n = 7) and limbic encephalitis (n = 1). None of the patients were positive for LGI1 antibody. Associated features included myasthenia (n = 1), thymoma (n = 1), and dermatological manifestations (n = 4). Patients were treated with intravenous methylprednisolone and plasma exchange during the acute symptomatic phase followed by pulsed intravenous methyl prednisolone to maintain remission. Mean-modified Rankin score at admission (pre-treatment), discharge, and last follow-up were 3.75, 2.5, and 0.42, respectively. One patient with underlying thymoma and myasthenic crisis died. The other seven patients were followed up for a mean duration of 19.71 months. All of them improved completely. Relapse occurred in one patient after 13 months but responded favorably to steroids. CONCLUSION: CASPR2 antibody-associated disease has favorable response to immunotherapy with complete improvement and good outcome. Underlying malignancy may be a marker for poor prognosis.

Optokinetic nystagmus in patients with SCA: A bedside test for oculomotor dysfunction grading.

OBJECTIVE: To characterize the clinical features in patients with spinocerebellar ataxia (SCA) type 1, SCA2, and SCA3 and to evaluate the oculomotor dysfunction by using optokinetic nystagmus (OKN) testing, which may be a sensitive marker. METHODS: In this prospective observational study, all patients underwent detailed neurologic examination with special emphasis on eye movements. OKN was evaluated with a tape. Disease severity was measured with the International Co-Operative Ataxia Rating Scale (ICARS). RESULTS: A total of 73 genetically confirmed patients were included, of whom 28, 30, and 15 patients were positive for SCA1, SCA2, and SCA3, respectively. Dystonia was more common in patients with SCA3 (46%), and absent ankle jerk was more common in those with SCA2 (21.4%). Brisk deep tendon reflexes were common in patients with SCA1 (46.6%), followed by patients with SCA3 (26.6%) and SCA2 (7.1%). Vertical OKN was impaired in all patients and absent in 86.6% of patients with SCA1, 96% of those with SCA2, and 80% of those with SCA3. Horizontal OKN was absent in 30% of patients with SCA1, 57% of patients with SCA2, and 33% of those with SCA3. Higher motor disability (posture and gait, kinetic functions [Motor Disability] subscore on the ICARS) was associated with higher oculomotor dysfunction measured by OKN-saccades impairment grading but not with the Ocular Disorder subscore of ICARS (ICARS-OD). CONCLUSION: OKN-saccades are a better and sensitive bedside clinical tool to quantify oculomotor dysfunction in neurodegenerative ataxias. Its role needs to be tested further in presymptomatic carriers. The current ICARS-OD scale to grade oculomotor dysfunction in degenerative ataxias need to be modified.