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Introduction/Aims: Studies conducted during the coronavirus disease 2019 (COVID-19) pandemic have reported varied data regarding the incidence of Guillain–Barre syndrome (GBS). The present study investigated demographic and clinical features, management, and outcomes of patients with GBS during a specified period of the COVID-19 pandemic, and compared these features to those of GBS in the previous year. Methods: A multicenter, ambispective cohort study including 26 centers across India was conducted. Data from a pre-COVID-19 period (March 1 to August 31, 2019) were collected retrospectively and collected ambispectively for a specified COVID-19 period (March 1 to August 31, 2020). The study was registered with the Clinical Trial Registry India (CTRI/2020/11/029143). Results: Data from 555 patients were included for analysis: pre-COVID-19 (n = 334) and COVID-19 (n = 221). Males were more commonly affected during both periods (male:female, 2:1). Gastroenteritis was the most frequent antecedent event in 2019 (17.4%), whereas fever was the most common event in 2020 (10.7%). Paraparesis (21.3% versus [vs.] 9.3%, P = 0.001) and sensory involvement (51.1% vs. 41.3%; P = 0.023) were more common during COVID-19 in 2020, whereas back pain (26.3% vs. 18.4%; P = 0.032) and bowel symptoms (20.7% vs. 13.7%; P = 0.024) were more frequent in the pre-COVID period. There was no difference in clinical outcomes between the two groups in terms of GBS disability score at discharge and 3 months after discharge. Independent predictors of disability in the pre-COVID period included areflexia/hyporeflexia, the requirementfor intubation, and time to bulbar weakness; in the COVID-19 period, independent predictors included time from onset to admission, intubation, and intubation requirement. The mortality rate was 2.3% during the entire study period (13/555 cases). Discussion: Results of this study revealed an overall reduction in the frequency of GBS during the pandemic. The lockdown likely reduced the risk for antecedent infections due to social distancing and improved hygiene, which may have resulted in the reduction of the frequency of GBS.

Metabolic myopathies are a diverse group of genetic disorders that result in impaired energy production. They are individually rare and several have received the 'orphan disorder' status. However, collectively they constitute a relatively common group of disorders that affect not only the skeletal muscle but also the heart, liver, and brain among others. Mitochondrial disorders, with a frequency of 1/8000 population, are the commonest cause of metabolic myopathies. Three main groups that cause metabolic myopathy are glycogen storage disorders (GSD), fatty acid oxidation defects (FAOD), and mitochondrial myopathies. Clinically, patients present with varied ages at onset and neuromuscular features. While newborns and infants typically present with hypotonia and multisystem involvement chiefly affecting the liver, heart, kidney, and brain, patients with onset later in life present with exercise intolerance with or without progressive muscle weakness and myoglobinuria. In general, GSDs result in high-intensity exercise intolerance while, FAODs, and mitochondrial myopathies predominantly manifest during endurance-type activity, fasting, or metabolically stressful conditions. Evaluation of these patients comprises a meticulous clinical examination and a battery of investigations which includes- exercise stress testing, metabolic and biochemical screening, electrophysiological studies, neuro-imaging, muscle biopsy, and molecular genetics. Accurate and early detection of metabolic myopathies allows timely counseling to prevent metabolic crises and helps in therapeutic interventions. This review summarizes the clinical features, diagnostic tests, pathological features, treatment and presents an algorithm to diagnose these three main groups of disorders.

Inflammatory neuropathies are a group of acquired neuropathies which could be due to autoimmune, infectious, paraneoplastic, or paraproteinemic etiology. The etiological diagnosis of inflammatory neuropathy is not simple, and often requires combination of clinical, electrophysiological, and histopathological findings to arrive at a precise diagnosis which is important for management of the disorder. Whereas there are comprehensive and sensitive panel of serological tests available for diagnosis of the infectious, paraneoplastic, paraproteinemic neuropathies, the diagnosis of immune-mediated demyelinating neuropathies remain a considerable challenge as there is both clinical and pathological overlap. Newer non-invasive methodologies such as high-resolution ultrasound, magnetic resonance imaging (MRI), and importantly, serological testing for antibodies are emerging, and it is essential for the practicing pathologist to be up-to-date with emerging modalities. In this review, we focus on the approach to diagnosis of immune-mediated demyelinating neuropathies.

Objective: To study impact of COVID-19 pandemic on frequency, clinical/electrophysiological profile and treatment outcomes in pediatric Guillain-Barré syndrome (GBS). Background: GBS is the most frequent cause of pediatric acute flaccid paralysis. The effect of the COVID-19 pandemic on pediatric GBS is unclear in the literature. Methods: We conducted an ambispective, multicentric, cohort study involving 12 of 27 centres in GBS Consortium, during two periods: pre-COVID-19 (March-August 2019) and during COVID-19 (March-August 2020). Children ≤12 years who satisfied National Institute of Neurological Diseases and Stroke criteria for GBS/variants were enrolled. Details pertaining to clinical/laboratory parameters, treatment and outcomes (modified Rankin Scale (mRS) at discharge, GBS Disability score at discharge and 3 months) were analysed. Results: We enrolled 33 children in 2019 and 10 in 2020. Children in 2020 were older (median 10.4 [interquartile range 6.75–11.25] years versus 5 (2.5–8.4) years; P = 0.022) and had more sensory symptoms (50% versus 18.2%; P = 0.043). The 2020 group had relatively favourable mRS at discharge (median 1 (1–3.5) versus 3 (2–4); P = 0.042) and GBS disability score at 3 months (median 0 (0–0.75) versus 2 (0–3); P = 0.009) compared to 2019. Multivariate analysis revealed bowel involvement (P = 0.000) and ventilatory support (P = 0.001) as independent predictors of disability. No child in 2020 had preceding/concurrent SARS-CoV2 infection. Conclusions: The COVID-19 pandemic led to a marked decline in pediatric GBS presenting to hospitals. Antecedent illnesses, clinical and electrophysiological profile of GBS remained largely unchanged from the pre-pandemic era.

Objective: Immunocharacterization of congenital muscular dystrophy (CMD) to determine the frequency of various subtypes in a large Indian Cohort. Materials and Methods: This retrospective (2014-2017) study was carried on muscle biopsies of clinically suspected cases of CMD with histological evidence of dystrophy/myopathic features. Immunohistochemistry (IHC) to antibodies against laminin (α2, α5,β1,γ1), Collagen-VI (A1,2,3), and Western blot (WB) for α-dystroglycan and POMT1 was performed. Results: The study included 57 cases, of which 15 cases (26.3%) had mean age at presentation of 3.5 years, M: F = 1.5:1, elevated creatinine kinase (CK) (mean 1657 U/L), global developmental delay, multiple contractures, abnormal facies, white matter hyperintensities and showed laminin-α2 deficiency (Merosin deficient CMD). In addition, secondary reduction in laminin-β1, over-expression of laminin-α5, and preserved laminin-γ1 was noted. Ullrich CMD constituted 11/57 cases (19.2%) with mean age at presentation of 5.3 years, M: F = 1.2:1 and normal CK. They presented with proximal muscle weakness, soft velvety palms and soles, contractures, and joint hyperextensibility. Collagen-VI (A1,2,3) showed either complete (n = 3) or sarcolemmal specific (n = 8) loss of staining. Out of the remaining 31 cases, WB for α-dystroglycan was performed in 17 cases which showed deficiency in seven (12.3%). Three of these in addition revealed secondary partial loss of laminin-α2. WB for POMT1 showed deficiency in a single case clinically diagnosed Walker–Warburg syndrome, who presented with seizures and classical features of pachygyria, lissencephaly, and cerebellar cyst on MRI. Twenty-four cases (42.2%) remained uncharacterized and need genetic evaluation. Conclusion: The study helped in characterizing 57.8% of the proband. Immunotyping helps to direct mutational analysis for targeted genes and offers a potential route for prenatal diagnosis.

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.

Background: NMDA receptor encephalitis (NMDARE) is the most prevalent autoimmune encephalitis and it encompasses a spectrum of clinical features. It is most commonly associated with alteration in consciousness, seizures, neuro-psychiatric symptoms, and movement disorders. Electroencephalography (EEG) plays a vital role and can give clues to diagnosis in a subset of patients. Methods: We retrospectively characterized the clinical and EEG findings in our NMDARE patients (n = 48). A total of 131 EEGs were analyzed. Results: We observed that patients with seizures had a younger age of onset (p < 0.001). The most common EEG pattern that was noted was diffuse slowing (n = 20) followed by generalized rhythmic delta activity (n = 9), focal spikes and slowing (n = 8 each). Delta brush pattern was seen in only 3 EEGs. Focal ictal rhythms were seen in 3 EEGs. There was no significant difference in outcomes such as seizure recurrence, modified Rankin score (mRS) at follow up/discharge or relapse between groups of patients who had EEG abnormalities in the first EEG and with those who did not. Conclusions: NMDARE has varied EEG findings, most of them being non-specific. When combined with clinical presentation, EEG is a useful tool in the diagnosis and management of NMDARE.

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.

Abstract Background Dysfunction in inwardly rectifying potassium channel Kir4.1 has been implicated in SeSAME syndrome, an autosomal-recessive (AR), rare, multi-systemic disorder. However, not all neurological, intellectual disability, and comorbid phenotypes in SeSAME syndrome can be mechanistically linked solely to Kir4.1 dysfunction. Methods We therefore performed whole-exome sequencing and identified additional genetic risk-elements that might exert causative effects either alone or in concert with Kir4.1 in a family diagnosed with SeSAME syndrome. Results Two variant prioritization pipelines based on AR inheritance and runs of homozygosity (ROH), identified two novel homozygous variants in KCNJ10 and PI4KB and five rare homozygous variants in PVRL4, RORC, FLG2, FCRL1, NIT1 and one common homozygous variant in HSPA6 segregating in all four patients. The novel mutation in KCNJ10 resides in the cytoplasmic domain of Kir4.1, a seat of phosphatidylinositol bisphosphate (PIP2) binding. The mutation altered the subcellular localization and stability of Kir4.1 in patient-specific lymphoblastoid cells (LCLs) compared to parental controls. Barium-sensitive endogenous K+ currents in patient-specific LCLs using whole-cell patch-clamp electrophysiology revealed membrane depolarization and defects in inward K+ ion conductance across the membrane, thereby suggesting a loss-of-function effect of KCNJ10 variant. Conclusion Altogether, our findings implicate the role of new genes in SeSAME syndrome without electrolyte imbalance and thereby speculate the regulation of Kir4.1 channel activity by PIP2 and integrin-mediated adhesion signaling mechanisms.

Wilson disease (WD) is an autosomal recessive disorder, characterized by excessive deposition of copper in various parts of the body, mainly in the liver and brain. It is caused by mutations in ATP7B. We report here the genetic analysis of 102 WD families from a south Indian population. Thirty-six different ATP7B mutations, including 13 novel ones [p.Ala58fs*19, p.Lys74fs*9, p.Gln281*, p.Pro350fs*12, p.Ser481*, p.Leu735Arg, p.Val752Gly, p.Asn812fs*2, p.Val845Ala, p.His889Pro, p.Ile1184fs*1, p.Val1307Glu and p.Ala1339Pro], were identified in 76/102 families. Interestingly, the mutation analysis of affected individuals in two families identified two different homozygous mutations in each family, and thus each affected individual from these families harbored two mutations in each ATP7B allele. Of 36 mutations, 28 were missense, thus making them the most prevalent mutations identified in the present study. Nonsense, insertion and deletion represented 3/36, 2/36 and 3/36 mutations, respectively. The haplotype analysis suggested founder effects for all the 14 recurrent mutations. Our study thus expands the mutational landscape of ATP7B with a total number of 758 mutations. The mutations identified during the present study will facilitate carrier and pre-symptomatic detection, and prenatal genetic diagnosis in affected families.

Objective: To describe clinical, electrophysiological, and histopathological profile of vasculitic neuropathy in elderly subjects aged 65 years or more. Design: Retrospective chart review. Setting: Departments of Neurology and Neuropathology, National Institute of Mental Health and Neurosciences, Bengaluru, Karnataka, India. Patients and Methods: Elderly subjects, diagnosed vasculitic neuropathy by nerve biopsy over one decade, were studied. Results: The cohort consisted of 46 subjects. Symptom duration was 21.54 ± 33.53 months. Onset was chronic in majority (82.6%). Key features included paresthesias (89%), weakness (80%), sensory loss (70%), wasting (63%), and relapsing-remitting course (6.5%). Most Common clinico-electrophysiological patterns were distal symmetrical sensorimotor polyneuropathy - 19, mononeuritis multiplex - 9, and asymmetric sensorimotor neuropathy - 10. Diagnosis of vasculitis was not suspected before biopsy in 31 (67.3%). Nerve biopsy revealed definite vasculitis - 12, probable - 10, and possible - 24. Treatment included immunomodulatory agents (41), symptomatic medications only (9), and antiretroviral therapy (1). Twenty-four patients were followed up for mean period of 6.5 months. Outcome at last follow-up was improved (13), unchanged (8), and worsened (3). Conclusion: Vasculitis is an important, treatable cause of neuropathy in elderly. Nerve biopsy should be used judiciously for early diagnosis and appropriate treatment.

An interesting association of ictal hypopnea and ictal generalized EEG attenuation (IGEA) as possible marker of sudden unexpected death in epilepsy (SUDEP) is reported. We describe a 5-years-old girl with left focal seizures with secondary generalization due to right occipital cortical dysplasia presenting with ictal hypopnea and IGEA. She had repeated episodes of the ictal apnoea in the past requiring ventilator support and intensive care unit (ICU) admission during episodes of status epilepticus. The IGEA lasted for 0.26-4.68 seconds coinciding with the ictal hypopnea during which both clinical seizure and electrical epileptic activity stopped. Review of literature showed correlation between post-ictal apnoea and post ictal generalized EEG suppression and increased risk for SUDEP. The report adds to the growing body of literature on peri-ictal apnea, about its association with IGEA might be considered as a marker for SUDEP. She is seizure free for 4 months following surgery.

Objectives: The aim of this study was to assess the effect of sodium valproic acid (SVA) on the sleep quality of patients with juvenile myoclonic epilepsy (JME). Materials and Methods: Standardized sleep questionnaires viz. Epworth Sleepiness Scale (ESS) and Pittsburgh Sleep Quality Index (PSQI) were administered to 30 drug-naïve patients with JME (male:female (M:F) = 14:16; age: 21 ± 3.7 years) and the changes following SVA monotherapy was analyzed using t- and chi-squared tests. Results: The mean age at onset of seizures and diagnosis was 15.43 ± 3.8 and 21 ± 5.1, years respectively. All had myoclonic jerks with mean duration of 5.23 ± 2.7 years, aggravated by sleep deprivation (23, 76.7%) and sleep-wake transition (29, 96.7%). Twenty-seven (90%) had generalized tonic-clonic seizures (GTCS), majority (70%) on awakening from sleep. Seizures were controlled in 25 patients (83.33%) with SVA monotherapy. Abnormal ESS was noted in five (16.66%) drug naοve patients compared to six (20%) patients while on SVA (P = 0.782). Mean ESS remained unchanged before and after SVA therapy (6.27 ± 4.4 vs 6.97 ± 4.7, P = 0.262). On the other hand, only four (13.3%) patients had abnormal PSQI scores at follow-up after initiation of SVA, as compared to 14 (46.7%) subjects in the drug naïve state (P = 0.037). Further, we also found significant reduction in mean PSQI scores after initiating SVA monotherapy (6.7 ± 5.6 vs 2.7 ± 2.84, P ͳ 0.0001). Conclusion: This study showed that the mean PSQI as well as the number of patients with abnormal PSQI significantly reduced after initiating SVA therapy, suggesting a significant improvement in night-time sleep quality with SVA treatment. However, SVA therapy did not alter ESS.

Tangier disease is a rare metabolic disorder that causes neuropathy in half of the affected individuals. We present the clinical, electrophysiological, and histopathological findings in a middle-aged gentleman of Tangier disease who was initially diagnosed as leprosy and treated with antileprosy drugs. The presence of a demyelinating electrophysiology in a patient with predominant upper limb involvement and facial diplegia should raise the suspicion of Tangier disease. Estimation of serum lipids should form a part of routine evaluation in order to avoid misdiagnosis.

Tangier disease is an autosomal recessive disorder characterized by an abnormal accumulation of cholesterol esters in various organs secondary to adenotriphosphate binding cassette transporter A-1 (ABCA-1) transporter deficiency and disrupted reverse cholesterol transport. It causes neuropathy in half of the affected individuals. We present the clinical, electrophysiological, and histopathological findings in a middle aged gentleman of Tangier disease who was initially misdiagnosed leprosy and treated with antileprosy drugs. The presence of a demyelinating neuropathy on electrophysiology in a patient with predominant upper limb involvement and facial diplegia should raise the suspicion of Tangier disease. The characteristic lipid profile of Tangier disease was noted in this patient viz. extremely low high density lipoprotein (HDL), elevated triglyceride (TG), and reduced apolipoprotein A1. Estimation of serum lipids should form a part of routine evaluation in order to avoid misdiagnosis.

Abetalipoproteinemia is an uncommon cause of ataxia and retinitis pigmentosa (RP). Most of the neurological and ocular manifestations occur secondary to deficiency syndromes that is consequent to fat malabsorption from the small intestine. In this report, we have described the phenotype of a young adult female who manifested with recurrent diarrheal illness in her first decade, followed by anemia, RP, and neurological involvement with progressive deafness, cerebellar and sensory ataxia, and subclinical neuropathy in her second decade of life. While RP and sensory ataxia due to vitamin E deficiency are well-recognized features of abetalipoproteinemia, deafness is rarely described. In addition, we have highlighted the abnormal posterior column signal changes in the cervical cord in this patient. Early recognition avoids unnecessary investigations and has a potential to retard the disease progression by replacing some of the deficient vitamins.

Background: Fatigue contributes significantly to the morbidity and affects the quality of life adversely in Guillain-Barre Syndrome (GBS). Objective: To determine the prevalence of fatigue in GBS in neurological rehabilitation setting and to study its clinical correlates. Materials and Methods: We performed secondary analysis of data of patients with GBS admitted in neurological rehabilitation ward of a tertiary care centre, recorded at both admission and discharge. Assessment of fatigue was done by Fatigue Severity Scale (FSS), disability-status by Hughe′s Disability Scale (HDS), functional-status by Barthel Index, anxiety/depression by Hospital Anxiety Depression Scale, sleep disturbances by Pittsburgh Sleep Quality Index and muscle weakness by Medical Research Council sum scores. Results: A total of 90 patients (62 men) with mean age 34 years (95% CI 32.2, 37.7) were included. Median duration of, stay at neurological rehabilitation ward was 30 days, while that of symptoms was 18.5 days. Presence of fatigue at admission (FSS ≥ 4 in 39% patients) was associated with ventilator requirement (P = 0.021) and neuropathic pain (P = 0.03). Presence of fatigue at discharge (FSS ≥ 4 in 12% patients) was associated with disability- HDS (≥3) (P = 0.008), presence of anxiety (P = 0.042) and duration of stay at rehabilitation ward (P = 0.02). Fatigue did not correlate with age, gender, antecedent illness, muscle weakness, depression and sleep disturbances. Conclusion: Fatigue is prevalent in GBS during early recovery phase of illness. Despite motor recovery fatigue may persist. Knowledge about fatigue as burden of disease in these patients will improve patient care.

Mutations in PLA2G6 were identified in patients with a spectrum of neurodegenerative conditions, such as infantile neuroaxonal dystrophy (INAD), atypical late-onset neuroaxonal dystrophy (ANAD) and dystonia parkinsonism complex (DPC). However, there is no report on the genetic analysis of families with members affected with INAD, ANAD and DPC from India. Therefore, the main aim of this study was to perform genetic analysis of 22 Indian families with INAD, ANAD and DPC. DNA sequence analysis of the entire coding region of PLA2G6 identified 13 different mutations, including five novel ones (p.Leu224Pro, p.Asp283Asn, p.Arg329Cys, p.Leu491Phe, and p.Arg649His), in 12/22 (54.55%) families with INAD and ANAD. Interestingly, one patient with INAD was homozygous for two different mutations, p.Leu491Phe and p.Ala516Val, and thus harboured four mutant alleles. With these mutations, the total number of mutations in this gene reaches 129. The absence of mutations in 10/22 (45.45%) families suggests that the mutations could be in deep intronic or promoter regions of this gene or these families could have mutations in a yet to be identified gene. The present study increases the mutation landscape of PLA2G6. The present finding will be useful for genetic diagnosis, carrier detection and genetic counselling to families included in this study and other families with similar disease condition.