Acquired hyperexcitable peripheral nerve disorders: Clinical and laboratory features, therapeutic responses, and long-term follow-up.

INTRODUCTION/AIMS: Hyperexcitable peripheral nerve disorders (HPNDs) are rare. Although their clinical and laboratory features have been well studied, information on treatment and follow-up is limited. The aim of this study is to explore the long-term clinical, investigative, and therapeutic profile of patients with acquired HPNDs. METHODS: This study retrospectively analyzed patients from a single tertiary care center with HPND (January 2012 to January 2022). Patients were recruited according to published inclusion and exclusion criteria. Details of clinical features, diagnostic tests, therapeutic interventions, and follow-up were recorded. This study included patients with follow-up of 2 or more years. RESULTS: A total of 32 patients (M = 26, F = 6) were studied. The common clinical features included myokymia, neuropathic or shock-like pain, cramps, sleep disturbances, encephalopathy, cerebellar ataxia, and seizures. A total of 81.25% of patients responded favorably to corticosteroids and membrane stabilizers. Among the nonresponders, five received intravenous immunoglobulin (IVIG), and one received plasma exchange (PLEX). Two patients required rituximab due to poor responses to the above treatments. The mean duration of response was 6 weeks (4-24 weeks) from the initiation of treatment. All patients had favorable outcomes, reaching clinical remission within 1-5 years from the initiation of treatment. Only two patients had relapses. Immunotherapy could be stopped in 78% of patients within 3 years and 100% by 5 years. DISCUSSION: Chronic immunosuppression starting with corticosteroids is required for satisfactory outcomes of HPNDs. These disorders usually run a monophasic course, and relapses are uncommon.

Life-Saving Treatments for Spinal Muscular Atrophy: Global Access and Availability.

Background and Objectives: Spinal muscular atrophy (SMA) is a neurodegenerative disorder manifesting with progressive muscle weakness and atrophy. SMA type 1 used to be fatal within the first 2 years of life, but is now treatable with therapies targeting splicing modification and gene replacement. Nusinersen, risdiplam, and onasemnogene abeparvovec-xioi improve survival, motor strength, endurance, and ability to thrive, allowing many patients to potentially attain a normal life; all have been recently approved by major regulatory agencies. Although these therapies have revolutionized the world of SMA, they are associated with a high economic burden, and access to these therapies is limited in some countries. The primary objective of this study was to compare the availability and implementation of treatment of SMA from different regions of the world. Methods: In this qualitative study, we surveyed health care providers from 21 countries regarding their experiences caring for patients with SMA. The main outcome measures were provider survey responses on newborn screening, drug availability/access, barriers to treatment, and related questions. Results: Twenty-four providers from 21 countries with decades of experience (mean 26 years) in treating patients with SMA responded to the survey. Nusinersen was the most available therapy for SMA. Our survey showed that while genetic testing is usually available, newborn screening is still unavailable in many countries. The provider-reported treatment cost also varied between countries, and economic burden was a major barrier in treating patients with SMA. Discussion: Overall, this survey highlights the global inequality in managing patients with SMA. The spread of newborn screening is essential in ensuring improved access to care for patients with SMA. With the advancement of neurotherapeutics, more genetic diseases will soon be treatable, and addressing the global inequality in clinical care will require novel approaches to mitigate such inequality in the future.

Molecular Diagnosis of Facioscapulohumeral Muscular Dystrophy in Patients Clinically Suspected of FSHD Using Optical Genome Mapping.

Background and Objectives: Facioscapulohumeral muscular dystrophy (FSHD) represents the third most common muscular dystrophy in the general population and is characterized by progressive and often asymmetric muscle weakness of the face, upper extremities, arms, lower leg, and hip girdle. In FSHD type 1, contraction of the number of D4Z4 repeats to 1-10 on the chromosome 4-permissive allele (4qA) results in abnormal epigenetic derepression of the DUX4 gene in skeletal muscle. In FSHD type 2, epigenetic derepression of the DUX4 gene on the permissive allele (4qA) with normal-sized D4Z4 repeats (mostly 8-20) is caused by heterozygous pathogenic variants in chromatin modifier genes such as SMCHD1, DNMT3B, or LRIF1. We present validation of the optical genome mapping (OGM) platform for accurate mapping of the D4Z4 repeat size, followed by diagnostic testing of 547 cases with a suspected clinical diagnosis of FSHD and next-generation sequencing (NGS) of the SMCHD1 gene to identify cases with FSHD2. Methods: OGM with Bionano Genomics Saphyr and EnFocus FSHD analysis software was used to identify FSHD haplotypes and D4Z4 repeat number and compared with the gold standard of Southern blot-based diagnosis. A custom Agilent SureSelect enrichment kit was used to enrich SMCHD1, followed by NGS on an Illumina system with 100-bp paired-end reads. Copy number variants were assessed using NxClinical software. Results: We performed OGM for the diagnosis of FSHD in 547 patients suspected of FSHD between December 2019 and December 2022, including 301 male (55%) and 246 female patients (45%). Overall, 308 of the referred patients were positive for D4Z4 contraction on a permissive haplotype, resulting in a diagnosis of FSHD1. A total of 252 of 547 patients were referred for concurrent testing for FSHD1 and FSHD2. This resulted in the identification of FSHD2 in 9/252 (3.6%) patients. In our FSHD2 cohort, the 4qA allele size ranged from 8 to 18 repeats. Among FSHD1-positive cases, 2 patients had biallelic contraction and 4 patients had homozygous contraction and showed early onset of clinical features. Nine of the 308 patients (3%) positive for 4qA contraction had mosaic 4q alleles with contraction on at least one 4qA allele. The overall diagnostic yield in our cohort was 58%. Discussion: A combination of OGM to identify the FSHD haplotype and D4Z4 repeat number and NGS to identify sequence and copy number variants in the SMCHD1 gene is a practical and cost-effective option with increased precision for accurate diagnosis of FSHD types 1 and 2.

Clinical Recommendations for the use of Neurotropic B vitamins (B1, B6, and B12) for the Management of Peripheral Neuropathy: Consensus from a Multidisciplinary Expert Panel.

INTRODUCTION: Peripheral neuropathy (PN) is an insidious disease that is often asymptomatic during the early stages but which can have a significant impact on quality of life at later stages when nerve damage occurs. There is currently no guidance on the use of neurotropic B vitamins (B1, B6, and B12) for the management of asymptomatic and symptomatic PN. OBJECTIVE: To provide guidance to primary care physicians on an integrated approach to managing PN with neurotropic B vitamins (B1, B6, and B12). MATERIALS AND METHODS: A multidisciplinary panel of eight experts participated in an iterative quasi-anonymous Delphi survey consisting of two rounds of questions and a virtual meeting. A literature review formed the basis of the survey questions. The first round included multiple select, qualitative, and Likert Scale questions; the subsequent round consisted of 2-point scale (agree or disagree) questions that sought to develop consensus-based statements refined from the first round and recommendations derived from discussions during the virtual expert panel meeting. RESULTS: Clinical recommendations for the use of neurotropic B vitamins (B1, B6, and B12) have been developed for the prevention of PN progression or to delay onset in patients at high risk of developing PN. Recommendations have also been provided for the assessment of PN etiology and considerations for the use of loading dose (high dose) and maintenance dose (lower dose) of these neurotropic B vitamins (B1, B6, and B12). CONCLUSION: These clinical recommendations provide an initial step towards formulating comprehensive guidelines for the early and long-term management of PN with neurotropic B vitamins (B1, B6, and B12) and move beyond addressing only neuropathic pain associated with the late stages of PN.

Five Cases of Idiopathic Sciatic Mononeuropathy: Clinical, Electrophysiological, Radiological, and Histological Features.

Background: Common etiologies of sciatic mononeuropathy are compressive, infiltrative, traumatic, or diabetic. However, in a proportion of patients, the etiology remains elusive despite extensive serological, electrophysiological, radiological, and histological investigations. Methods: Patients with unexplained sciatic mononeuropathy were studied with regard to their clinical, radiological, pathological, and treatment aspects. Results: We could identify five cases of sciatic mononeuropathy wherein the etiology remained unknown even after a comprehensive evaluation. The compressive, metabolic, hematological, and immune causes were ruled out with necessary investigations. The clinical, electrophysiological, radiological, and histological features of these patients are discussed. Conclusion: The etiology of sciatic mononeuropathy can remain obscure in certain instances in spite of the comprehensive workup. The role of investigations and the exclusion process of various diagnostic entities are discussed.

A case of non-Hodgkin lymphoma diagnosed after 35-month of initial presentation as recurrent vitritis with multiple negative biopsies.

To report a case of non-Hodgkin lymphoma (NHL) that was diagnosed 35-month of initial ocular manifestation. Retrospective chart review. A 53-year-old male presented with painless diminution of vision in both eyes. He subsequently underwent extensive laboratory investigations including multiple vitreous biopsies with a suspicion of intraocular lymphoma. Cytology from the vitreous aspirate failed to diagnose any relevant pathology. After 35-month from the onset of his ocular symptom, a brain biopsy revealed a round cell tumor suggestive of NHL. Even with high index of suspicion, consultation with ocular oncologist, imaging, and diagnostic vitrectomy, the diagnosis of lymphoma remains challenging.

Neurology Exit Examination System in India: A Survey of Examiners' Perceptions and Recommendations.

Background: The traditional Neurology exit examination in India has remained unchanged over the last few decades. In developed countries, objective evaluation methods have replaced the traditional ones. A need for such methods has not been explored in India. Objective: We aimed to study the perceptions and key recommendations of Neurology examiners on the existing examination pattern. Material and Methods: We conducted an online survey of examiners perceptions and recommendations using a set of 10 multiple-choice questions and an open-ended question. Results: 46 examiners provided completed responses suitable for analysis. Nearly equal proportions (30%) of the examiners had 10 years, 10-25 years and >25 years' experience. 92% were not satisfied with current system, 95% did not find adequate time for correction of theory scripts, 90% felt that theory questions were random, and 95% had legibility issues. 84% felt that the practical exams do not test true learning, 98% felt the examination stress impairs the performance and 85% felt that there are no objective criteria to pass the candidate. 83% felt the current system-needed changes. The key suggestions provided by the examiners to improve the system included objective assessments like MCQ, OSCE, OSLER and DOPS, inclusion of larger number of short answer type questions and periodic internal assessments of the candidates. Conclusions: A vast majority of examiners favoured changes to the current examination system and provided key recommendations. A larger study is needed to extrapolate these findings to the rest of India.

Genetic Appraisal of Hereditary Muscle Disorders In A Cohort From Mumbai, India.

BACKGROUND: Hereditary muscle disorders are clinically and genetically heterogeneous. Limited information is available on their genetic makeup and their prevalence in India. OBJECTIVE: To study the genetic basis of prevalent hereditary myopathies. MATERIAL AND METHODS: This is a retrospective study conducted at a tertiary care center. The study was approved by the institutional ethics board. The point of the collection was the genetic database. The genetic data of myopathy patients for the period of two and half years (2019 to mid-2021) was evaluated. Those with genetic diagnoses of DMD, FSHD, myotonic dystrophies, mitochondriopathies, and acquired myopathies were excluded. The main outcome measures were diagnostic yield and the subtype prevalence with their gene variant spectrum. RESULTS: The definitive diagnostic yield of the study was 39% (cases with two pathogenic variants in the disease-causing gene). The major contributing genes were GNE (15%), DYSF (13%), and CAPN3 (7%). Founder genes were documented in Calpainopathy and GNE myopathy. The uncommon myopathies identified were Laminopathy (0.9%), desminopathy (0.9%), and GMPPB-related myopathy (1.9%). Interestingly, a small number of patients showed pathogenic variants in more than one myopathy gene, the multigenic myopathies. CONCLUSION: This cohort study gives hospital-based information on the prevalent genotypes of myopathies (GNE, Dysferlinopathy, and calpainopathy), founder mutations, and also newly documents the curious occurrence of multigenicity in a small number of myopathies.

Nodo-paranodopathies: Concepts, Clinical Implications, and Management.

Peripheral neuropathies are traditionally categorized into demyelinating or axonal. It has been proposed that dysfunction at nodal/paranodal region may be a key for better understanding of pathophysiology in patients with immune mediated neuropathies. In last few years, antibodies targeting node and paranode of myelinated nerves have been increasingly detected in patients with immune mediated neuropathies. These patients have clinical phenotype similar common inflammatory neuropathies like Guillain Barre syndrome and chronic inflammatory demyelinating polyradiculoneuropathy with some additional atypical neurological and systemic features, and they respond poorly to conventional first line immunotherapies like IVIG. This review summarizes the structure of the node, concept and pathophysiology of nodopathies. We provide an overview of clinical phenotypes in patients with specific nodal/paranodal antibodies, along with electrophysiological and other diagnostic features and suggest therapeutic line of management based on current evidence.

Guillian--Barre' Syndrome in Patients with SARS-CoV-2: A Multicentric Study from Maharashtra, India.

BACKGROUND: Guillian--Barre' Syndrome (GBS) has been shown to be associated with severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) infection. The aim of our study was to study the clinical profile and outcomes of GBS in COVID-19 from the Western region of India, the State of Maharashtra. METHODS: This was a retrospective, multicenter observation study from different hospitals in Maharashtra beginning from March 2020 until November 2020. RESULTS: We report 42 patients with COVID-19 GBS. Mean age was 59 years (range, 24--85 years). 31/42 (73.8%) were men. GBS was the presenting symptom in 14/42 (33%), while six of them remained asymptomatic for COVID-19 despite positive SARS-CoV-2 on nasopharyngeal swab reverse transcriptase polymerase chain reaction. The median interval between COVID-19 and GBS was 14 days (SD + 11), with minimum of 1 and maximum 40 days. Clinical presentation was like that of typical GBS. Electrophysiological studies showed a predominant demyelinating pattern in 25/42 (59.5%). Inflammatory markers were elevated in 35/42 (83.3%) and 38/42 (90.5%) had an Abnormal high-resolution CT (HRCT) chest. 14/42 (33.3%) patients required a ventilator, with nine deaths. Intravenous immunoglobulin was the mainstay of treatment for GBS. Majority had a good outcome and were walking independently or with minimal support at discharge. In subgroup analysis, the postinfectious group had a better outcome than the parainfectious group. CONCLUSION: GBS in COVID-19 occurs as both parainfectious and postinfectious GBS. Parainfectious GBS needs more rigorous monitoring and may benefit from COVID-19 specific treatment. Routine screening for SARS-CoV-2 should be implemented in patients with GBS in view of the ongoing pandemic.

Medical Management of Trigeminal Neuralgia.

BACKGROUND: Trigeminal neuralgia (TN) is a painful condition, often leading to poor quality of life. OBJECTIVE: The aim of this review was to discuss the various treatment modalities for the medical management of TN. MATERIALS AND METHODS: We reviewed the available literature on TN in clinical databases including PubMed, Google Scholar, and the Cochrane Database of Systematic Reviews, with a specific focus on the pharmacological treatment and newer drugs under development for the treatment of TN. RESULTS: Carbamazepine (CBZ) is the gold standard of treatment for TN. The first-line drugs for the treatment of TN are CBZ and oxcarbazepine (OXC). A proportion of cases (30%) are initially resistant to the first-line drugs. Alternative drugs need to be considered if the first-line drugs are not well tolerated or become ineffective with prolonged therapy. The second-line drugs comprise lamotrigine, baclofen, gabapentin, and pregabalin used as monotherapy or in combination with CBZ/OXC. Botulinum toxin A may be a promising presurgical option. Newer drug like vixotrigine has shown good results in phase two randomized control trials. About 50% of cases develop treatment resistance to oral drugs over the subsequent years of therapy and require surgical options. CONCLUSION: The first-line drugs for the treatment of TN (irrespective of the age group or type) are CBZ and OXC. Combination therapy with second-line or other drugs may become necessary with poor response to CBZ/OXC, or if adverse events occur. Patients should be offered surgical options if there is poor response or tolerance to the medical therapy.

Chronic immune polyradiculopathies: Three clinical variants of one disease?

INTRODUCTION: Chronic immune polyradiculopathies (sensory, motor, and mixed) are uncommon. METHODS: In this single-center, retrospective study, the inclusion criteria for participants were progressive sensory ataxia and/or areflexic limb weakness; tibial somatosensory evoked potential (SSEP) abnormalities of the N22 and P40 potentials with normal sensory and motor nerve conduction studies or root involvement, according to magnetic resonance imaging (MRI); and albuminocytological dissociation. RESULTS: Eight patients were included in our study. Two had weakness, two had sensory ataxia, and four had both weakness and ataxia. Patients with weakness had abnormal SSEPs and patients with sensory ataxia also had absent F waves. Electromyography showed chronic denervation. MRI scans confirmed thickening and enhancement of roots. The patients responded to corticosteroid treatment. DISCUSSION: The overlapping clinicoelectrophysiological findings and similarities in radiological and therapeutic responses suggest that these entities are clinical variants of the same disease. The terms CIS(m)P, CI(s)MP, and CISMP (for chronic immune sensory motor polyradiculopathy) could be used to denote the predominant clinical involvement.

Neuropathies of leprosy.

Neuropathies form an integral part of the symptomatology of leprosy. Neuropathies of leprosy take various forms and shapes. At one end is the cutaneous nerve involvement adjacent to the anaesthetic skin patch and the other is of symmetrical pansensory neuropathy and the devastating sensory ataxia of leprous ganglionits. Lepra reactions add to the spectrum. Hosts immunological status largely decides the clinical manifestations seen in nerves and skin. A wide array of diagnostic techniques like ultrasonography, magnetic resonance neurography, serological markers, molecular tests, skin biopsy and in selected cases, the nerve biopsy with special stains and electron microscopy are obtainable to help the clinical diagnosis. The unsuspecting clinician, lack of community awareness and limited availability of diagnostic tests are important adverse factors in the total outcome. Multi drug therapy is efficacious and corticosteroids reduce the impact of nerve damage in leprosy. The efficacy, dose and duration of corticosteroid therapy are presently inexact and other immune suppressants like azathioprine are being evaluated. Chronic disabilities and residual deficits require attention of multiple specialties. In the coming time, focus on prevention could lead to favourable results. This review will discuss the classification systems, common and uncommon clinical features, diagnostic armamentarium and therapeutic and preventive aspects of neuropathies of leprosy.

Early and consistent pattern of proximal weakness in GNE myopathy.

BACKGROUND: GNE myopathy is widely regarded as a distal myopathy. Involvement of proximal musculature in this condition has not been systematically studied. METHODS: The phenotype of genetically confirmed patients with GNE myopathy was analyzed. Fourteen groups of muscles were evaluated with Medical Research Council (MRC) grading and the average muscle scores (AMS:1-10) were calculated. RESULTS: Fully documented AMS data was available in 31 of 65 patients. It showed a consistent pattern of severe weakness of hip adductors, hip flexors, knee flexors, and foot dorsiflexors, with milder weakness of the hip extensors and abductors. The knee extensors were largely unaffected. The proximal weakness appeared early in the course of the disease. Proximal muscle weakness was also present in the remaining 34 patients in whom the data were limited. A variant in exon 13 (c.2179G > A) was very common (81.5%). CONCLUSIONS: The GNE phenotype in this Indian cohort exhibited mixed proximal and distal involvement. Weakness of adductors and flexors of the hip formed an integral part of the phenotype.