Cerebrotendinous Xanthomatosis, a Treatable Disorder Often Missed: Case Series of Three Patients Confirmed by Genetic Testing.

ABSTRACT: Cerebrotendinous xanthomatosis (CTX) is a treatable autosomal recessive disorder with varied clinical manifestations and age of onset and is often diagnosed late. We report three cases of CTX who presented at our center with clinical features of frequent diarrhea, early cataracts, xanthomas, cognitive decline, ataxia, neuropathy, and other manifestations of CTX. Magnetic resonance imaging (MRI) brain in all three patients revealed abnormalities consistent with CTX. Diagnosis was confirmed by next-generation sequencing. Chenodeoxycholic acid (CDCA) is recommended as the drug of choice, as it can halt the disease progression and reverse some of the symptoms. In addition to late diagnosis, nonavailability of CDCA in our part of world adds to the problem of management of such patients; therefore, they are often started on alternative therapies, which are less effective.

Calcitonin gene-related peptide (CGRP) concentrations outside migraine attacks in peripheral blood as a potential biomarker for chronic migraine / Concentrações de peptídeo relacionado ao gene da calcitonina (CGRP) fora dos ataques de enxaqueca no sangue periférico como um potencial biomarcador para enxaqueca crônica

Introduction: Chronic migraine is a debilitating condition that affects a significant portion of the population. Accurate diagnosis and treatment of chronic migraine remain a challenge due to the lack of objective biomarkers. Calcitonin gene-related peptide (CGRP) is a neuropeptide involved in the pathophysiology of migraine and has been proposed as a potential biomarker for migraine. Methods: We measured CGRP levels in peripheral blood samples collected from 142 participants with chronic or episodic migraine and 24 healthy controls during ictal periods, i.e., outside migraine attacks. We compared CGRP levels between the three groups and assessed the correlation between CGRP levels and clinical features of chronic migraine. Conclusion: Our study provides evidence that CGRP levels in peripheral blood during ictal periods may serve as a potential biomarker for chronic migraine. Further studies are needed to validate these findings and to explore the clinical utility of CGRP as a biomarker for chronic migraine.

Introdução: A enxaqueca crônica é uma condição debilitante que afeta uma parcela significativa da população. O diagnóstico preciso e o tratamento da enxaqueca crónica continuam a ser um desafio devido à falta de biomarcadores objetivos. O peptídeo relacionado ao gene da calcitonina (CGRP) é um neuropeptídeo envolvido na fisiopatologia da enxaqueca e foi proposto como um potencial biomarcador para enxaqueca. Métodos: Medimos os níveis de CGRP em amostras de sangue periférico coletadas de 142 participantes com enxaqueca crônica ou episódica e 24 controles saudáveis ​​durante períodos ictais, ou seja, fora das crises de enxaqueca. Comparamos os níveis de CGRP entre os três grupos e avaliamos a correlação entre os níveis de CGRP e as características clínicas da enxaqueca crônica. Conclusão: Nosso estudo fornece evidências de que os níveis de CGRP no sangue periférico durante os períodos ictais podem servir como um potencial biomarcador para enxaqueca crônica. Mais estudos são necessários para validar estes resultados e explorar a utilidade clínica do CGRP como biomarcador para enxaqueca crónica.

Miller Fisher syndrome associated with COVID 19.

Miller Fisher syndrome (MFS), is an acute peripheral neuropathy, a variant of Guillain-Barre syndrome, that develops following exposure to different viral, bacterial, and fungal pathogens. Patients usually present with a triad of ophthalmoplegia, ataxia, and areflexia. During Covid pandemic MFS has been described associated with novel coronavirus disease 2019 (COVID-19). Here we describe the clinical course, Cerebrospinal fluid (CSF) findings, nerve conduction studies, treatment and outcome of the patient having MFS concurrent with COVID 19.

Interleukin 32 gene promoter polymorphism: A genetic risk factor for multiple sclerosis in Kashmiri population.

OBJECTIVE: Although the exact cause of multiple sclerosis is not known, there are a number of factors involved mainly environmental and genetic factors. The present study was done to determine association between IL-32 gene promoter polymorphism and IL-32 levels with multiple sclerosis. METHODS: 48 relapsing remitting multiple sclerosis patients and 60 healthy controls were compared for IL-32 gene promoter polymorphism and IL-32 levels. RESULTS: There was no significant difference in genotype CT between the MS patients and healthy controls (p 0.130) where as a significant difference in genotype (CC) frequencies among MS patients and healthy controls (p 0.039) was observed. The difference in C allele frequency was also statistically significant between two study groups (p 0.01). Multivariate regression analysis revealed that the CC genotype might impact the risk of disease susceptibility up to 3.71 times and the presence of C allele might increase the risk of susceptibility to multiple sclerosis by 2.26 fold. The serum IL-32 levels were not statistically different multiple sclerosis patients and healthy controls and between wild and mutant genotypes. CONCLUSIONS: IL-32 gene promoter polymorphism is a genetic risk factor for multiple sclerosis patients particularly women.

Isolated neurobrucellosis-characteristic clinical and laboratory features.

To report various neurological syndromes, CSF findings, imaging and diagnostic methods used in neurobrucellosis patients admitted in our Neurology department over a period of 6 years. Case records of patients admitted to our department from August 2014 to May 2020 were searched for neurobrucellosis and data were obtained. A total of 19 patients were diagnosed as neurobrucellosis over a period of 6 years. Ten patients had chronic meningitis, five had VIII nerve involvement, one had optic neuritis, two had acute meningitis, one had subacute meningitis, four had myelopathy, five had polyradiculitis and two had spondylodiscitis. CSF was abnormal in 17 patients. Neutrophilic pleocytosis was seen in 12 patients who included nine patients with chronic symptomatology. Brain imaging was abnormal in three chronic meningitis patients. One had diffuse meningeal enhancement, another had hydrocephalus while the third patient had meningeal enhancement with basal exudates and contrast enhancement of bilateral VIII nerve. One of the patients of acute meningitis had hydrocephalus while the other one had bilateral T2/FLAIR hyperintensities with enhancement of meninges and leptomeningeal vessels. Elevated antibody titers only in serum was seen in six patients while elevated antibody titers only in CSF was seen in seven patients. Four patients had elevated antibody titers in both serum and CSF. CSF culture was positive in three patients. Neurobrucellosis is a rare clinical complication of brucellosis but may pose a problem in diagnosis as it can mimic tuberculosis. Involvement of VIII nerve and neurophilic pleocytosis in CSF despite chronic symptomatology can be diagnostic clues favoring neurobrucellosis.

Comparative Efficacy of IV Phenytoin, IV Valproate, and IV Levetiracetam in Childhood Status Epilepticus.

BACKGROUND AND PURPOSE: Status epilepticus (SE) is a common pediatric neurological emergency that requires immediate and vigorous management. Currently, phenytoin is the most common agent used in the setting of SE following benzodiazepine for further seizure prevention. Other drugs recently introduced for management of SE are valproic acid and levetiracetam. METHODS: This prospective randomized study included 150 pediatric patients admitted as SE. Patients were randomized into three equal groups (50 each) to receive one of the three anticonvulsants in addition to standard treatment. Patients were monitored in hospital regarding their vitals, time to regain consciousness, and seizure recurrence. RESULTS: At 24 hours seizures were controlled in 44 patients (88%) in phenytoin group, 39 patients (78%) in levetiracetam (LEV) group and 46 patients (92%) in valproate (VAL) group (p=0.115). The mean time to regain consciousness in phenytoin, LEV and VAL groups was 122.3±45.4, 120.8±42.8, and 75.0±30.7 minutes (mean±standard deviation) respectively. Patients in VAL group regained consciousness earlier than both phenytoin and LEV group patients (p<0.0001). At 3 months follow-up, seven (14.28%) out of 49 patients in phenytoin group, 14 (28.57%) out of 49 in LEV group and two (4%) out of 50 patients in VAL group had a seizure recurrence (p=0.0032). CONCLUSIONS: In our study we found that both IV LEV and IV VAL safe and efficacious. The primary outcome, seizure recurrence at 24 hours, did not show a statistically significant difference in three groups (p>0.05). Also, seizure recurrence at 1 week did not reach a statistically significant difference. However, time to regain consciousness and seizure recurrence at 3 months was significantly less in VAL group (p<0.05).

High prevalence of factor V Leiden and prothrombin G20101A mutations in Kashmiri patients with venous thromboembolism.

AIM: The genetic variants of the factor V (G1691A), prothrombin (G20210A) and MTHFR (C677T) genes have been widely implicated as inherited risk factors for developing venous thrombosis. This study was undertaken to reveal the frequency of these mutations in Kashmiri patients with venous thromboembolism. METHODOLOGY: A case-control study was designed with 250 VTE patients and 250 healthy controls. The mutations were analysed using ARMS-PCR and PCR-RFLP approach. RESULT: The factor V Leiden G1691A mutation was found in 17/250 (6.8%) VTE patients and prothrombin G20210A mutation was found in 7/250 (2.8%) VTE patients while no mutation was found in any of the healthy controls. Both the mutations were found to be significantly associated with the increased risk of VTE (p = 0.0001 and 0.0150 respectively) while no association of VTE risk with MTHFR C677T polymorphism was found (p = 0.53). CONCLUSION: The increased frequency of factor V Leiden G1691A and prothrombin G20210A mutation in VTE patients indicates a significant role of these mutations in the development of VTE in our population. We therefore suggest the routine screening of these two mutations as thrombophilic markers in Kashmiri patients with venous thromboembolism.

Nonalcoholic Wernicke's Encephalopathy: A Retrospective Study from a Tertiary Care Center in Northern India.

OBJECTIVE: The objective of this study was to describe the demographic features, clinical presentation, and management and outcome of fifty cases of nonalcoholic Wernicke's encephalopathy from a tertiary care hospital of a region with reported incidence of thiamine deficiency disorders. MATERIALS AND METHODS: In a retrospective study, fifty adult cases of Wernicke's encephalopathy were analyzed. The diagnosis of Wernicke's encephalopathy was made according to the European federation of neurological societies guidelines 2010. Response to thiamine replacement and associated brain magnetic resonance imaging (MRI) findings were also considered as supportive evidence. RESULTS: The mean age of patients was 50.38 years with 20 males and 30 females. The most common clinical manifestations were alteration in sensorium in 30 (60%), ataxia in 18 (36%), memory impairment in 15 (30%), nystagmus in 35 (70%), ophthalmoparesis in 11 (22%), and seizures in 4 (8%). A total of 42 patients had a history of recurrent vomiting. All patients had polished rice as their staple diet. Thirty-five patients had associated polyneuropathy and 15 had a gastrointestinal disorder. Twenty patients underwent MRI which showed both typical and atypical lesions. Majority of patients showed partial or complete response to intravenous thiamine. On discharge, the most common residual symptoms were lower limb weakness, ataxia, and memory impairment. CONCLUSION: The study shows high incidence of nonalcoholic Wernicke's encephalopathy in the region with predominant causative factor being a thiamine deficient diet. Recurrent vomiting can be a prominent early symptom of thiamine deficiency and its recognition can help in the early diagnosis of Wernicke's encephalopathy and related thiamine deficiency disorders. Thiamine fortification of food should be done in areas with reported incidence of thiamine deficiency disorders.

Demographic and clinical profile of Multiple Sclerosis in Kashmir: A short report.

BACKGROUND: Multiple sclerosis (MS) is a chronic autoimmune and inflammatory disease of the central nervous system (CNS). There have been only few population/hospital based studies on MS in India, and at the same time there is no data on its profile in Kashmir. METHODS: A total of 41 MS patients diagnosed on the basis of 2010 Revised Mc Donald criteria were enrolled in this study from Kashmir region of India. Clinical, demographic, radiological and biochemical parameters were analyzed for most of the patients. RESULTS: Male to female ratio was found to be 1:3.1 with mean age at the time of analysis 32.26±7.54 (range 18-48) years. The mean disease duration was found to be 3.2±3.6 years. The most common course was relapsing-remitting (RR) present in 87.80% of cases followed by secondary progressive (SP) in 9.76% and primary progressive (PP) in 2.44%. Numbness, weakness of limbs, prickling and tingling sensations, muscle stiffness, and visual disturbances were most common manifestations. Condition of bilateral internuclear ophthalmoplegia (INO) and vertigo was rarely observed. Oligoclonal bands (OCB) were present in cerebrospinal fluid (CSF) of majority of the patients. Symptomatic and steroidal treatment mode was given to majority of the patients (92.68%) and only 7.32% patients were given disease modifying drug. CONCLUSION: This is the first preliminary report on MS profile in Kashmir. The high prevalence of female patients and RR course of MS, low prevalence of progressive cases, predominance of OCB positive cases, insignificant family history in all cases, predominance of cases with low socio-economic status, and high rate of less educated and unemployed cases are the most important findings. By and large MS pattern in Kashmir was found to be relatively similar to West and rest of the Asia. Larger comprehensive studies are mandatory to completely understand MS pattern in Kashmir. There is utmost requirement to maintain a local MS registry in Kashmir so as to get an idea about the actual number of persons suffering from the disease and compare the data with other regions of India.

Multiple Sclerosis and EIF2B5: A Paradox or a Missing Link.

Multiple sclerosis (MS) is an encumbering inflammatory condition of the central nervous system (CNS) caused by axonal demyelination. There is sufficient evidence suggesting role of eukaryotic translation initiation factor 2B (EIF2B) gene family encoding the five subunits of eIF2B complex-α, ß, γ, δ and ε respectively, in causing vanishing white matter (VWM) disease of the brain. Incidentally researchers have proposed overlapping between MS and VWM in terms of clinical, biochemical and genetic aspects, which incited us to write this chapter to explore the association between EIF2B5 and MS. eIF2B plays an essential role in translation initiation and its regulation in eukaryotes. Among EIF2B gene family, EIF2B5 gene encodes the catalytic and a crucial epsilon subunit of the eIF2B protein as most of the alterations have been found in this gene. The recent findings on the association between EIF2B5 and MS susceptibility point towards unfathomable and contentious role of EIF2B5 in MS development. This chapter briefly reviews the insights gleaned from recent studies conducted in understanding the association between EIF2B5 and MS risk. The need of hour is to conduct large scale conclusive studies aimed at expounding the mechanisms behind this relationship.

Multiple sclerosis in Kashmir: Where we stand.

Multiple sclerosis (MS) is a disabling neurological disorder commonly diagnosed in young adults. Its causes still remain inexplicable and presently it can only be managed by different drug treatments. There has been a remarkable shift in MS perspective across world. One of its peculiar attribute is unstable (changing) prevalence rate across different parts of the world. Earlier MS was believed to be less prevalent in India, however, there has been growing evidence suggesting its increasing prevalence which has changed its perspective from being less prevalent to more prevalent. There is a complete lack of data on the prevalence rate and epidemiological basis of MS in Kashmir Valley of India. By and large MS research in this region seems to be hampered due to lack of proper research infrastructure, absence of MS registry, inadequate funding and more importantly by absence of active local and foreign collaborations between scientists and clinicians. This review tries to raise some key issues encountered while conducting MS research in Kashmir and at the same time highlighting the measures to be adopted for carrying out a large scale molecular epidemiological study.

Association of ACE Gene I/D polymorphism with migraine in Kashmiri population.

INTRODUCTION: Migraine is a complex, recurrent headache disorder that is one of the most common complaints in neurology practice. The role of various genes in its pathogenesis is being studied. We did this study to see whether an association exists between ACE gene I/D polymorphism and migraine in our region. MATERIALS AND METHODS: The study included 100 patients diagnosed with migraine and 121 healthy controls. The study subject were age and gender matched. The analysis was based on Polymerase Chain Reaction (PCR) and included following steps: DNA extraction from blood, PCR and Restriction Fragment Length Polymorphism (RFLP). RESULTS: Out of 100 cases, 69 were females and 31 were males. Fifty-seven were having migraine without aura and 43 had migraine with aura. 45 of the cases had II polymorphism, 40 had ID polymorphism and 15 had DD polymorphism in ACE gene. CONCLUSION: We were not able to find a statistically significant association between ACE gene I/D polymorphism with migraine. The reason for difference in results between our study and other studies could be because of different ethnicity in study populations. So a continuous research is needed in this regard in order to find the genes and different polymorphism that increase the susceptibility of Kashmiri population to migraine.

No evidence for a role of Ile587Val polymorphism of EIF2B5 gene in multiple sclerosis in Kashmir Valley of India.

Multiple sclerosis (MS) is an inflammatory neurodegenerative disease of the nervous system with a profound genetic element. It is already known that alterations in Eukaryotic Translation Initiation Factor 2B (EIF2B) gene encoding the five subunits of eIF2B complex cause Vanishing White Matter (VWM) disease of the brain and emerging evidences have advocated certain resemblances between MS and VWM in terms of clinical and epidemiological characteristics, thus validating the association study between EIF2B and MS. Moreover, a recent study has implicated EIF2B5 Ile587Val (rs843358) polymorphism as a susceptibility factor for MS. In order to investigate the association of EIF2B5 Ile587Val polymorphism with MS susceptibility in Kashmir region in India, we screened EIF2B5 Exon 13 in 30 MS patients and 65 controls (a total of 95 participants). During the present course of study, we could not find statistically significant difference in the frequency of Ile587Val between MS patients and controls, thus indicating that such alteration does not appear to influence MS development in Kashmiri population. Our results provide evidence against a major role for Ile587Val polymorphism in MS susceptibility.

Complete ophthalmoplegia: A rare presentation of idiopathic intracranial hypertension.

Idiopathic intracranial hypertension (IIH) is a disorder defined by clinical criteria that include signs and symptoms isolated to those produced by increased intracranial pressure (ICP; e. g., headache, papilledema, and vision loss), elevated ICP with normal cerebrospinal fluid (CSF) composition, and no other cause of intracranial hypertension evident on neuroimaging or other evaluations. The most common signs in IIH are papilledema, visual field loss, and unilateral or bilateral sixth cranial nerve palsy. Here we report a case of IIH presenting as headache with vision loss, papilledema, complete ophthalmoplegia with proptosis in one eye, and sixth cranial nerve palsy in the other eye. Patient was managed with acetazolamide, topiramate, and diuretics. Symptoms remained static and she was planned for urgent CSF diversion procedure.

Novel mutations identified in EIF2B5 gene in Kashmiri patients as susceptibility factor for multiple sclerosis.

White matter disease refers to a set of diseases that affect the white matter of the brain and all of which have different consequences on brain function. Most of the studies have shown that it results from the defects during protein synthesis, with the gene defects in EIF2B 1-5, encoding the five subunits of eukaryotic translation initiation factor 2B (eIF2B) α, ß, γ, δ and ε, respectively. eIF2B plays a crucial role in protein translation and its regulation under different conditions. The previous studies have shown that mutations in five subunits of eIF2B cause white matter disease of the brain and thus EIF2B is the main culprit in development of white matter disease. In this study, the mutational screening of EIF2B5 gene encoding eIF2Bε was performed for the first time in 12 Kashmiri patients, each having a unique white matter disease condition. We found two novel missense mutations in EIF2B5: c.580A>G, p.Thr194Ala and c.611C>T, p.Ala204Val among the patients with demyelinating disease (multiple sclerosis), but no mutation was found in other patients. In conclusion our study suggests involvement of the EIF2B5 gene in MS development, thus suggesting p.Thr194Ala to be a susceptibility factor for the development of multiple sclerosis.

Multiple cerebral infarctions with severe multi-organ dysfunction following multiple wasp stings.

Wasp and bee sting are commonly encountered worldwide. Local reactions are more common, generally are self-limiting and settle within a few hours. Multiple stings can lead to various clinical manifestations like vomiting, diarrhea, dyspnea, generalized edema, hypotension, syncope, acute renal failure, and even death. Rarely, they can cause vasculitis, serum sickness, neuritis, and encephalitis. We are reporting a case of 40-year-old male who presented with stroke, right hemiparesis with severe multi-organ dysfunction due to multiple wasp stings.