Impact of Thymectomy on Crisis Incidence and Quality of Life amongst Generalised Myasthenia Gravis Patients.

Background: Thymectomy, combined with corticosteroids, immunosuppressive agents, and cholinesterase inhibitors, has been accepted as the standard treatment for myasthenia gravis (MG) patients. Data on the effect of thymectomy on occurrence of myasthenic crisis are few. Objectives: To assess the long-term impact of thymectomy in patients with generalized Myasthenia gravis (GMG) in terms of occurrence of myasthenia crisis and quality of life. Methods: A retrospective analysis of 274 clinical records of patients diagnosed with myasthenia gravis (MG) in Nizam's institute of medical sciences (NIMS), a tertiary level teaching hospital between January 2000 and December 2015 was done. Severity of the disease was assessed using Myasthenia Gravis Foundation of America (MGFA) classification and quantitative myasthenia gravis (QMG) score. Myasthenia crisis was diagnosed in our patients when they required ventilator assistance due to respiratory failure caused by muscle weakness (MGFA class V). Quality of life (QoL) was assessed. Results: Of 230 cases included in the final analysis, 108 (46.9%) underwent thymectomy. Posttreatment crisis occurred in 53.3% of the nonthymectomy subjects, and 25.9% of thymectomy group (P < 0.001). In multivariate logistic regression analysis, after controlling for the effect of gender, age at diagnosis and grade of the disease, the odds ratio of myasthenic crisis in people with thymectomy was 0.186.(95% CI 0.087 to 0.387, P = 0.001). No statistically significant differences were observed in quality of life scores between thymectomy and nonthymectomy groups, either before (P = 0.86) or after surgery (P = 0.939). Conclusions: The odds of myasthenia crisis was lesser in people, who underwent thymectomy even after controlling for MGFA grade and other potential confounders but no significant differences in quality of life were found with thymectomy.

Association of HLA DRB1-DQB1 Haplotypes with the Risk for Neuromyelitis Optica among South Indians.

Background: Neuromyelitis optica (NMO) is an autoimmune demyelinating disorder, mainly characterized by severe optic neuritis, transverse myelitis and the high levels of antibodies against NMO-immunoglobulin G (IgG) or aquaporin-4 (AQP4). HLA-DR and HLA-DQ alleles within the HLA class II region on chromosome 6p21 are known to play a significant role in several autoimmune diseases including NMO. The rationale of the current case-control study is to explore the association of HLA-DRB1 and HLA-DQB1 alleles with the risk of NMO and its association with the clinical and serological markers. Methods: A total of 158 samples (38 NMO cases and 120-age and ethnicity matched controls) were genotyped for the HLA-DRB1 and HLA-DQB1 alleles by using PCR-SSP method. Results: Our analysis showed significant association of HLA-DRB1*10 allele (OR 2.63, 95% CI: 1.18-5.83, p=0.02) with NMO whereas DRB1*14 showed protective role against NMO (OR 0.33: 95% CI: 0.11-0.94, p=0.043). HLA-DRB1*10 allele also showed significant association in patients with NMO-IgG positive antibody (OR 3.28: 95% CI: 1.42-7.5, p=0.006). There was no association of HLA DQB1 alleles with NMO and also with NMO-IgG antibody. Among the haplotypes groups, HLA-DRB1*10-DQB1*05 (OR 2.61, 95% CI: 1.11-6.1, p=0.03), HLA-DRB1*15-DQB1*03 (OR 4.5, 95% CI: 1.81-11.5, p=0.001) were strongly associated with the risk of NMO, whereas DRB1*14-DQB1*05 (OR 0.20, 95% CI: 0.060-0.721, p=0.008) showed negative association with NMO. Conclusion: From this study, it is concluded that the HLA-DRB1*10 and DRB1*10-DQB1*05 and HLA-DRB1*15-DQB1*03 haplotypes may influence the susceptibility to NMO among the South Indians. Additionally we found DRB1*14 allele and DRB1*14-DQB1*05 haplotype showed protective role for NMO.

Clinicoradiological Profile of Superficial Middle Cerebral Vein Thrombosis.

BACKGROUND: The diagnosis of isolated cortical vein thrombosis (ICVT) involving superficial middle cerebral vein (SMCV) remains challenging even in the present era of modern MRI protocols. OBJECTIVE: The purpose of this study is to review the clinical and radiological characteristics of SMCV thrombosis in our hospital. METHODS: Chart review of cases of SMCV thrombosis admitted in a tertiary care university hospital in South India during a 1-year period from September 2015 to August 2016. RESULTS: Five SMCV thrombosis patients were identified and presented with focal seizures. Neuroimaging showed edema (with or without hemorrhage) of cortex and white matter of inferior frontal gyrus, temporal pole, superior temporal gyrus, insular cortex, and external capsule. The thrombosis of SMCV was demonstrated by Spin echo T1-weighted, GRE-weighted axial, and postcontrast T1-weighted images in coronal and sagittal planes, with a slice thickness of <3 mm. Four received anticoagulation and all improved rapidly and completely. CONCLUSION: SMCV thrombosis should be considered in patients having recent onset seizures in appropriate setting based on MRI evidence of parenchymal edema and/or hemorrhage in the perisylvian region along with evidence of thrombosed vein in that region. Appropriate imaging sequences help in confirmation of diagnosis.

Serum B12, Homocysteine Levels, and their Effect on Peripheral Neuropathy in Parkinson's Disease: Indian Cohort.

BACKGROUND: Cobalamin deficiency, either due to dietary inadequacy or increased consumption attributable to levodopa-mediated metabolic disturbance, and resultant hyperhomocysteinemia may contribute to peripheral neuropathy (PN) in Parkinson's disease (PD). AIM: The aim of the study is to assess the prevalence of Vitamin B12 deficiency, hyperhomocysteinemia in Indian PD patients, and their association with PN. MATERIALS AND METHODS: Clinical details were collected in 93 patients over a period of 2 years. Seventy controls were included in the study. Serum B12, homocysteine, folate, electroneurography, and autonomic function tests were done. The prevalence of B12 deficiency and hyperhomocysteinemia in PD patients and controls was assessed. The association of B12 and homocysteine levels with patients' age, disease duration, levodopa equivalent daily dose, cumulative levodopa dose, Unified Parkinson's Disease Rating Scale-III off score, modified Hoehn and Yahr score, and presence or absence of PN was studied. RESULTS: Serum B12, homocysteine levels, prevalence of B12 deficiency, and hyperhomocysteinemia were no different between cases and controls. Seven of 93 (9.68%) PD patients had PN. The median values of serum B12, folate, and homocysteine levels across patients with or without PN could not be compared as only seven of our patients had PN. CONCLUSION: The prevalence of B12 deficiency, hyperhomocysteinemia, and incidence of PN among our patients is very less when compared to the Western population. The conjecture that PN in PD patients may be secondary to B12 deficiency/hyperhomocysteinemia stands as a speculation.

Validation of the 2015 diagnostic criteria for neuromyelitis optica spectrum disorders in a cohort of South Indian patients.

BACKGROUND: Neuromyelitis Optica spectrum disorders (NMOSD) are one of the most common CNS demyelinating disorders as they will present with disabling recurrent demyelinating attacks. Hence, it is of paramount importance to diagnose early, and early diagnoses and intervention will prevent further relapses associated with NMOSD. New international consensus criteria have been proposed and studies validating its application towards diagnoses of NMOSD in south Asian population are meagre. Hence we validated the proposed International Panel for NMO Diagnosis (IPND), 2015 criteria to study the clinical, demographic profile and sero-status of patients who are presenting with core clinical symptoms of NMOSD in South India and compare it with 2006 criteria. METHODS: A retrospective study was conducted in a tertiary hospital for a period of one year. Patients who had at least one core clinical feature of NMOSD were included. Demographics and clinical data were recorded and analysed. Cases were evaluated using 2015 IPND and 2006 criteria for all patients, data was analysed using SPSS. RESULTS: A total of 110 patients were included and 91(82.72%) patients fulfilled IPND 2015 criteria. Out of 91 patients, 70 patients were AQP4 antibody positive and 21 were negative. Out of 110, only 30 (27.2%) satisfied 2006 criteria (24 or 80% were seropositive). 2015 criteria were more sensitive in identifying 61 new NMOSD cases juxtaposed to 2006 criteria, this difference was statistically significant (P<0.05). CONCLUSION: The 2015 IPND criteria were more sensitive and specific than previous 2006 criteria as it covered diverse clinical manifestations of NMOSD. Applying this criteria, NMOSD could be diagnosed among patients with monophasic illness, isolated recurrent optic neuritis, isolated recurrent myelitis, cerebral syndrome, diencephalic syndrome, brainstem syndrome and area postrema syndrome, thus improving the diagnostic yield.

Worsening Guillain-Barré syndrome: harbinger of IRIS in HIV?

We report an HIV patient aged 38 years with acute inflammatory demyelinating polyradiculoneuropathy subtype of Guillain-Barré syndrome (GBS) as the only manifestation of seroconversion and worsening of GBS being the harbinger of immune reconstitution inflammatory syndrome (IRIS). To date, only 5 cases of GBS during IRIS are reported. They manifested either during the third week or later after starting highly active antiretroviral therapy (HAART). Our patient witnessed worsening weakness by fifth day after starting HAART, even before the occurrence of Pneumocystis jirovecii pneumonia, cautioning one of the impending serious complications of IRIS and helped us initiate steroids at an early date.

Clinicopathologic and molecular spectrum of RNASEH1-related mitochondrial disease.

OBJECTIVE: Pathologic ribonuclease H1 (RNase H1) causes aberrant mitochondrial DNA (mtDNA) segregation and is associated with multiple mtDNA deletions. We aimed to determine the prevalence of RNase H1 gene (RNASEH1) mutations among patients with mitochondrial disease and establish clinically meaningful genotype-phenotype correlations. METHODS: RNASEH1 was analyzed in patients with (1) multiple deletions/depletion of muscle mtDNA and (2) mendelian progressive external ophthalmoplegia (PEO) with neuropathologic evidence of mitochondrial dysfunction, but no detectable multiple deletions/depletion of muscle mtDNA. Clinicopathologic and molecular evaluation of the newly identified and previously reported patients harboring RNASEH1 mutations was subsequently undertaken. RESULTS: Pathogenic c.424G>A p.Val142Ile RNASEH1 mutations were detected in 3 pedigrees among the 74 probands screened. Given that all 3 families had Indian ancestry, RNASEH1 genetic analysis was undertaken in 50 additional Indian probands with variable clinical presentations associated with multiple mtDNA deletions, but no further RNASEH1 mutations were confirmed. RNASEH1-related mitochondrial disease was characterized by PEO (100%), cerebellar ataxia (57%), and dysphagia (50%). The ataxia neuropathy spectrum phenotype was observed in 1 patient. Although the c.424G>A p.Val142Ile mutation underpins all reported RNASEH1-related mitochondrial disease, haplotype analysis suggested an independent origin, rather than a founder event, for the variant in our families. CONCLUSIONS: In our cohort, RNASEH1 mutations represent the fourth most common cause of adult mendelian PEO associated with multiple mtDNA deletions, following mutations in POLG, RRM2B, and TWNK. RNASEH1 genetic analysis should also be considered in all patients with POLG-negative ataxia neuropathy spectrum. The pathophysiologic mechanisms by which the c.424G>A p.Val142Ile mutation impairs human RNase H1 warrant further investigation.

Intrasinus thrombolysis in cerebral venous sinus thrombosis: Experience from a university hospital, India.

BACKGROUND: Intrasinus thrombolysis (IST) is believed to improve outcome in patients of cerebral venous sinus thrombosis (CVST) unresponsive to heparin. PURPOSE: The purpose of this article is to describe our experience with IST in patients of CVST unresponsive to heparin. MATERIALS AND METHODS: Hospital databases were searched, and patients with CVST who underwent IST from May 2011 to March 2014 were identified. Data on clinical presentation, duration of symptoms, and indications and dosage of IST were retrieved and outcomes analyzed. RESULTS: Twenty-four patients received IST. The presenting symptoms included headache (n = 19), seizures (n = 16), and altered sensorium (n = 14); signs included papilledema (n = 20) and hemiparesis (n = 15). Nineteen patients received unfractionated heparin (UFH), four received low-molecular-weight heparin (LMWH), and one received both. In one patient, microcatheter could not be passed, two patients bled intracranially, and three had nonintracranial bleeds. Among four deaths, none was due to iatrogenic bleeding. On discharge, 10 patients (43.5%) had good improvement with the modified Rankin Scale (score; mRS) ≤2 and eight (34.8%) had partial improvement with mRS = 3, 4. Seventeen patients (73.9%) had mRS ≤2 at 6 months follow-up. Bleeding complications of urokinase were less than those of alteplase. Recanalization of the involved sinuses was achieved in all. Early intervention led to successful recanalization. Functional recanalization decreased intracranial bleeding. CONCLUSION: Till date, our study is the largest series of IST in CVST reported from India. IST may be more effective than systemic heparin anticoagulation in moribund and unresponsive patients despite the potential for bleeding manifestations. Functional recanalization is adequate for good results. However, a randomized prospective study comparing heparin anticoagulation with IST is warranted.

Factors influencing nonadministration of thrombolytic therapy in early arrival strokes in a university hospital in Hyderabad, India.

BACKGROUND: It is a well-known fact that very few patients of stroke arrive at the hospital within the window period of thrombolysis. Even among those who do, not all receive thrombolytic therapy. OBJECTIVE: The objectives of this study were to determine the proportion of early arrival ischemic strokes (within 6 h of stroke onset) in our hospital and to evaluate the causes of nonadministration of intravenous and/or intraarterial thrombolysis in them. MATERIALS AND METHODS: Data of all early arrival acute stroke patients between January 2010 and January 2015 were included. Factors determining nonadministration of intravenous and/or intraarterial thrombolysis in early arrival strokes were analyzed. RESULTS: Out of 2,593 stroke patients, only 145 (5.6%) patients presented within 6 h of stroke onset and among them 118 (81.4%) patients had ischemic stroke and 27 (18.6%) patients had hemorrhagic stroke. A total of 89/118 (75.4%) patients were thrombolyzed. The reasons for nonadministration of thrombolysis in the remaining 29 patients were analyzed, which included unavoidable factors in 8/29 patients [massive infarct (N = 4), hemorrhagic infarct (N = 1), gastrointestinal bleed (N = 1), oral anticoagulant usage with prolonged international normalized ratio (INR) (N = 1), and recent cataract surgery (N = 1)]. Avoidable factors were found for 21/29 patients, include nonaffordability (N = 7), fear of bleed (N = 4), rapidly improving symptoms (N = 4), mild stroke (N = 2), delayed neurologist referral within the hospital (N = 2), and logistic difficulty in organizing endovascular treatment (N = 2). CONCLUSION: One-fourth of early ischemic stroke patients in our study were not thrombolyzed even though they arrived within the window period. The majority of the reasons for nonadministration of thrombolysis were potentially preventable, such as nonaffordability, intrahospital delay, and nonavailability of newer endovascular interventions.

Identification of a novel splice site HSPG2 mutation and prenatal diagnosis in Schwartz Jampel Syndrome type 1 using whole exome sequencing.

Schwartz-Jampel Syndrome type 1 is a rare autosomal recessive musculoskeletal disorder (OMIM #255800) caused by various mutations in the HSPG2 gene encoding protein perlecan, a ubiquitous heparan sulfate proteoglycan, which is an integral component of basement membranes and possesses angiogenic and growth-promoting attributes primarily by acting as a co-receptor for the basic fibroblast growth factors in human body. We report a novel homozygous intronic 5' splice site mutation in this gene (c.4740 + 5G>A) in a child with clinical features of Schwartz-Jampel syndrome type 1. The mutation was detected by exome sequencing and later confirmed by Sanger sequencing. The mother was found to be heterozygous for the mutation and an ongoing pregnancy found to be unaffected. cDNA analysis revealed skipping of exon 37 of HSPG2 gene in the patient due to the splicing error caused by this mutation. This is likely to result in loss of 38 amino acids from the domain III of the perlecan protein and presumably affects its structure and function as per protein modeling predictions. This report demonstrates the utility of exome sequencing as a routine molecular diagnostic approach of choice for this rare disorder.

Incidence and spectrum of paraneoplastic neurological syndromes: single center study.

Paraneoplastic neurological syndromes (PNS) are remote effects of cancer. They are much less common, but are nevertheless important because they cause severe neurological morbidity and mortality. The present cases were studied to characterize the clinical features of patients of suspected PNS and to study their association with different types of tumors. In this study conducted from a super speciality teaching institute from South India, forty five (incidence-0.25%) patients were diagnosed with PNS based on the clinical data. They were subdivided into two groups patients with central nervous system (CNS) manifestations and those with neuromuscular manifestations. Immunological markers were assessed in a subset of patients. Majority of them (75.6%) were above 40 years. There was no sex predilection and a chronic presentation was common (42.2%). While more than half had involvement of peripheral nervous system (64.4%), CNS manifestations were present in 16 (35.6%) cases. Immunological markers were present in 10 out of 14 (58.8%) patients. Classic PNS was seen 22 cases (48.9%), while 23 (51.1%) were non classical. Most common tumor was lung cancer followed by myeloma and breast carcinoma. Present study construed that, in patients with neurological syndromes of unknown cause, search should be focused for occult malignancy based on the phenotype and onconeural antibodies, targeting the lung and breast in particular.

Comparison of frequencies of non motor symptoms in Indian Parkinson's disease patients on medical management versus deep brain stimulation: A case-control study.

BACKGROUND: Non motor symptoms (NMS) of idiopathic Parkinson's disease (PD) are a major cause of disability and recognition of these symptoms and treatment is important for comprehensive health care. Deep brain stimulation of bilateral subthalamic nucleus deep brain stimulation (STN DBS) has been shown to improve motor symptoms in PD and effects on NMS are unknown. To investigate the NMS among PD patients who underwent STN DBS. METHODS: We recruited prospectively 56 patients with PD, who had undergone bilateral STN DBS and 53 age and duration of illness matched PD patients on dopaminergic therapy (controls). NMS were assessed using 30 item questionnaire NMS Quest. These questions evaluated 9 domains, gastrointestinal, urinary, cardiovascular, sexual, cognition (apathy/attention/memory), anxiety/depression, hallucinations/delusions, sleep and miscellaneous. Comparison was done on individual symptoms as well as in various domains. This study was carried at Nizam's Institution of Medical Sciences and study period was from January 2011 to December 2012. RESULTS: Patients who underwent STN DBS had a significantly lower mean total score on NMS quest (6.7 ± 3.8) compared to controls (8.4 ± 3.7) (P < 0.00100). Symptoms in the domains of cardiovascular, gastrointestinal, sleep were significantly less frequent while sexual disturbances were significantly more frequent among patients compared to controls. On individual symptom analysis, nocturia  (P < 0.00010), unexplained pains (P < 0.00010), nausea and vomiting, constipation, lightheadedness, depression, and insomnia were less prevalent, while sexual disturbances were significantly more common in STN DBS group compared to controls. CONCLUSION: Bilateral STN DBS not only improves the motor symptoms but also improves many NMS in PD patients.

Safinamide for the treatment of Parkinson's disease.

Parkinson's disease (PD) is a neurodegenerative disease caused by a complex interaction of loss of dopaminergic and non-dopaminergic neurotransmitter systems. Drugs acting on the dopaminergic pathways are the mainstay of treatment for motor symptoms today. Safinamide (NW-1015) is a novel drug with multiple actions. It is a monoamine oxidase B inhibitor and improves dopaminergic transmission. In addition, it has antiglutamatergic effects and can thus reduce dyskinesias, which is a side effect limiting most dopaminergic therapy. In Phase III trials, safinamide has been found to be a useful adjunctive to dopamine agonists in early PD and has been shown to increase time without increasing troublesome dyskinesias when used as an adjunct to levodopa in patients with advanced PD. A possible neuroprotective role in inhibiting PD disease progression is envisaged and warrants future studies.

Convulsive status epilepticus: clinical profile in a developing country.

PURPOSE: In developing countries optimal care of status epilepticus (SE) is associated with major barriers, particularly transportation. METHODS: A prospective study of SE was performed between 1994 and 1996 to determine the clinical profile, response to treatment and outcome, Glasgow Outcome Scale (GOS). RESULTS: Of the 85 patients admitted, the mean age was 33 years (8-75 years), 16% <16 years of age. The mean duration of SE before admission was 18.02 h (1-72 h). Only 23 (28%) patients, all locals, presented within <3 h of onset. Etiology included acute symptomatic (54%), remote symptomatic (7%), cryptogenic (19%), and established epilepsy (20%). Central nervous system infections accounted for 24 (28%) of the etiologies. Seventy-five (88%) patients responded to first-line drugs and 10 (12%) required second-line drugs. The mean duration of SE was significantly long in nonresponders (Mean +/- SD: 32.6 +/- 20.11 vs. 15.2 +/- 18.32, p < 0.006). Duration (p < 0.01; OR 1.04, 95% CI 1.01-1.07) and acute symptomatic etiology (p < 0.038; OR 10.38, 95% CI 1.13-95.09) were the independent predictors of no-response to first-line drugs. Of the nine deaths (10.5%), eight were in acute symptomatic group. Predictors of mortality included female sex (p < 0.017, OR 13.41, 95% CI 1.59-115.38) and lack of response to first-line drugs (p < 0.0001, OR 230.27, 95% CI 8.78-6037.19). Longer duration was associated with poor GOS 1-4 (p = 0.001). Of the 37 patients with <6 h, 81% had GOC5 outcome. CONCLUSION: This study suggests that longer duration of SE and acute symptomatic etiology are independent predictors of lack of response to first-line drugs. Failure to respond to first-line drugs and duration predict the outcome.

Diagnosis of mitochondrial diseases: clinical and histological study of sixty patients with ragged red fibers.

BACKGROUND: Mitochondrial diseases are caused by mutations in mitochondrial or nuclear genes, or both and most patients do not present with easily recognizable disorders. The characteristic morphologic change in muscle biopsy, ragged-red fibers (RRFs) provides an important clue to the diagnosis. MATERIALS AND METHODS: Demographic data, presenting symptoms, neurological features, and investigative findings in 60 patients with ragged-red fibers (RRFs) on muscle biopsy, seen between January 1990 and December 2002, were analyzed. The authors applied the modified respiratory chain (RC) diagnostic criteria retrospectively to determine the number of cases fulfilling the diagnostic criteria of mitochondrial disease. RESULTS: The most common clinical syndrome associated with RRFs on muscle biopsy was progressive external ophthalmoplegia (PEO) with or without other signs, in 38 (63%) patients. Twenty-six patients (43%) had only external ophthalmoplegia, 5 (8%) patients presented with encephalomyopathy. Specific syndromes were the presenting feature in 8 (13%), Kearns-Sayre syndrome (KSS) in 4 and myoclonus epilepsy with ragged-red fibers (MERRF) in 4. Myopathy was the presenting feature in 5 (8%) and 4 presented with infantile myopathy. Of the 60 patients, 18 (30%) had proximal muscle weakness. Two patients with KSS and one patient with myopathy had complete heart block necessitating pace making. When the modified RC diagnostic criteria were applied, only 26 (43%) patients had one other major criterion in addition to RRFs for the diagnosis of mitochondrial diseases. The remaining 34 (57%) patients with RRFs on muscle biopsy had only some clinical features suggestive of RC disorder but did not fulfill the clinical criteria (of the modified diagnostic criteria) for the diagnosis of mitochondrial diseases. CONCLUSION: In patients with clinical features suggestive of RC disorder, demonstration of RRFs on muscle biopsy helps in confirming the diagnosis of mitochondrial disease in only a subgroup of patients.