Role of PON1 L55M Gene Polymorphism in Parkinson's Disease among North Indian Population.

BACKGROUND AND OBJECTIVES: The role of various genetic markers including alpha synuclein, Parkin, etc., is known in the pathogenesis of Parkinson's disease (PD). Novel genetic markers including paraoxonase 1 (PON1) have also been linked to PD pathogenesis in recent studies. The PON1 L55M allele carriers may have defective clearance of environmental toxins and may result in increased susceptibility to PD. Hence, we studied the role of PON1 L55M polymorphism in PD among a North Indian population. MATERIALS AND METHOD: Seventy-four PD patients and 74 age- and sex-matched controls were recruited in this hospital-based case-control study. Baseline characteristics were recorded using structured questionnaire. DNA was extracted from 3-4 ml of venous blood, followed by PCR and restriction digestion. PON1 L55M genotypes were visualized as bands: LL (177 bp), LM (177, 140 bp) and MM (140,44 bp) on 3% agarose gel. Mann-Whitney U test and Chi-squared test were used for comparing two groups of skewed and categorical variables, respectively. Measures of strength of association were calculated by binary regression analysis. P value < 0.05 was considered as significant. RESULTS: Parkinson's disease patients had significantly higher exposure to pesticides (12.2%; P (organophosphate exposure) < 0.001) and well water drinking (28.4%; P = 0.006) compared to controls. Frequency distribution of LL, LM, MM genotypes was 67.5% (50/74), 28.4% (21/74), and 4.1% (3/74), respectively, for cases and 72.6% (54/74), 26% (19/74) and 1.4% (1/74), respectively, for controls. PON1 L55M genotype distribution between Parkinson's disease cases and controls was not significant (P = 0.53). PON1 L55M polymorphism was not associated with PD after adjusting for confounders by binary regression analysis. CONCLUSION: There was no significant association between PON1 L55M polymorphism and PD. Larger population-based studies would be required from India before drawing any definite conclusions.

Tubercular Mediastinal Lymphadenopathy Presenting as an Isolated Unilateral Vocal Cord Palsy and the "Sail" Sign.

Tuberculosis continues to remain a major public health challenge, especially in low- and middle-income countries. Unilateral vocal cord palsy in adults as the sole manifestation of tubercular mediastinal lymphadenopathy has been rarely reported. A 22-year-old lady presented with a history of hoarseness of voice for the past month. The general physical examination revealed palpable lymph nodes in the left axilla. Axial CT sections at the level of the vocal cords demonstrated dilation of the right laryngeal ventricle and mild anteromedial deviation of the ipsilateral arytenoid cartilage ("sail" sign) suggestive of a right vocal cord palsy. Contrast-enhanced CT chest revealed right paratracheal, right hilar, and subcarinal lymph nodes with areas of central necrosis. She was started on anti-tubercular therapy and her voice completely improved after three months of treatment. The "Sail" sign on axial CT scans is a useful radiological sign for diagnosing unilateral vocal cord palsy. Rarely, compression of the recurrent laryngeal nerve by enlarged mediastinal lymph nodes due to tuberculosis can present with unilateral vocal cord palsy as the sole manifestation in adults.

IMPETUS Stroke: Assessment of hospital infrastructure and workflow for implementation of uniform stroke care pathway in India.

BACKGROUND: India accounts for 13.3% of global disability-adjusted life years (DALYs) lost due to stroke with a relatively younger age of onset compared to the Western population. In India's public healthcare system, many stroke patients seek care at tertiary-level government-funded medical colleges where an optimal level of stroke care is expected. However, there are no studies from India that have assessed the quality of stroke care, including infrastructure, imaging facilities, or the availability of stroke care units in medical colleges. AIM: This study aimed to understand the existing protocols and management of acute stroke care across 22 medical colleges in India, as part of the baseline assessment of the ongoing IMPETUS stroke study. METHODS: A semi-structured quantitative pre-tested questionnaire, developed based on review of literature and expert discussion, was mailed to 22 participating sites of the IMPETUS stroke study. The questionnaire assessed comprehensively all components of stroke care, including human resources, emergency system, in-hospital care, and secondary prevention. A descriptive analysis of their status was undertaken. RESULTS: In the emergency services, limited stroke helpline numbers, 3/22 (14%); prenotification system, 5/22 (23%); and stroke-trained physicians were available, 6/22 (27%). One-third of hospitals did not have on-call neurologists. Although non-contrast computed tomography (NCCT) was always available, 39% of hospitals were not doing computed tomography (CT) angiography and 13/22 (59%) were not doing magnetic resonance imaging (MRI) after routine working hours. Intravenous thrombolysis was being done in 20/22 (91%) hospitals, but 36% of hospitals did not provide it free of cost. Endovascular therapy was available only in 6/22 (27%) hospitals. The study highlighted the scarcity of multidisciplinary stroke teams, 8/22 (36%), and stroke units, 7/22 (32%). Lifesaving surgeries like hematoma evacuation, 11/22 (50%), and decompressive craniectomy, 9/22 (41%), were performed in limited numbers. The availability of occupational therapists, speech therapists, and cognitive rehabilitation was minimal. CONCLUSION: This study highlighted the current status of acute stroke management in publicly funded tertiary care hospitals. Lack of prenotification, limited number of stroke-trained physicians and neurosurgeons, relatively lesser provision of free thrombolytic agents, limited stroke units, and lack of rehabilitation services are areas needing urgent attention by policymakers and creation of sustainable education models for uniform stroke care by medical professionals across the country.

Neurogenic Supine Hypertension and Cardiovascular Autonomic Dysfunction in Patients with Parkinson's Disease.

Background: Natural history and disease progression in patients with Idiopathic Parkinson's Disease (PD) is quite heterogeneous. Autonomic dysfunction occurs commonly among Idiopathic PD patients. Heart rate variability and ambulatory blood pressure monitoring are used to assess cardiac autonomic dysfunction. The prevalence and magnitude of supine hypertension in Indian PD patients has not been studied to date. The present study aimed to record cardiovascular autonomic functions and supine hypertension in PD patients and to correlate them with the age of onset, duration and severity of the disease, and non-motor symptom burden. Material and Methods: The cross-sectional study involved 60 PD patients. Webster rating scale was used to determine the disease severity. Non-motor symptom burden was assessed using the Non-Motor Symptom Scale (NMSS). Ambulatory blood pressure monitoring and heart rate variability parameters determined cardiac autonomic function. Supine hypertension was defined as Systolic Blood Pressure (SBP) ≥150 mmHg and/or DBP ≥90 mmHg. Less than 10% decrease or even increase in blood pressure during the night were classified as non-dippers. Pearson coefficient was used appropriately to establish correlation. P ≤ 0.05 was considered significant. Results: Age of onset was 61.2 ± 8.7 years and duration of disease was 1.7 ± 1.1 years. Mean Webster and non-motor symptom scores were 12.7 ± 4.4 and 15.5 ± 8.0, respectively. About 50 patients (83%) were non-dipper, while 32 (53%) had supine hypertension. Low Frequency oscillations (LF) (r = 0.28), High Frequency oscillations (HF) (r = 0.29), Standard Deviation NN intervals (SDNN) (0.26), and Root Mean Squared Successive Differences of NN intervals (RMSSD) (r = 0.28) correlated significantly with non-motor symptoms scale. LF (r = -0.39), HF (r = -0.43), SDNN (-0.40), RMSSD (r = -0.41), NN50 (r = -0.38), PNN50 (r = -0.42), mean SBP (r = 0.26), and mean DBP (r = 0.33) correlated significantly with disease duration. PNN50 (r = -0.255), mean SBP (r = -0.29), and mean DBP (r = -0.27) correlated significantly with age at onset. Conclusion: Awareness regarding neurogenic supine hypertension is needed as it occurs commonly among Indian PD patients. Heart rate variability (HRV) parameters and ambulatory blood pressure are of significant help in the detection of early cardiovascular autonomic dysfunction and correlate significantly with disease duration and non-motor symptom burden among PD patients.

Multi-Modal Rehabilitation Therapy in Parkinson's Disease and Related Disorders.

Long-term use of dopaminergic therapy in Parkinson's disease (PD) is associated with reduction in efficacy and disabling dyskinesias. The current medical or surgical treatment modalities are ineffective for atypical parkinsonism syndromes. Hence, there is a need for holistic and cost-effective non-pharmacological interventions that act via multiple mechanisms to improve motor as well as non-motor symptoms among PD patients. Rehabilitation strategies focusing on multiple mechanisms can lead to improvement in certain symptoms among PD patients, which may be refractory to medical and surgical therapy. However, there is scanty literature available on the role of various rehabilitation strategies in patients with atypical parkinsonism patients. Multiple rehabilitation strategies such physiotherapy, aerobic exercises, strength/resistance exercises, treadmill training, cueing, dance and music, speech language therapy, occupational therapy, hydrotherapy, and martial arts have been found to improve motor as well as non-motor symptoms among PD patients. Newer modalities such as virtual-reality-based devices, exergaming, wearable sensors, and robotic prosthetic devices may be exciting future prospects in rehabilitation among patients with PD and atypical parkinsonian syndromes. This narrative review assessed and summarized the current evidence regarding the role of various rehabilitation strategies in PD and atypical parkinsonian syndromes. Furthermore, evidence regarding recent advancements in rehabilitation for patients with parkinsonism was highlighted. Despite the beneficial effect of rehabilitation in PD, there is still scanty literature available from India on rehabilitation strategies among PD patients. Larger prospective randomized control trials from India and other low- and middle-income countries, focusing on various rehabilitation strategies among PD patients, are an unmet need.

Comparison of dexamethasone regimens in tubercular meningitis (TBM): a randomized open label clinical trial.

INTRODUCTION: Corticosteroids are used as adjunctive treatment in tuberculous meningitis (TBM). However, there is no universally accepted regimen, type, duration, or route of steroid administration. METHODOLOGY: In a randomized open labelled pilot study, TBM patients were divided into overlap oral dexamethasone (OOD) and direct oral dexamethasone (DOD) arms. The total duration of steroid administration was 8 weeks. The primary outcome was symptomatic resolution at 1 month post randomization. The secondary outcomes were mortality and modified Rankin scale (mRS) at 3 and 6 months after initiation of steroids. RESULTS: Symptomatic resolution after one month of randomization in 53 randomized patients was similar in OOD (71.4% (15/21)) versus DOD ((85.0% (17/20)) arm (p value:0.45). Median mRS was also similar in OOD versus DOD (OOD: 2.5 (IQR: 1.0; 6.0) versus DOD: 1.0 (IQR: (0.0; 4.0); p value: 0.31)) arm at 6 months. The mortality at 6 months was 31.8% (7/22) in the OOD versus 20.0% (4/20) in the DOD arm (p value: 0.49). CONCLUSIONS: In this open label pilot study, the outcomes were similar in OOD versus DOD arms in terms of symptomatic resolution at 1 month, and morbidity, and mortality at 3 and 6 months. Patients with stage I to III TBM may be given injectable steroids for 1 week after which they may be switched to oral steroid. This regime cannot be applied to stage IV TBM and patients with complications like optico-chiasmatic or spinal arachnoiditis or vasculitic infarcts.

Anoctamin-5 Muscular Dystrophy: Report of Two Cases with Different Phenotypes and Genotypes from the Indian Subcontinent.

Anoctaminopathies are a group of autosomal recessive skeletal muscle disorders with various clinical phenotypes, caused by anoctamin 5 (ANO5) gene mutations and the abnormal expression of ANO5 protein. Patients with recessive mutations in ANO5 present with variable symptoms ranging from asymptomatic hyperCKemia and exercise-induced myalgia to proximal and/or distal muscle weakness. Here, we describe the clinical, pathological, and molecular findings of two unrelated patients with ANO5-related muscular dystrophy (MD). Ninety-six histologically identified MD cases were subjected to next-generation sequencing using a customized panel of 54 genes (IIlumina Design Studio). Two patients were diagnosed with ANO5-related MD. One patient had a pathogenic homozygous mutation of c.1406G>A in exon 14, while the other patient had a novel heterozygous mutation of c.2141C>G in exon 19 of ANO5 gene. Both showed two different phenotypes (limb girdle MD and Miyoshi myopathy) and histomorphological patterns. Muscle biopsy of one patient in addition showed amyloid deposit in the walls of interstitial blood vessels. ANO5-related MD is a heterogeneous disease with different clinical phenotypes as well as genotypes. All muscle biopsies with unclassified muscular dystrophies should be subjected to Congo red stain. The results of this study suggest that screening for ANO5 gene should represent an early step in the diagnostic work-up of the patients with undiagnosed MD and persistent asymptomatic hyperCKemia, even when muscle biopsy histomorphology is normal.

Serum S100B and NSE Levels Correlate With Infarct Size and Bladder-Bowel Involvement Among Acute Ischemic Stroke Patients.

Objectives Stroke is a major global health concern. Due to limited availability of neuroimaging particularly in rural and regional areas in India as well as its limitation, the interest in use of biochemical markers for stroke diagnosis, severity, and prognosis is increasing. Only a handful of studies on stroke biomarkers have been conducted in India. Hence, this study was conducted to investigate the correlation of serum neuron-specific enolase (NSE) and S100 calcium-binding protein B (S100B) levels with stroke severity according to infarct size in acute ischemic stroke patients. Material and Methods Sixty stroke patients were recruited for the study and were evaluated. Noncontrast computed tomography (CT) scan of the brain was performed for all patients within 48 hours of onset of symptoms. Infarct volume was measured by evaluating dimensions in three planes on CT head. Serum NSE and S100B levels were measured by commercially available immunoassay kits. Continuous data was represented as mean ± standard deviation. Categorical data was expressed in terms of percentages and proportions. Pearson's correlation coefficient was applied to assess correlation between NSE and S100B and infarct size. Infarct size was classified arbitrarily into three groups according to infarct volume (low, moderate, and large) and analysis of variance was applied for comparing mean S100B and NSE levels in the three groups. To assess the independent predictors of infarct size among stroke cases, multivariate logistic regression analysis was used. Association between serum S100B or NSE levels and clinical features was done by the Mann-Whitney U test. Results Correlation between serum S100B protein levels and NSE with larger infarct volume was highly significant ( r (S100B) = 0.611, p (S100B) < 0.0001; r (NSE) = 0.258, p (NSE) = 0.047). Using multivariate regression analysis, bladder and bowel involvement, prior stroke history, and dyslipidemia among stroke patients correlated with a larger infarct size. Mann-Whitney U test showed both NSE and S100B levels were significantly associated with bladder bowel involvement among stroke cases. Conclusion There was a positive correlation between serum S100B and NSE levels with infarct size. In addition, bladder-bowel involvement among stroke patients was associated with increased S100B levels. Therefore, levels of protein S100B and NSE may serve as indicator of infarct size and may be predictors of severe clinical presentations of acute ischemic stroke.

PON1 (Paraoxonase 1) Q192R Gene Polymorphism in Ischemic Stroke among North Indian Population.

Background: PON1 is an High Density Lipoprotein (HDL)-associated esterase. Two common polymorphisms in the PON1 gene, Q192R and L55M substitutions, determine the inter-individual variation in PON1 activity. The association of these polymorphisms with the risk of ischemic stroke remains controversial. In the present study, the role of PON1 Q192R gene polymorphism in ischemic stroke was studied in the Indian population. Design and Methods: In the present case-control study, the PON1 Q192R gene polymorphism was screened in ischemic stroke patients (n: 63) and age, sex-matched controls (n: 63) using thePolymerase Chain Reaction-Restriction Segment Length Polymorphism (PCR-RFLP) method. Results: The mean age of stroke presentation was 58.11 ± 15.4 years. A total of 17.4% cases presented with young stroke (<45 years age) and 9.52% cases were seen to have a recurrent stroke. The distribution of -192Q/R PON1 gene polymorphism was not seen to differ between cases and controls. The traditional stroke risk factors did not have any effect on the PON1 genotype expression. A multivariate logistic regression analysis was done in order to assess an independent association of age, gender, traditional stroke risk factors, and PON1 polymorphism with acute ischemic stroke. However, neither the RR genotype nor the presence of the R allele was associated with an increase in the risk of acute ischemic stroke (OR [RR genotype]-4.76, P value: 0.24, 95% CI: 0.3497-64.8531; OR [R allele]-0.94, P value: 0.90, 95% CI: 0.3516-2.4989). Conclusion: PON1 Q192R gene polymorphism is not associated with an increased risk of acute ischemic stroke in the North Indian population. Further studies with a larger sample size are needed before PON1 Q192R gene polymorphism can be considered as a genetic risk factor for ischemic stroke.

Emerging Trends in Stroke Epidemiology in Indian Women Over the Last Decade.

Background and Objective: Temporal trends in clinico-epidemiological parameters of stroke among Indian women have not been studied. We aimed to study the changes in these parameters over the last decade. Material and Methods: 417 strokes (ischemic/hemorrhagic) were prospectively recruited in two timelines. In total, 267 strokes were recruited in 2005 while 150 strokes were recruited in 2016-17. Patients underwent stepwise evaluation via a structured proforma. Demographic factors, stroke subtypes, and risk factors were analyzed. Results: Female strokes had a higher mean age in 2017 compared to 2005 (60.90 ± 16.9 vs. 53.21 ± 16.75 years, P = 0.002). Hemorrhagic strokes among females increased over the last decade. Female strokes with dyslipidemia were significantly lower in 2017 compared to 2005 (P = 0.002). Proportion of hypertensive and diabetic strokes were not significantly different between these two periods. Conclusions: Over the past decade, the mean age of stroke onset has increased while the prevalence of dyslipidemia has reduced significantly among Indian female stroke patients.

Morvan's syndrome: An unusual presentation of a solid pseudopapillary pancreatic tumor.

Morvan's syndrome is a rare anti-contactin-associated protein-like 2 (CASPR2) antibody-mediated autoimmune disorder. The clinical features of this syndrome include muscular twitching, insomnia, dysautonomia, peripheral nerve hyperexcitability, and fluctuating delirium. An underlying tumor is commonly found among Morvan's syndrome cases, with thymoma being the most frequent association. We describe an unusual case of a 39-year-old female with excruciating bilateral leg pain, insomnia, hyperhidrosis, peripheral nerve hyperexcitability, serum anti-CASPR2 antibody positivity, and a solid pseudopapillary tumor of the pancreas on histopathology. Furthermore, the patient's symptoms improved after receiving intravenous immunoglobulin (0.4 g/kg per day for 5 days). To the best of our knowledge, this is the first case of Morvan syndrome associated with a solid pseudopapillary pancreatic tumor to be reported in the literature to date. Our case adds to the spectrum of malignancies that are associated with Morvan's syndrome. The recognition of this rare syndrome and its various associations are important for the neurologist, as it is a potentially treatable condition.

Role of ACE Polymorphism in Acute Ischemic Stroke.

BACKGROUND: Stroke is one of the leading causes of death and disability in India. Angiotensin-converting enzyme (ACE) is involved in the development of hypertension, atherosclerosis, cardio, and cerebrovascular disease and is a plausible genetic candidate for stroke. The role of ACE polymorphism is still uncertain and requires further investigation. OBJECTIVE: The aim of this study was to study the role of ACE insertion/deletion polymorphism in acute ischemic stroke (AIS). MATERIALS AND METHODS: One hundred thirty AIS cases and 130 age and sex matched healthy controls were recruited. Ten milliliters venous blood was drawn and 6 mL of blood was used for routine hematological, biochemical tests. Remaining 4 mL of EDTA blood was used for DNA extraction, PCR amplification, and restriction digestion. Three genotypes (II, ID, and DD) were visualized on 3% agarose gel. Association between genotypes among stroke case was done by Chi-square test with P value <0.05 taken as significant. RESULTS: DD genotype was significantly associated with the risk of stroke with P value of 0.0001. Both the dominant and recessive models showed that the DD genotype was independently associated with an increased risk of ischemic stroke (OR = 20.732; 95% CI: 2.7241-157.7864; P value = 0.003 for the recessive model and OR = 2.848; 95% CI: 1.5127-5.3649; P value = 0.001 for dominant model). CONCLUSIONS: Our study showed a strong association between ACE polymorphism and the risk of AIS. This study paves the way for further studies to confirm the role of ACE polymorphism as genetic risk factors for AIS.

Teleneurorehabilitation Among Person with Parkinson's Disease in India: The Initial Experience and Barriers to Implementation.

OBJECTIVE: We aimed to assess the feasibility of teleneurorehabilitation (TNR) among persons with Parkinson's disease (PD), considering difficulties imposed by the COVID-19 pandemic in access to healthcare, particularly in low-resource settings. The feasibility of TNR in India has not been formally assessed so far. METHODS: We conducted a single-center, prospective cohort study at a tertiary center in India. Persons with PD with Hoehn & Yahr (H&Y) stages 1-2.5, who were not enrolled into any formal exercise program, were offered TNR as per a predesigned program for 12 weeks. Baseline and post-intervention assessment included Movement Disorders Society-Unified Parkinson's Disease Rating Scale (MDS-UPDRS), part II and III, Parkinson's Disease Questionnaire (PDQ)-8 and Non-Motor Symptoms Scale (NMSS). We assessed adherence to TNR and problems expressed by patients/caregivers by means of open-ended surveys addressing barriers to rehabilitation. RESULTS: We recruited 22 for TNR. Median age (interquartile range [IQR]) was 66.0 (44.0-71.0) years; 66.7% were H&Y stage 2.0. One patient died of COVID-19-related complications. Of the remaining 21, 14 (66.7%) had adherence of ≥75%; 16/21 (76.2%) patients had problems with attending TNR sessions as the family shared a single phone. Slow Internet speed was an issue among 13/21 (61.9%) of the patients. Other issues included lack of rapport, migration to distant hometowns and motor-hand impairment. CONCLUSION: Multiple challenges were faced in implementing a telerehabilitation program among persons with PD, exacerbated by the COVID-19 pandemic. These barriers were present at various levels: recruitment, adherence issues and maintenance. Future TNR programs must address these concerns.