Clinicoradiological features of cerebral microbleeds diagnosed on magnetic resonance neuroimaging.

Objectives: Cerebral microbleeds (MBs) are recently described entity on magnetic resonance (MR) neuroimaging and are considered one of the markers of small vessel disease. We aimed to study the clinicoradiological features of cerebral MBs that were diagnosed in MR neuroimaging. Materials and Methods: We studied 109 South Indian patients, who presented to a tertiary care institution for MR neuroimaging with cerebral MBs as diagnosed on MR neuroimaging based on either the gradient T2* imaging or susceptibility-weighted imaging. The clinical details and coexisting MR features of infarcts, macrohemorrhages, lacunar infarcts, and white matter leukoaraiosis were evaluated and analyzed. Results: Of 109 patients, 79 were males and 30 were females. Associated clinical comorbidities noted include hypertension (62.39%), diabetes (23.85%), and alcoholism (31.19%) apart from the history of anti-platelet/anti-coagulant usage (15.5%), previous cardiac disease (12.84%), and previous stroke/transient ischemic attacks (9.17%). Other co-existing neuroimaging abnormalities noted include cortical infarcts (27.52%), old hemorrhages (29.36%), lacunar infarcts (56.88%), and white matter leukaraiosis (67.89%). Conclusion: The clinicoradiological features of cerebral MBs in South Indian patients are similar to other Asian and Western studies with significant coexistence of clinical comorbidities and imaging features of small vessel changes. Further studies with a larger sample are needed to correlate the grade of MBs to the individual risk of these clinicoradiological characteristics.

Effectiveness of nurse-led fever, sugar-hyperglycemia, and swallowing bundle care on clinical outcome of patients with stroke at a tertiary care center: A randomized controlled trial.

Objectives: Stroke is a medical emergency, the leading cause of death, and a significant cause of disability in developing countries. The primary goals of stroke management focus on reducing disability, which needs prompt treatment in time. Fever, sugar-hyperglycemia, and swallowing (FeSS) bundle are a promising nurse-led composite for reducing disability and death. The present study aims to assess the effect of FeSS bundle care on disability, functional dependency, and death among acute stroke patients. Materials and Methods: A randomized controlled trial was conducted among 104 acute stroke patients, who were admitted within the first 48 h of stroke symptoms and had no previous neurological deficits. Randomization was stratified based on gender and type of stroke. The intervention group received FeSS bundle care, which included nurse-led fever and sugar management for the first 72 h, and a swallowing assessment done within the first 24 h or before the first oral meal. A follow-up assessment was done after 90 days to assess the disability, functional dependency, and mortality status using a modified Rankin scale and Barthel index. Results: No significant difference was noted in the 90-day disability and functional dependency between the groups. A reduction in mortality was noted in the intervention group. The risk ratio for mortality between groups was 2.143 (95% confidence interval: 0.953-4.820). Conclusion: Although no significant reduction in disability, there was a reduction in mortality in the intervention group. Hence, the study suggested the promotion of nurse-led intervention using the FeSS bundle in stroke units.

Effect of continuous 2 MHz transcranial ultrasound as an adjunct to tenecteplase thrombolysis in acute anterior circulation ischemic stroke patients: an open labeled non-randomized clinical trial.

The treatment of acute ischemic stroke has improved in last few decades. While meta-analyses of several trials have established the safety and efficacy of Intravenous (IV) Tenecteplase thrombolysis, concomitant continuous transcranial doppler (TCD) ultrasound administration has not been assessed in any clinical trial. The aim of this study was to determine the effects of continuous 2 MHz TCD ultrasound during IV Tenecteplase thrombolysis for Middle cerebral artery (MCA) stroke. A total of 19 patients were included, 13 received TCD ultrasound and 6 sham TCD with IV Tenecteplase. TCD spectrum and difference in Pre and post TCD parameters were measured. Asymptomatic hemorrhagic transformation of infarct was seen in two patients. There was no mortality or clinical worsening in the sonothrombolysis group as against sham sonothrombolysis group. Median of peak systolic velocity was increased in both the sonothrombolysis (P = 0.0002) and sham sonothrombolysis group (P-value = 0.001). The difference in change in mean flow velocity between two groups, sonothrombolysis (11 cm/sec) and sham sonothrombolysis (3.5 cm/sec) were also significantly different (P = 0.014). This pilot work has established safety of continuous 30 min TCD application along with IV Tenecteplase thrombolysis and it concludes that concomitant 2 MHz TCD ultrasound administration significantly increased the MCA blood flow compared to chemothrombolysis alone.CTRI Registered Number: CTRI/2021/02/031418.

Somatosensory evoked potentials amplitude is enhanced after non-invasive brain stimulation in chronic ischemic stroke: Preliminary results from a randomised control trial.

OBJECTIVE: To investigate the effects of transcranial electrical and magnetic non-invasive brain stimulation (NIBS) protocols on somatosensory evoked potential (SEP) in chronic ischemic stroke. METHODS: 33 patients were randomly assigned to one of the four treatment groups of the transcranial direct current stimulation (tDCS) and/or repetitive transcranial magnetic stimulation (rTMS) protocol. SEP parameters were recorded before and after ten days of the treatment session. All the statistical analyses were carried out using SPSS version 19. RESULTS: It was found that there is a statistically significant improvement in the N20-P22 mean amplitude after treatment sessions in all groups except the group where tDCS and rTMS groups were sham. On paired t-tests, the difference betweeen post and pre-stimulation SEP amplitudes for the real tDCS and real rTMS coupled group was 1.045 ± 0.732 (p value = 0.005). For sham tDCS+real rTMS group, 1.05 ± 0.96 (P = 0.04); for real tDCS+sham rTMS 0.543 ± 0.332 (P = 0.01) and for double sham stimulation, 0.204 ± 0.648 (P =  0.4) respectively CONCLUSION: In ischemic stroke patients, either or coupled true transcranial tDCS and rTMS was found to be safe and significantly enhanced the amplitude of cortical somatosensory potentials when combined with standard physiotherapy, in the interim analysis of an ongoing randomised controlled trial. CLINICAL TRIAL REGISTRY OF INDIA: CTRI/2019/11/022009 SIGNIFICANCE: The results of this research indicates the importance of RCTs in developing robust improved NIBS protocols coupled to physiotherapy to enhance the sensory-motor functional recovery following ischemic stroke.

Impact of CYP2C9*2 and *3 polymorphisms on valproate-associated adverse drug reactions in individuals living with epilepsy: a case-control study.

Epilepsy is characterized by repeated seizure activity. Valproate, a commonly used antiepileptic drug, shows large inter-individual variation in plasma valproic levels and causes many adverse drug reactions. Aim: To find the influence of CYP2C9*2 and *3 polymorphisms on valproate-associated adverse drug reactions and plasma valproic acid levels in people with epilepsy. Methods: We recruited 158 people with epilepsy (79 cases and 79 controls) from an epilepsy clinic. Steady-state plasma valproic acid levels were measured using liquid chromatography-mass spectrometry and genotyping of CYP2C9 variants was carried out with helps of RT-PCR. Results: The presence of a mutant heterozygous genotype showed an odds ratio (OR) of 2.82 (95% CI: 1.10-7.24) and the adjusted OR was 5.39 (95% CI: 1.69-17.16). There was no significant difference in steady-state plasma valproate concentration between genotypes. Conclusion: The presence of a mutant heterozygous CYP2C9 genotype possesses five-times the risk of developing adverse drug reactions to valproate in people with epilepsy.

Ayurvedic Treatment in the Rehabilitation of Ischemic Stroke Patients in India: A Randomized Controlled Trial Study Protocol.

In patients with ischemic stroke, motor and sensory impairments are common and are associated with functional disability. Conventional physiotherapy (CP) is the primary modality of rehabilitation for post-stroke sensorimotor dysfunction. Ayurveda is a commonly practiced alternative system of medicine that offers unique rehabilitative measures for post-stroke recovery. We hypothesize that Ayurvedic rehabilitative treatment (ART) is superior to similar duration CP in improving the sensorimotor recovery of patients with ischemic stroke at 90 days after enrollment. AyuRvedic TrEatment in the Rehabilitation of Ischemic STrOke Patients in India: A Randomized controllEd trial (RESTORE) is an investigator-initiated, multicenter, prospective, randomized, controlled, parallel-arm, blinded outcome assessment trial being conducted under the Indian Stroke Clinical Trial (INSTRuCT) Network across the four comprehensive stroke centers in India. Consecutive hemodynamically stable adult patients with their first acute ischemic stroke between 1 and 3 months from stroke onset are being randomized (1:1) into two treatment groups to receive either 1 month of ART or 1 month of CP. The primary outcome measure is the Fugl Meyer Assessment-upper extremity for physical performance at 90 days. The secondary outcomes are the modified Rankin Scale, Barthel Index, Berg Balance, and SF-36 at 90 days. The safety outcomes include a composite of irreversible morbidity and mortality. A sample size of 140 (70 in each group) patients with ischemic stroke will allow us to detect a minimal clinical important difference of 9.4 (standard deviation) with superiority margin of 5, an attrition rate of 10%, alpha of 5%, and power of 80%. This randomized trial will systematically assess the efficacy and safety of traditional ART compared to CP. The trial has been registered in the Clinical Trial Registry India (CTRI/2018/04/013379).

Exosome therapies improve outcome in rodents with ischemic stroke; meta-analysis.

OBJECTIVE: Exosome therapy has been theorized to be safer, more effective, and less cumbersome in replacing stem cell therapies for tissue repair and regeneration. There remains considerable uncertainty on whether exosome therapy is efficacious and safe for recovery from brain injury due to cerebral infarction. There is growing consensus that systematic reviews of data, from preclinical studies which yielded conflicting and confusing results, can provide valuable directions for novel therapeutic options for several clinical conditions. This study systematically evaluated the efficacy of exosome therapy in ischemic stroke in preclinical studies in rodent models. METHODS: We reviewed existing literature on exosome therapy in rodent stroke models from various databases, and reviewed the interventional measures, and outcome measures systematically, with changes in the infarct volume and functional scores as outcome parameters. Seventeen homogeneous studies were found qualitatively acceptable for meta-analysis. The study used software RevMan 5.3 to conduct the meta-analysis (PROSPERO Register Number: CRD42022314138) RESULTS: Compared to placebo, exosomes treated ischemic stroke models showed significantly reduced brain infarct volume and improved functional recovery on days 7 and 28. Though there are no safety concerns reported in any preclinical studies, there is insufficient data to make robust conclusions on the therapy's safety. INTERPRETATION: Therapy with subcellular exosomes is a promising treatment to be explored further in animal ischemic stroke models to arrive at robust conclusions for its safety and therapeutic dosage. This must precede Phase I and II- human randomized clinical trials to establish the safety and proof of concept of efficacy of exosome therapy in human ischemic stroke.

Clinicoradiological Profile of Incomplete Hippocampal Inversion Diagnosed on MR Neuroimaging.

Background and Purpose: Incomplete hippocampal inversion (IHI) is a developmental failure of normal hippocampal inversion. Previous studies have described IHI in epilepsy and non-epilepsy subjects. IHI has also been reported with malformations of cortical development (MCDs) and corpus callosal agenesis that have association with neuropsychiatric disorders such as autism spectrum disorder (ASD). This study aims to describe the clinical profile of magnetic resonance imaging (MRI)-diagnosed IHI. Materials and Methods: We studied patients with IHI who were identified after a retrospective review of the MRI archives of the past 3 years. The MRI findings of partial and total IHI were included. The clinical profiles associated with IHI were classified into epilepsy and non-epilepsy categories. Results: A retrospective review of MRI done over 3 years revealed 54 cases of IHI (32 left-sided, 20 bilateral, and 2 isolated right-sided), and out of 74 IHI, 59 were of total type and 15 partial. Thirty-six subjects (61.1%) had epilepsy (9 with neurodevelopmental problems), 17 subjects (31.5%) had ASD, and 4 subjects (7.4%) had only neurodevelopmental disorders. MCDs were seen in 7 (12.9%): polymicrogyria (4), periventricular heterotopia (2), and pachygyria (1). Hippocampal volume loss was seen in 10, and contralateral mesial temporal sclerosis was seen in 2 patients. Conclusion: Hippocampal inversion has been reported in MRI scans of patients with epilepsy, ASD, MCDs, and many other related disorders. Further studies are required to know its occurrence among patients who get MRI scans due to many other disorders such as headaches, psychiatric disorders, minor hear trauma, and perinatal insults. If possible, studies among normal populations also need to be done.

Endovascular thrombectomy and intravenous alteplase in patients with acute ischemic stroke due to large vessel occlusion: A clinical practice guideline.

AIM: Whether or not use of intravenous alteplase in combination with endovascular thrombectomy (EVT) improves outcomes versus EVT alone, for acute stroke patients with large vessel occlusion presenting directly to a comprehensive stroke center, is uncertain. METHODS: Six randomized trials exploring this issue were published, and we synthesized this evidence to inform a rapid guideline based on the Guidelines International Network principles and guided by the GRADE approach. RESULTS: We enlisted an international panel that included 4 patient partners and 1 caregiver, individuals from 6 countries. The panel considered low certainty evidence that EVT alone, relative to EVT with intravenous alteplase, possibly results in a small decrease in the proportion of patients that achieve functional independence and possibly a small increase in mortality. Both effect estimates were downgraded twice due to very serious imprecision. The panel also considered moderate certainty evidence that EVT alone probably decreases symptomatic intracranial hemorrhage, versus EVT with alteplase, and combination therapy was more costly than EVT alone. As a result of the low certainty for improved recovery without impairment and mortality for combination therapy versus EVT alone, and moderate certainty for increased harm with combination therapy, the panel made a weak recommendation in favor of EVT alone for stroke patients eligible for both treatments, and initially presenting directly to a comprehensive stroke center that provides both treatments. CONCLUSIONS: Consistent with this weak recommendation, optimal patient management will likely often include co-treatment with intravenous alteplase, depending on local circumstances and patient presentation.

Short-term Effect of Noninvasive Brain Stimulation Techniques on Motor Impairment in Chronic Ischemic Stroke: A Systematic Review with Meta-Analysis.

Background: In recent years, noninvasive brain stimulation (NIBS) has shown promise for stroke rehabilitation as a novel nonpharmaceutical neuromodulatory intervention with attractive neurophysiological theories backing it up. Objective: To find out the short-term effects of NIBS techniques on motor impairment in chronic ischemic stroke. Materials and Methods: A systematic review with meta-analysis was performed separately for transcranial direct current stimulation (tDCS), transcranial magnetic stimulation (TMS), and studies that combined both, utilizing various databases for a period spanning from 2001 to 2019. Good-quality randomized controlled trials (RCTs) on chronic ischemic stroke cases with homogeneous clinical upper motor short-term outcome measures were considered for the meta-analysis. RevMan 5.1 software was used for the meta-analysis. Meta-analysis registration: CRD42021196299; https://www.crd.york.ac.uk/PROSPERO. Results: A total of 319 studies were identified initially. After necessary filters to comply with the strict recruitment criteria, only four studies qualified, two each for tDCS and TMS and none qualified for analysis under the combined category. tDCS showed a nonsignificant effect on the upper limb motor function improvement (-0.10 [95% confidence interval {CI}: -0.84 to 0.64; I2 0%; P = 0.8]), whereas the repetitive TMS showed a significant effect (0.75 [95% CI: 0.03-1.48; I2 0%; P = 0.04]). The safety analysis did not reveal any major concerns for several published protocols. Conclusions: tDCS alone did not significantly benefit motor recovery; rTMS was effective in providing immediate functional benefits in chronic ischemic stroke. While the current stroke rehabilitation protocols with NIBS appear safe, more good-quality stratified RCTs with more innovative experimental protocols are needed to analyze and quantify the efficacy of these techniques in stroke rehabilitation.

A telephonic survey of health-related quality of life of outpatient department dropout Parkinson's disease patients during the COVID-19 pandemic.

INTRODUCTION: COVID-19 pandemic has severely jeopardized world health care. The most affected population is of elderly and patients with chronic diseases. The current study aims to investigate the health-related quality of life of Parkinson's disease outpatient dropout patients. METHODS: In this cross-sectional telephonic observational study, we investigated the demographic features and quality of life of Idiopathic PD patients (cases) attending neurology clinics during the pre-COVID-19 pandemic for at least 6 months and dropped out after that. We then compared them with their matched controls, who started visiting clinics once the OPD began functioning again. We used the European quality of life (EQ-5Q-5D) scale to assess health-related quality of life (HRQOL). RESULTS: We recruited 31 PD patients and their 42 matched controls. 90.3% of cases reported worsening PD symptoms, and 83.8% were unable to visit a doctor despite the need. The slowness of activities, increase in tremors, and sleep disturbances were the common complaints. 26% of the patients had difficulty procuring the medicines. EQ-5D-5L and Visual analog scale scores were significantly lower in cases versus controls with between mean group difference of - 0.2837 (p < 0.001, 95% CI - 0.4269 to - 0.1377) and - 21.985 (p < 0.001, 95% CI - 31.8 to - 12.1), respectively, depicting the poor quality of life of cases. CONCLUSION: There is a significant worsening of disease status and HRQOL of PD patients not attending OPD, which needs urgent interventions. There is an unmet need to actively track these patients and address their issues to provide holistic health care.

Neuropsychiatric Features, Health-Related Quality of Life, and Caregiver Burden in Parkinson's Disease.

Aim: Parkinson's disease (PD) is a progressive neurodegenerative disease and significantly impacts patients and their caregivers. The current study aims at recognizing its neuropsychiatric symptoms, its impact on the health-related quality of life (HRQOL) of the patients, and the caregiver burden in a middle- to-low-income country. Methods: We conducted a cross-sectional survey of 73 idiopathic Parkinson's disease (IPD) patients and their caregivers from January 2021 to June 2021. Neuropsychiatric Inventory (NPI-12) and Parkinson's disease questionnaire (PDQ-39) were used to assess patients' symptoms and HRQOL, respectively. We used the Zarit caregiver burden interview (ZBI) and Hamilton depression scale (Ham-D) for the caregiver's burden assessment. Results: Of the 73 patients, 43 (59%) were men, and 30 (41%) were women. Their mean age was 60.25 years (± 11.1), and the mean duration of PD was 6.4 years (± 3.4). Eighty-six percent of the patients reported having one or more neuropsychiatric symptoms. HRQOL, as indicated by PDQ-39, correlated most significantly with H and Y staging (r = 0.680, P < 0.001) of the disease. Sixty-eight percent of the caregivers felt a disease burden, and 55% had depression. On regression analysis, NPI total score on caregiver burden (beta = 0.883, P < 0.001, confidence interval [CI] of 1.087 to 1.400,) and H and Y staging on depression (beta = 0.772, P < 0.001, [CI of 0.629 to 0.934) were having the most decisive impact. Conclusion: Our study showed the presence of frequent neuropsychiatric symptoms in PD patients. It has a detrimental effect on the quality of life of patients and results in a significant increase in caregiver burden and depression among them.

Glaucoma and optical coherence tomography changes in migraine: A comparative cross-sectional study.

PURPOSE: To study the prevalence of glaucoma among adults with migraine and the effect of migraine on peripapillary retinal nerve fiber layer (pRNFL) and central macular thickness (CMT) using optical coherence tomography (OCT) compared to those without migraine headache, i.e. in tension-type headache (TTH) and normal group. METHODS: One hundred and eleven patients (222 eyes) were recruited in three groups. migraine, TTH, and normal subjects visiting hospital outpatient services. After noting demographic details and pertinent history, ophthalmological evaluation including optic disc for glaucomatous changes along with computerized visual field testing and OCT for pRNFL thickness and CMT was performed in all eyes. Continuous variables were compared using ANOVA or Kruskal-Wallis test, while categorical variables including the association of glaucoma with migraine were analyzed using Chi-square or Fisher's exact test. RESULTS: Prevalence of glaucoma in migraine group (12.2%) was more than in comparison groups (6.8% in TTH, 4.1% in normal) which was however not significant (Fisher's exact P = 0.207). Average pRNFL thickness (103.59 ± 12.82 µm) and thickness in nasal (90.49 ± 19.19 µm) and temporal quadrants (70.58 ± 16.13 µm) and CMT (213.78 ± 19.81 µm) were significantly reduced (ANOVA P < 0.05) in migraine patients when compared to the other groups and this was independent of the presence of glaucoma. CONCLUSION: Prevalence of glaucoma is not significantly higher in migraine patients. However, migraine causes thinning of retinal layers on OCT that is statistically significant.

CYP2C19 & UGT1A6 genetic polymorphisms and the impact on Valproic acid-induced weight gain in people with epilepsy: Prospective genetic association study.

OBJECTIVES: To study the association between CYP2C19*2 (681 G > A) and UGT1A6*2 (552A > C) polymorphisms on Valproic acid (VPA)-induced weight gain in People with epilepsy (PWE). METHODS: We recruited PWE on VPA monotherapy and genotyped for CYP2C19 and UGT1A6 polymorphisms. Association between CYP2C19 polymorphism and weight gain was the primary outcome parameter. We followed them up monthly for six months and recorded Body mass index (BMI), drug compliance, side effects, food frequency, physical activity. RESULTS: Of 108 participants recruited, we assessed the association between the polymorphism and weight gain in 101 PWE for CYP2C19*2 and 103 PWE for UGT1A6*2 polymorphism. The proportion of participants with weight gain was higher in those with poor and intermediate metabolizer genotypes of CYP2C19 (*1/*2 and *2/*2) compared to extensive metabolizers (*1/*1) [53.3 % vs 31.7 %, RR 1.68, 95 % CI (1.01-2.79), P = 0.03]. However, CYP2C19*2 allele did not show an increased risk of weight gain over the CYP2C19*1 allele. No association could be demonstrated with UGT1A6 genotypes and weight gain. In logistic regression analysis, CYP2C19*2 carrier genotype was the independent predictor of weight gain. OR 2.89 [95% CI (1.07-7.84)]. There were no significant association with serum TSH, fT4, testosterone, and valproate levels with CYP2C19 or UGT1A6 polymorphisms. SIGNIFICANCE: People with epilepsy carrying CYP2C19 polymorphisms (*1/*2) and (*2/*2) had 3 times higher risk of VPA-induced weight gain compared to wild type (*1/*1).

Evaluation of White Matter Tracts Fractional Anisotropy Using Tract-Based Spatial Statistics and Its correlation with Amyotrophic Lateral Sclerosis Functional Rating Scale Score in Patients with Motor Neuron Disease.

Background Motor neuron diseases cause progressive degeneration of upper and lower motor neurons. No Indian studies are available on diffusion tensor imaging (DTI) findings in these patients. Aims This study was done to identify white matter tracts that have reduced fractional anisotropy (FA) in motor neuron disease (MND) patients using tract-based spatial statistics and to correlate FA values with Amyotrophic Lateral Sclerosis Functional Rating Scale (ALSFRS-R) score. Settings and Design A case-control study in a tertiary care hospital. Materials and Methods We did DTI sequence (20 gradient directions, b -value 1,000) in 15 MND patients (10 men and 5 women; mean age: 46.5 ± 16.5 years; 11 amyotrophic lateral sclerosis [ALS], 2 monomelic amyotrophy, 1 progressive muscular atrophy, and 1 bulbar ALS) and 15 age- and sex-matched controls. The data set from each subject was postprocessed using FSL downloaded from the FMRIB Software Library, Oxford, United Kingdom (http://www.fmrib.ox.ac.uk/fsl). Statistical Analysis The statistical permutation tool "randomize" with 5,000 permutations was used to identify voxels that were different between the patient data set and the control data set. Mean FA values of these voxels were obtained separately for each tract as per "JHU white-matter tractography atlas." SPSS was used to look to correlate tract-wise mean FA value with ALSFRS-R score. Results We found clusters of reduced FA values in multiple tracts in the brain of patients with MND. Receiver operating characteristic curves plotted for individual tracts, showed that bilateral corticospinal tract, bilateral anterior thalamic radiation, bilateral uncinate fasciculus, and right superior longitudinal fasciculus were the best discriminators (area under the curve > 0.8, p < 0.01). FA values did not correlate with ALFRS-R severity score. Conclusion In MND patients, not only the motor tracts, but several nonmotor association tracts are additionally affected, reflecting nonmotor pathological processes in ALS.

Zonisamide in Parkinson's disease: a current update.

Parkinson's disease (PD) is a progressive neurodegenerative disease due to the depletion of the neurotransmitter dopamine in basal ganglia. There is a scarcity of available therapies for motor and non-motor symptoms of PD. Zonisamide (ZNS) may be one such potential candidate to alleviate PD symptoms. It was serendipitously found to be useful for PD in a patient with both epilepsy and PD. Since then, there have been many clinical trials, case series, observational studies, and case reports published supporting the efficacy of ZNS in PD. This review focuses on the efficacy and usefulness of ZNS in various motor and non-motor symptoms of PD. A predefined inclusion and exclusion criteria were used for the search protocol and databases searched were PubMed, Cochrane Library, Ovid, and clinicaltrials.gov. Most of the randomized clinical trials used UPDRS III as the primary efficacy point and showed positive results favouring ZNS. This review shows that there is evidence of the efficacy of ZNS in motor symptoms as an adjunctive therapy to levodopa, but for non-motor symptoms, the evidence is lacking and needs further investigation.

INSTRuCT: Protocol, Infrastructure, and Governance.

Background and Purpose: Very few large scale multicentric stroke clinical trials have been done in India. The Indian Council of Medical Research funded INSTRuCT (Indian Stroke Clinical Trial Network) as a task force project with the objectives to establish a state-of-the-art stroke clinical trial network and to conduct pharmacological and nonpharmacological stroke clinical trials relevant to the nation and globally. The purpose of the article is to enumerate the structure of multicentric stroke network, with emphasis on its scope, challenges and expectations in India. Methods: Multiple expert group meetings were conducted by Indian Council of Medical Research to understand the scope of network to perform stroke clinical trials in the country. Established stroke centers with annual volume of 200 patients with stroke with prior experience of conducting clinical trials were included. Central coordinating center, standard operating procedures, data and safety monitoring board were formed. Discussion: In first phase, 2 trials were initiated namely, SPRINT (Secondary Prevention by Structured Semi-Interactive Stroke Prevention Package in India) and Ayurveda treatment in the rehabilitation of patients with ischemic stroke in India (RESTORE [Rehabilitation of Ischemic stroke Patients in India: A Randomized controlled trial]). In second phase, 4 trials have been approved. SPRINT trial was the first to be initiated. SPRINT trial randomized first patient on April 28, 2018; recruited 3048 patients with an average of 128.5 per month so far. The first follow-up was completed on May 27, 2019. RESTORE trial randomized first patient on May 22, 2019; recruited 49 patients with an average of 3.7 per month so far. The first follow-up was completed on August 30, 2019. Conclusions: In next 5 years, INSTRuCT will be able to complete high-quality large scale stroke trials which are relevant globally. REGISTRATION: URL: http://www.ctri.nic.in/; Unique Identifier: CTRI/2017/05/008507.