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.

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).

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.

Everyday Abilities Scale for India in Screening for Poststroke Dementia Among Young Stroke Survivors.

INTRODUCTION: Cognitive dysfunction after stroke is an important concern. We explored the utility of everyday abilities scale for India (EASI) for screening for dementia among young stroke survivors. METHODS: We interviewed 150 young stroke survivors and caregivers. Vascular dementia was diagnosed according to American Heart Association-American Stroke Association (ASA-AHA) criteria. EASI was administered to all caregivers. Receiver operating characteristic curve analysis was used to determine the area under the curve and optimum cut-points for EASI for the identification of dementia. RESULTS: Median EASI scores among subjects with dementia (n=35; 23.3%) was 2 (interquartile range: 0-4) and significantly different from those without (median: 0; interquartile range: 0-1; P<0.001). The area under the curve was 0.768 (95% confidence interval: 0.674-0.863), and at the optimum cut-point of 2 on EASI, a sensitivity of 60% and specificity of 91.3% was achieved for the identification of dementia. CONCLUSION: EASI appears to be a promising tool to screen for dementia among young stroke survivors.

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.

Neuropsychiatric symptoms among young stroke survivors-frequency, patterns, and associated factors.

BACKGROUND: Although neuropsychiatric symptoms are reported in stroke survivors, details of its prevalence and patterns among young stroke subjects are sparse. METHODS: In a hospital-based cross-sectional study in India, we recruited 150 young stroke subjects (aged < 45 years) and their caregivers > 3 months from ictus. Neuropsychiatric symptoms were evaluated using the Neuropsychiatric Inventory-12 (NPI-12) and self-reported depression with the Centre for Epidemiological Studies - Depression (CES-D) scale. Descriptive statistics were used. Multivariate analysis was performed to identify associated factors. All statistical analyses were carried out using STATA ver. 14.2, StataCorp, TX, USA. RESULTS: Eighty-four (56%; 95% CI: 47.7-64.1%) had ≥ 1 symptoms on the NPI-12 over median time from stroke of 2 years (IQR 2). Self-reported depression was seen in 71 (47.3%). Post-stroke epilepsy was associated with presence of at least one neuropsychiatric symptom. Dementia was associated with increased odds; and having spouse as principal caregiver with reduced odds, of self-reported depression. Multiple infarcts on imaging were associated with self-reported depression (OR: 3.29; 95%CI: 1.31-8.27) and presence of any neuropsychiatric symptom (OR: 3.55; 95% CI: 1.42-8.88). CONCLUSION: Young stroke survivors frequently have neuropsychiatric symptoms with depression being most common. Presence of multiple infarcts on imaging was associated with self-reported depression and presence of any neuropsychiatric symptom.

COVID-19, Moral Injury and the Bhagvad Gita.

During life challenging times like the present COVID-19 pandemic, the health care worker (HCW) is faced with a number of questions of an existential nature. There is a sense of guilt, anguish, helplessness, uncertainty and powerlessness when one is fighting something on such a powerful scale with limited resources and no definite end in sight. There are circumstances when these feelings can overwhelm a person leading to demoralization and potentially a moral injury. Spiritual practices and advice may help to deal with moral paradoxes and ethical dilemmas when other secular supports are undermined or inaccessible. The Holy Indian Epic, the Bhagvad Gita has described the moral distress of the warrior Arjuna, during the battle of Kurukshetra and the advice given to him by the Lord Krishna the gist of which can be encapsulated in the form of the four Ds- Detachment, Duty, Doer-ship and Dhyana or meditation. In this article, the authors explore how these concepts may be useful aids to the HCW faced with moral and psychological distress.

Comparison of proximal and distal corticosteroid injections for carpal tunnel syndrome.

INTRODUCTION: Evidence for the efficacy of distal corticosteroid injection compared with proximal injection in carpal tunnel syndrome (CTS) is inadequate. METHODS: We conducted a randomized, double-blind noninferiority trial of 131 wrists with CTS. Forty milligrams of methylprednisolone was injected medial to the palmaris longus tendon 2 cm proximal to the wrist crease, or at the volar aspect, 2 to 3 cm distal to the wrist crease. Proximal & distal groups received a placebo. The primary outcome was difference in CTS Symptom Severity Scale (SSS) score at 1 month. Secondary outcome measures included the difference in SSS score at 3 months, Functional Status Scale (FSS) score at 1 and 3 months, and pain of injections. RESULTS: No significant differences were noted between groups in scores on the SSS and FSS. Pain was lower in the proximal group compared with the distal group. DISCUSSION: Corticosteroid injections for CTS distal to the wrist are not inferior to proximal injections, yet they are more painful.

Prevalence and determinants of sleep disorders in a community in rural southern India.

Background: . We assessed the prevalence of sleep disorders among people above 15 years of age from a rural area of Puducherry, south India. Methods: . We did a community-based cross-sectional study among people residing in four service area villages of a rural primary health centre in Puducherry, India. Probability sampling techniques were used to select participants. The Pittsburgh Sleep Quality Index was administered to detect sleep disorders among the participants. The data were entered and analysed using EpiData entry 3.1 and Stata 12 software, respectively. Association between various individual factors and sleep disorders was assessed using generalized linear models adjusting for clustering at the household level and expressed as prevalence ratio with 95% confidence interval (CI). Results: . The mean (SD) age of the 501 participants was 38.3 (15.4) years. Poor quality of sleep was present in 36.3% (95% CI 32.2%-40.6%). In multivariate generalized linear model, age >60 years (adjusted prevalence rate ratio [aPRR] 1.68; 95% CI 1.11-2.53), female sex (aPRR 1.57; 95% CI 1.18-2.08), living in a broken family (aPRR 1.47; 95% CI 1.06-2.02) and having a television in their sleeping room (aPRR 1.40; 95% CI 1.40-1.79) were independently associated with poor quality of sleep. Conclusions: . A high prevalence suggests that sleep disorders are a problem in the rural community too. Capacity building among the existing health workforce to identify and treat sleep disorders and health education activities focusing on sleep hygiene among the general public are needed to tackle sleep disorders in the community.

Progressive multifocal leukoencephalopathy in idiopathic CD4+ lymphocytopenia.

Progressive multifocal leukoencephalopathy is a central nervous system demyelinating disease caused by infection with John Cunningham virus. It affects predominantly the subcortical white matter, producing progressive neurological deficits and large confluent white matter lesions on imaging. It is usually seen in immunodeficient individuals, such as those suffering from acquired immunodeficiency syndrome, those on treatment with monoclonal antibodies, and those following therapeutic bone marrow suppression. Here, we report a rare case of progressive multifocal leukoencephalopathy in an apparently immunocompetent adult, who was found to have idiopathic CD4 lymphocytopenia upon further investigation.

Single nucleotide polymorphism of CYP3A5*3 contributes to clopidogrel resistance in coronary artery disease patients among Tamilian population.

Clopidogrel is an antiplatelet drug. It is used for the treatment as well as for the prophylaxis of coronary artery disease. Clopidogrel resistance is an emerging problem in clinical settings. The aim of the present study was to evaluate the effect of CYP3A5*3 genetic polymorphism on clopidogrel resistance. One hundred and forty-seven patients from outpatient Department of Cardiology on 75 mg/day of clopidogrel as maintenance dose were recruited from April 2010 to July 2011. All subjects gave written informed consent to participate in the study. DNA extraction was performed using phenol chloroform extraction procedure and genotyping by standard Taqman based RT-PCR method. Platelet aggregation was done at the end of 7th and 14th day by using chronolog lumi Aggregometer which is expressed as impedance in ohms. Impedance values of >5 ohms at the end of 6 min were considered as clopidogrel resistance. Subjects (N = 147) were analysed for CYP3A5*3 polymorphism, of which 49 (33%) were found to be clopidogrel resistant. Homomutants of CYP3A5*3 gene had 2.78 (0.97-7.98; p < 0.05) fold risk and heteromutants had 2.4 (0.93-6.46; p < 0.05) fold risk of developing clopidogrel resistance. Carriers of defective allele G of CYP3A5*3 had higher propensity to cause clopidogrel resistance with an odds ratio of 1.63. Variant alleles and genotypes of CYP3A5*3 polymorphism contributed significantly to clopidogrel resistance with a higher odds ratio. Thus, pharmacogenomics paves way for the emergence of stratified medicine in clopidogrel therapy and personalised pharmacotherapy in ischaemic heart disease.

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.

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.

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.

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.