Ashu Bhasin

Autologous Mesenchymal Stem Cells in Chronic Stroke

Background: Cell transplantation is a ‘hype and hope’ in the current scenario. It is in the early stage of development with promises to restore function in chronic diseases. Mesenchymal stem cell (MSC) transplantation in stroke patients has shown significant improvement by reducing clinical and functional deficits. They are feasible and multipotent and have homing characteristics. This study evaluates the safety, feasibility and efficacy of autologous MSC transplantation in patients with chronic stroke using clinical scores and functional imaging (blood oxygen level-dependent and diffusion tensor imaging techniques). Methods: Twelve chronic stroke patients were recruited; inclusion criteria were stroke lasting 3 months to 1 year, motor strength of hand muscles of at least 2, and NIHSS of 4–15, and patients had to be conscious and able to comprehend. Fugl Meyer (FM), modified Barthel index (mBI), MRC, Ashworth tone grade scale scores and functional imaging scans were assessed at baseline, and after 8 and 24 weeks. Bone marrow was aspirated under aseptic conditions and expansion of MSC took 3 weeks with animal serum-free media (Stem Pro SFM). Six patients were administered a mean of 50–60 × 106 cells i.v. followed by 8 weeks of physiotherapy. Six patients served as controls. This was a non-randomized experimental controlled trial. Results: Clinical and radiological scanning was normal for the stem cell group patients. There was no mortality or cell-related adverse reaction. The laboratory tests on days 1, 3, 5 and 7 were also normal in the MSC group till the last follow-up. The FM and mBI showed a modest increase in the stem cell group compared to controls. There was an increased number of cluster activation of Brodmann areas BA 4 and BA 6 after stem cell infusion compared to controls, indicating neural plasticity. Conclusion: MSC therapy aiming to restore function in stroke is safe and feasible. Further randomized controlled trials are needed to evaluate its efficacy.

Efficacy of minocycline in acute ischemic stroke: A single-blinded, placebo-controlled trial

BACKGROUND Minocycline is a semisynthetic derivative of the tetracycline group of antibiotics, which have neuroprotective effects. In animal stroke models, minocycline had shown promising evidence to improve clinical and functional outcomes. OBJECTIVE To analyze the effect of oral minocycline in acute ischemic stroke patients. MATERIALS AND METHODS This was a randomized single-blinded open-label study. The study group received oral minocycline 200 mg/day for 5 days and the control group received oral vitamin B capsules. Baseline assessment included the following: National Institute of Health Stroke Scale (NIHSS) score, modified Barthel Index (mBI), modified Rankin Scale (mRS) score, Magnetic Resonance Imaging (MRI) of brain including Diffusion Weighted Imaging (DWI), chest X-ray, and routine laboratory investigations. The clinical scales were repeated at days 1, 7, and 30. The end point was outcomes at 3 months (90 days). Statistical analysis was done with SPSS 11.5 (P<0.05). Paired t-test and multiple-measures Analysis Of Variance (ANOVA) were used. RESULTS Fifty patients with acute ischemic stroke were included in the study. Of these, 23 patients received minocycline and 27 patients received placebo i.e., vitamin B capsules. NIHSS score in patients receiving minocycline had shown statistically significant improvement at day 30 and 90 as compared with the controls. Similarly, mRS scores and BI showed significant improvement in patients receiving minocycline at three months as compared to the control group. No mortality, myocardial infarctions, recurrent strokes, and hemorrhagic transformations were noted in both groups. CONCLUSIONS Patients with acute ischemic stroke had significantly better outcome with minocycline treatment as compared with those administered placebo. The above findings suggest that minocycline can be helpful in reducing the clinical deficits after acute ischemic stroke.

Normobaric oxygen therapy in acute ischemic stroke: A pilot study in Indian patients

Purpose: Clinical and radiological assessment of effects of normobaric high-flow oxygen therapy in patients with acute ischemic stroke (AIS). Materials and Methods: Patients with anterior circulation ischemic strokes presenting within 12 h of onset, ineligible for intravenous thrombolysis, an National Institute of Health Stroke Scale (NIHSS) score of >4, a mean transit time (MTT) lesion larger than diffusion-weighted image (DWI) (perfusiondiffusion mismatch), and an evidence of cortical hypoperfusion on magnetic resonance imaging (MRI) were included into the trial. Active chronic obstructive pulmonary disease (COPD), requirement of >3/L min oxygen delivery to maintain SaO2 > 95%, rapidly improving neurological deficits, pregnancy, contraindications to MRI, or unstable medical conditions were excluded. The experimental group received humidified oxygen at flow rates of 10 L/min for 12 h. The NIHSS, modified Rankin Score (mRS), Barthel Index (BI) were measured at 0, 1, 7 day of admission and at 3 months follow-up. MRI with DWI/PWI was performed at admission, 24 h later and at 3 months follow-up. Results: Of 40 patients (mean age = 55.8 years ± 13.2) (range, 26–82), 20 patients were randomized to normobaric oxygen (NBO). The mean NIHSS in NBO and control groups were 14.25 and 12.7 at admission which decreased to 11.6 and 9.5 on the seventh day, and 9.4 and 9.05 at 3 months, respectively. The mean mRS (3.7/3.7) and BI (58.2/53.9) in NBO and control groups improved to 2/2.2 and 73.05/73.8 at the end of 3 months, respectively. Conclusions: NBO did not improve the clinical scores of stroke outcome in Indian patients with AIS.

Design of adaptive haptic-enabled virtual reality based system for upper limb movement disorders: A Usability Study

Neurological disorders are major cause of global disease burden. They often impair hand function, a critical element of our day-to-day activities of daily living. Conventional rehabilitation techniques aim to improve ones ability to use affected limbs which are tailored to individual capabilities (performance and stress level) by clinicians based on the patients health and progress in skill. However, in developing countries, like India with increasing healthcare costs for availing specialized services, patients are often discharged sooner than required from healthcare units following stroke. Additionally, the situation becomes critical with limited availability of trained healthcare resources. Thus design of intelligent home-based technology-assisted individualized rehabilitation platform with real-time feedback with monitored skill progress is essential. In our present research, we have designed a Virtual Reality (VR) based haptic-enabled Physiologically Aided (PA) Rehabilitation System for patients with upper limb movement disorders. Additionally, we have made a comparative analysis of our PA system with Performance Sensitive (PS) system while offering tasks of varying difficulty levels along with audio-visual feedback. We have designed a Usability Study as proof-of-concept application where we have focused on the patients shoulder abduction and adduction exercise. The preliminary results of our study are promising. This shows that our system can be a step towards designing a VR-based technology-assisted rehabilitation platform for stroke patients with a potential to address at least some of the issues associated with upper limb movement disorders.

Paracrine Mechanisms of Intravenous Bone Marrow-Derived Mononuclear Stem Cells in Chronic Ischemic Stroke.

Background: The emerging role of stem cell technology and transplantation has helped scientists to study their potential role in neural repair and regeneration. The fate of stem cells is determined by their niche, consisting of surrounding cells and the secreted trophic growth factors. This interim report evaluates the safety, feasibility and efficacy (if any) of bone marrow-derived mononuclear stem cells (BM-MNC) in chronic ischemic stroke by studying the release of serum vascular endothelial growth factor (VEGF) and brain-derived neurotrophic growth factor (BDNF). Methods: Twenty stroke patients and 20 age-matched healthy controls were recruited with the following inclusion criteria: 3 months to 1.5 years from the index event, Medical Research Council (MRC) grade of hand muscles of at least 2, Brunnstrom stage 2-5, conscious, and comprehendible. They were randomized to one group receiving autologous BM-MNC (mean 60-70 million) and to another group receiving saline infusion (placebo). All patients were administered a neuromotor rehabilitation regime for 8 weeks. Clinical assessments [Fugl Meyer scale (FM), modified Barthel index (mBI), MRC grade, Ashworth tone scale] were carried out and serum VEGF and BDNF levels were assessed at baseline and at 8 weeks. Results: No serious adverse events were observed during the study. There was no statistically significant clinical improvement between the groups (FM: 95% CI 15.2-5.35, p = 0.25; mBI: 95% CI 14.3-4.5, p = 0.31). VEGF and BDNF expression was found to be greater in group 1 compared to group 2 (VEGF: 442.1 vs. 400.3 pg/ml, p = 0.67; BDNF: 21.3 vs. 19.5 ng/ml) without any statistically significant difference. Conclusion: Autologous mononuclear stem cell infusion is safe and tolerable by chronic ischemic stroke patients. The released growth factors (VEGF and BDNF) in the microenvironment could be due to the paracrine hypothesis of stem cell niche and neurorehabilitation regime.

Restorative Therapy in Stroke

A variety of therapeutic approaches that could be considered neurorestorative are currently in clinical trials after stroke. There are essentially two varieties of restorative approaches. One is cell-based and includes stem cell transplantation with and without augmentation with growth factors and other variety is the pharmacological approach. These strategies are being explored for the ultimate aim to regain maximum restoration possible and eventual complete normalcy of function. Functional recovery post stroke may require new synaptic connections within and away from the damaged tissue. In an infracted area, the ischemic core may not respond to any pharmacological or rehabilitative intervention. For these reasons, the prospects of repairing the neuron system, using various putative restorative strategies seems promising and urgently required for further exploration, refinement and optimization. Ongoing animal and human trials have largely helped in burgeoning our hopes on this method of restorative therapy after stroke.

High sensitive C-reactive protein and interleukin 6 in atrial fibrillation with rheumatic mitral stenosis from Indian cohort

Introduction Presence of chronic low grade inflammation has often been implicated in the etiology of atrial fibrillation (AF). Whether pre-existing inflammatory state promotes AF or initiation of AF activates inflammation is a dilemma among clinicians. This study investigates the role of high sensitive C reactive protein (hs-CRP) and interleukin 6 (IL-6) in AF with rheumatic mitral stenosis (Rh-MS) as markers of chronic inflammation. Methods This case control cohort included sixty five (n = 65) Rh-MS patients having other valve lesions as trivial to mild. Out of them twenty nine (n = 29; group C) had baseline AF and rest were normal sinus rhythm (NSR). A 24 h holter recording was done in NSR patients to diagnose paroxysmal AF/tachyarrhythmia forming group B (n = 12) and not having any tachyarrhythmia were designated as NSR; group A (n = 24). Results hs-CRP and IL6 showed statistically significant increase in group C (permanent AF) compared to group A (95% CI: 4.2–0.9, p = 0.007; 95% CI: 1.2–0.89; p = 0.05 respectively), while it was non significant between group A and group B (p > 0.05). A weak positive correlation was observed with hs-CRP and left atrial volume index (LAVi) (r = 0.45, p = 0.06) in AF group as compared to NSR group. 68.2% of patients in AF group (27/41) had moderate to severe spontaneous echo contrast (SEC) as compared to 37.5% (10/24) in NSR group. Conclusion Increased hs-CRP and IL-6 levels in the paroxysmal and permanent AF group may favour the hypothesis that low grade chronic inflammation could be the cause of atrial fibrillation than a consequence.

An intelligent, adaptive, performance‐sensitive, and virtual reality‐based gaming platform for the upper limb

Stroke is a leading cause of adult disability, characterized by a spectrum of muscle weakness and movement abnormalities related to the upper limb. About 80% of individuals who had a stroke suffer from upper limb dysfunction. Conventional rehabilitation aims to improve ones ability to use paralyzed limbs through repetitive exercise under one‐on‐one supervision by physiotherapists. This poses difficulty given the limited availability of healthcare resources and the high cost of availing specialized services at healthcare centers, particularly in developing countries like India. Thus, the design of cost‐effective, home‐based, and technology‐assisted individualized rehabilitation platform that can deliver real‐time feedback on ones skill progress is critical. This paper describes the design of a novel, multimodal, virtual reality (VR)‐based, and performance‐sensitive exercise platform that can intelligently adapt its task presentation to ones performance. Here, we aim to address unilateral shoulder abduction and adduction that are essential for the performance of daily living activities. We designed an experimental study in which six individuals who had chronic stroke (post‐stroke period: >6 months) participated. While they interacted with our VR‐based tasks, we recorded their physiological signals in a synchronized manner. Preliminary results indicate the potential of our VR‐based, adaptive individualized system in the performance of individuals who had a stroke suffering from upper limb movement disorders.

Comparison of Constraint Induced Movement Therapy and Neuromuscular Electrical Simulation on Clinical Outcomes in Chronic Stroke

Background and Purpose: Stroke is a leading cause of functional impairment. A wide range of therapeutic techniques for post stroke rehabilitation exist, however methodology, cost and modes of action vary and no evidence based guidelines exist for their use. A direct comparison of these techniques would help in the development of the same. In this study, we compare the disability outcomes of Constraint Induced Movement Therapy (CIMT) and Neuromuscular Electrical Stimulation (NMES) in chronic stroke. Methods: It was a prospective non-randomized clinical trial. One hundred twenty six patients who met the inclusion criteria were alternatively assigned to either the CIMT group (n=63) or the NMES group (n=63). Both therapies were given for 8 weeks duration. Patients were assessed using Modified Rankin Scale (mRS), Barthel Index(BI), Fugl-Meyer Scale(FMA) and Motor Assessment Scale at baseline and at two and four month of treatment. Results: Both CIMT and NMES groups showed significant improvement from baseline (p<0.001). The CIMT group showed catch up improvement in BI (p<0.001) and FMA scales (p<0.001) at the two month follow up visit. At the four month follow up visit, there was no significant difference in scores between the groups across all scales. Conclusion: CIMT and NMES are effective techniques for post stroke rehabilitation. Although CIMT may show a greater improvement in initial stages, there is no difference in clinical outcomes at a later stage. KeywordsStroke, Rehabilitation, Constraint Induced Movement Therapy, Neuromuscular Electrical Stimulation

Review-Stem Cells in Neurological Diseases:Indian Perspective

Stem cell therapy is under investigation in neurological diseases with currently sub optimal or no treatment available. They are hypothesized to produce new cells, or act as “chaperones or scaffolds” to repair and reconstruct neuronal circuitry and release the relevant neurotransmitters for ultimate functional improvement in the individual. They have the potential either to divide or multiply or differentiate into one or more cell type, usually in response to some kind of signal. In recent years, bone marrow derived stem cells have been successfully exploited as neurorestorative tool to augment brain recovery. In this review we have discussed the types and sources of stem cells, notable clinical studies published and ongoing trials in India involving Stroke, Parkinson’s disease, Spinal cord injury, ALS, Multiple Sclerosis etc and discuss the future prospects for more trials. All these studies proved the safety and feasibility of cell transplantation. Steady and focused progress in stem cell research in both preclinical and clinical settings in Indian subcontinent should support the hope for development of cell-based therapies as treatment in near future.