M.V. Padma Srivastava

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.

Management of refractory status epilepticus at a tertiary care centre in a developing country

BACKGROUND Refractory status epilepticus (RSE) is a common Neurological Emergency with increased mortality and morbidity in developing countries where facilities of intubation, adequate ventilation, Intensive Care Units (ICUs) and general anaesthesia are not ubiquitously available. Treatment protocols use antiepileptic drugs (AEDs) and need ICU facilities after failure of standard AEDs. Our aim was to see the response to two additional drugs in the armamentarium against refractory status, that is, valproate and levetiracetam. METHODS Patients with generalized RSE admitted in neurology and neurosurgery services at AIIMS during December 2006 to June 2008 were included in the study. The patients were allotted to two groups based on certain criteria. Demographic details, reason for delay, etiology precipitating status, ongoing AEDs therapy, duration of status, the time taken for cessation along with clinical, EEG and MRI correlates were noted. Outcome parameters were analyzed by an independent blinded observer. RESULTS 82 patients with RSE were studied out of which 41 patients were given IV valproate (Group A) and 41 patients were given IV levetiracetam (Group B). Cessation of status failed in 13 patients in valproate group and 11 patients in levetiracetam group. Majority of the patients did not require ICU settings despite being classified as refractory. CONCLUSION RSE can be controlled with intravenous loading and maintenance of valproate or levetiracetam which do not cause respiratory depression, hypotension, need of intubation and ICU care. These must always be considered in a developing country scenario where ICU facilities are not always available or while transporting to centres where these facilities are available.

Meta-analysis of apolipoprotein E levels in the cerebrospinal fluid of patients with Alzheimer's disease

The possible association between Apolipoprotein E (ApoE) levels in the cerebrospinal fluid (CSF) and Alzheimers disease (AD) has been studied extensively. However, previous findings have been inconsistent. We conducted a meta-analysis of observational studies, seeking to provide insights into ApoEs potential as a biomarker for AD. A systematic literature search of PubMed (MEDLINE), EMBASE, and Web of Science was performed to retrieve relevant studies evaluating ApoE levels in CSF from AD subjects and controls. The association between ApoE levels in the CSF and AD was estimated by the weighted mean difference (WMD) and 95% confidence interval (CI) using a random-effect model. We identified 24 studies that included 1064AD cases and 1338 non-demented controls. Although the pooled WMD did not indicate a significant association between AD and ApoE levels (-0.30mg/l; 95% CI: -0.69 to 0.09; P=0.13), sub-group analysis controlling for patient sample size (n≥43) revealed significantly lower ApoE levels (WMD: -0.66mg/l; 95% CI: -1.02 to -0.31; P=0.0002) among patients with AD than in controls. Publication bias was absent and sensitivity analysis did not result in any significant change in the pooled estimates, indicating highly stable results. The present meta-analysis indicates the potential of CSF ApoE levels as a predictor of AD association.

Risk factors of dementia in North India: a case–control study

Objective: The prevalence of dementia in northern India is among the lowest in the world but reasons are unclear. The aim of the study was to evaluate the risk and protective factors for dementia in North India. Methods: In a case–control study, we investigated demographic, medical, genetic, dietary, lifestyle, and sociocultural protective and risk factors associated with dementia. Results: 150 patients of dementia (118 males and 32 females) and 150 healthy controls (112 males and 38 females) were included in the study. Diabetes, depression, hyperhomocysteinemia, hyperlipidemia, APOE ε4 gene, BMI, use of saturated fatty acids, pickles in diet, urban living, and lack of exercise were associated with independent risk of dementia. Various dietary factors and sociocultural factors, like cognitively stimulating activities, active socialization, living in joint families, increased intake of polyunsaturated fats, fruits, and salads conferred protection against dementia. Conclusions: Dietary, lifestyle, and sociocultural interventions may be protective against dementia.

Translation of Pre-Clinical Studies into Successful Clinical Trials for Alzheimer's Disease: What are the Roadblocks and How Can They Be Overcome?

Preclinical studies are essential for translation to disease treatments and effective use in clinical practice. An undue emphasis on single approaches to Alzheimers disease (AD) appears to have retarded the pace of translation in the field, and there is much frustration in the public about the lack of an effective treatment. We critically reviewed past literature (1990-2014), analyzed numerous data, and discussed key issues at a consensus conference on Brain Ageing and Dementia to identify and overcome roadblocks in studies intended for translation. We highlight various factors that influence the translation of preclinical research and highlight specific preclinical strategies that have failed to demonstrate efficacy in clinical trials. The field has been hindered by the domination of the amyloid hypothesis in AD pathogenesis while the causative pathways in disease pathology are widely considered to be multifactorial. Understanding the causative events and mechanisms in the pathogenesis are equally important for translation. Greater efforts are necessary to fill in the gaps and overcome a variety of confounds in the generation, study design, testing, and evaluation of animal models and the application to future novel anti-dementia drug trials. A greater variety of potential disease mechanisms must be entertained to enhance progress.

Changes in psychiatric comorbidity during early postsurgical period in patients operated for medically refractory epilepsy—A MINI-based follow-up study

PURPOSE The purpose of this study was to assess axis-I DSM-IV psychiatric disorders in patients at baseline and 3 months after surgery for medically refractory temporal lobe epilepsy. METHOD The Mini International Neuropsychiatric Interview (MINI) and Quality of Life in Epilepsy Inventory-10 (QOLIE-10) were evaluated before and 3 months after surgery in 50 consecutive patients (21 females, 29 males) with medically refractory temporal lobe epilepsy (persistent seizures>2/month, despite treatment with ≥2 appropriate drugs in adequate doses for ≥2 years) who underwent surgery [anterior temporal lobectomy with amygdalo-hippocampectomy (for mesial temporal sclerosis in 40), electrocorticography-guided lesionectomy (for other lesions in 10)]. RESULTS Twenty-six patients (52%) had an axis-I psychiatric disorder [26% depressive disorder, 28% anxiety disorder] at baseline, while 30 (60%) patients had an axis-I psychiatric disorder [28% depressive disorder, 28% anxiety disorder] at 3 months after surgery. Twenty percent developed a new psychiatric disorder, while 12% showed improvement postsurgery. Mean QOLIE-10 scores improved from 23.78 to 17.80 [24 (48%) patients showed ≥5-point improvement]. Thirty-four (68%) patients had no seizure, 6 (12%) had non-disabling seizures, while 2 (4%) had disabling seizures after surgery. High frequency of seizures prior to surgery (p<0.038) and seizure occurrence after surgery (p<0.055) predicted the presence of psychiatric disorders after surgery. No clinical characteristic could predict development of new psychiatric disorder after surgery. CONCLUSION Psychiatric dysfunction in the early postsurgery period is seen in nearly half of patients undergoing surgery for temporal lobe epilepsy, is mild in nature, and does not adversely affect quality of life but may cause significant clinical problems when it arises de novo postsurgery.

Validation of diagnostic algorithm to differentiate between tuberculous meningitis and acute bacterial meningitis

BACKGROUND Discrimination between tuberculous and acute bacterial meningitis is difficult by clinical features alone and laboratory methods may only supplement the clinical suspicion. We aimed to validate the diagnostic criteria by Thwaites et al. [1] and construct our own diagnostic predictors based on the clinical and laboratory features. METHODS 380 patients of acute bacterial meningitis (ABM) and 210 patients of tuberculous meningitis (TBM) were enrolled retrospectively from June 2004 to June 2007 and prospectively from July 2007 to September 2008. HIV positive patients were excluded. Detailed history, clinical examination CSF analysis, haematological, biochemical investigations and imaging was performed in all patients. RESULTS Factors associated with the diagnosis of TBM in the present study included rural area of residence, longer duration of disease, presence of clear CSF, lower percentage of CSF neutrophils, presence of diplopia and hemiparesis. On validation, age did not appear as a significant factor in our population. The diagnostic algorithm from our study group had a sensitivity of 95.71% and specificity of 97.63%. CONCLUSIONS The diagnostic criterion has a fair validation in our population when the age factor is excluded. The rule is useful in HIV negative patients with low CSF sugar and negative organism yield in the CSF.

Predictors of refractory epilepsy in North India: A case–control study

The study was done to identify the predictors of refractory epilepsy in the North Indian population attending a tertiary care centre. This case-control study from August 2006 to December 2008 enrolled 200 consecutive patients of intractable epilepsy and 200 age matched controls with well controlled epilepsy. The factors which were significant in univariate analysis were age of onset before fourteen years (OR 7.92), partial seizures (OR 6.27), presence of neurological deficits (OR 19.68), perinatal insult (OR 11.00), delayed milestones (OR 13.93), history of CNS infection (OR 7.45), febrile seizures (4.33), high initial seizure frequency of more than one per month (OR 14.26), non response to first Anti Epileptic Drug (AED) (OR 6.71) and abnormal brain imaging (OR 20.47). On multivariate analysis significant predictors were radiological evidence of structural cerebral abnormality (OR 20.47), non response to first AED (OR 19.21), delayed mile stones (OR 9.09), high initial seizure frequency of more than one per month (OR 6.71), partial seizure type (OR 6.27), febrile seizures (OR 5.66) and age of onset before fourteen years (OR 3.09). It is thus possible to identify a certain profile of patients with epilepsy who are likely to be refractory to medical therapy. These observations would be useful in selecting patients early for evaluation in Northern India where a high surgical treatment gap exists.

Association between angiotensin converting enzyme gene insertion/deletion polymorphism and ischemic stroke in north Indian population: a case–control study and meta-analysis

Abstract Objective: The purpose of this case–control study was to determine the relationship between angiotensin converting enzyme (ACE) insertion/deletion polymorphism and serum ACE level in north Indian patients with ischemic stroke. Methods: In the present study, 224 ischemic stroke patients and 224 age- and sex-matched control participants were recruited. Genotyping was performed using polymerase chain reaction (PCR) method. Serum ACE levels were measured by colorimetric method. Our results were integrated with other reported studies from India for a meta-analysis. Results: We observed that DD genotypes were more frequently distributed in cases (32·6%) compared with controls (26·8%). Borderline significance was observed between DD genotype and risk of small vessel disease (SVD) stroke as compared to controls (OR, 1·9; 95% CI, 0·88-4·4; P value 0·09) assuming dominant model of inheritance. The mean ACE serum level in IU/l for II, ID, and DD genotypes were 17·1 ± 7·7, 26 ± 12·4, and 51·3 ± 21 (P value < 0·001) in cases and 16·5 ± 9·4, 26·8 ± 13, and 45·19 ± 18·3 (P value < 0·001) in controls, respectively. Discussion: The results of the study show lack of significant association between ACE insertion/deletion polymorphism and ischemic stroke, however, higher risk was observed with DD genotype in small vessel disease stroke, but with borderline significance. Meta-analysis of studies from India showed that DD genotype is associated with risk of ischemic stroke.