Manjari Tripathi

CPAP for Prevention of Cardiovascular Events in Obstructive Sleep Apnea

BACKGROUND Obstructive sleep apnea is associated with an increased risk of cardiovascular events; whether treatment with continuous positive airway pressure (CPAP) prevents major cardiovascular events is uncertain. METHODS After a 1-week run-in period during which the participants used sham CPAP, we randomly assigned 2717 eligible adults between 45 and 75 years of age who had moderate-to-severe obstructive sleep apnea and coronary or cerebrovascular disease to receive CPAP treatment plus usual care (CPAP group) or usual care alone (usual-care group). The primary composite end point was death from cardiovascular causes, myocardial infarction, stroke, or hospitalization for unstable angina, heart failure, or transient ischemic attack. Secondary end points included other cardiovascular outcomes, health-related quality of life, snoring symptoms, daytime sleepiness, and mood. RESULTS Most of the participants were men who had moderate-to-severe obstructive sleep apnea and minimal sleepiness. In the CPAP group, the mean duration of adherence to CPAP therapy was 3.3 hours per night, and the mean apnea-hypopnea index (the number of apnea or hypopnea events per hour of recording) decreased from 29.0 events per hour at baseline to 3.7 events per hour during follow-up. After a mean follow-up of 3.7 years, a primary end-point event had occurred in 229 participants in the CPAP group (17.0%) and in 207 participants in the usual-care group (15.4%) (hazard ratio with CPAP, 1.10; 95% confidence interval, 0.91 to 1.32; P=0.34). No significant effect on any individual or other composite cardiovascular end point was observed. CPAP significantly reduced snoring and daytime sleepiness and improved health-related quality of life and mood. CONCLUSIONS Therapy with CPAP plus usual care, as compared with usual care alone, did not prevent cardiovascular events in patients with moderate-to-severe obstructive sleep apnea and established cardiovascular disease. (Funded by the National Health and Medical Research Council of Australia and others; SAVE ClinicalTrials.gov number, NCT00738179 ; Australian New Zealand Clinical Trials Registry number, ACTRN12608000409370 .).

Brain oxidative stress: Detection and mapping of anti-oxidant marker 'Glutathione' in different brain regions of healthy male/female, MCI and Alzheimer patients using non-invasive magnetic resonance spectroscopy

Glutathione (GSH) serves as an important anti-oxidant in the brain by scavenging harmful reactive oxygen species that are generated during different molecular processes. The GSH level in the brain provides indirect information on oxidative stress of the brain. We report in vivo detection of GSH non-invasively from various brain regions (frontal cortex, parietal cortex, hippocampus and cerebellum) in bilateral hemispheres of healthy male and female subjects and from bi-lateral frontal cortices in patients with mild cognitive impairment (MCI) and Alzheimers disease (AD). All AD patients who participated in this study were on medication with cholinesterase inhibitors. Healthy young male (age 26.4±3.0) and healthy young female (age 23.6±2.1) subjects have higher amount of GSH in the parietal cortical region and a specific GSH distribution pattern (parietal cortex>frontal cortex>hippocampus ~ cerebellum) has been found. Overall mean GSH content is higher in healthy young female compared to healthy young male subjects and GSH is distributed differently in two hemispheres among male and female subjects. In both young female and male subjects, statistically significant (p=0.02 for young female and p=0.001 for young male) difference in mean GSH content is found when compared between left frontal cortex (LFC) and right frontal cortex (RFC). In healthy young female subjects, we report statistically significant positive correlation of GSH content between RFC and LFC (r=0.641, p=0.004) as well as right parietal cortex (RPC) and left parietal cortex (LPC) (r=0.797, p=0.000) regions. In healthy young male subjects, statistically significant positive correlation of GSH content was observed between LFC and LPC (r=0.481, p=0.032) regions. This statistical analysis implicates that in case of a high GSH content in LPC of a young male, his LFC region would also contain high GSH and vice versa. The difference in mean of GSH content between healthy young female control and female AD patients in RFC region (p=0.003) and difference in mean of GSH content between healthy young male control and male AD patients (p=0.05) in LFC region is found to be statistically significant. It is the first scientific report correlating alteration (in selective brain regions) of GSH level with clinical status of male and female subjects using non-invasive imaging technique.

Cardiovascular autonomic functions in well-controlled and intractable partial epilepsies.

BACKGROUND Epilepsy is associated with imbalance of sympathetic and parasympathetic activity which may lead to sudden unexplained death in epilepsy (SUDEP). Well-controlled (WcE) and intractable epilepsy (IE) subjects may present different autonomic profiles, which can be helpful in explaining the predisposition of the latter to SUDEP. PURPOSE To compare inter-ictal cardiovascular autonomic function in subjects with partial WcE and IE. METHODS Thirty WcE and 31 IE subjects underwent a battery of autonomic function tests: deep breathing, Valsalva maneuver, isometric exercise, cold pressor and tilt-table. Autonomic tone was assessed by heart rate variability (HRV). Their autonomic severity score and anxiety status was also assessed. RESULTS IE subjects had elevated low frequency component (52.0 vs. 37.6, p=0.047) and decremented high frequency component (114 vs. 397, p=0.013) of HRV and higher diastolic BP (75.62+/-9.77 vs. 68.64+/-0.43, p=0.036). In deep breathing test, they had lesser HR changes (20+/-10.18 vs. 29.68+/-11.23, p=0.007) and lower E:I (1.29+/-0.16 vs. 1.43+/-0.21, p=0.008). IE subjects had higher dysautonomia (chi square 165.0, p<0.0001). CONCLUSIONS We observed a higher vasomotor tone, higher sympathetic tone, lower parasympathetic tone, lower parasympathetic reactivity and more severe dysautonomia in the IE subjects. Refractoriness may lead to an alteration in cardiovascular autonomic regulation, which might be a predisposing factor for SUDEP.

Molecular and clinical correlation in five Indian families with spinocerebellar ataxia 12

Spinocerebellar ataxia 12 (SCA12) is a recently identified form of autosomal dominant cerebellar ataxia associated with the expansion of an unstable CAG repeat in the 5′ untranslated region of the gene PPP2R2B. We analyzed 77 Indian families with autosomal dominant cerebellar ataxia phenotype and confirmed the diagnosis of SCA12 in 5 families, which included a total of 6 patients and 21 family members. The sizes of the expanded alleles ranged from 55 to 69 CAG repeats, and the sizes of the normal alleles ranged from 7 to 31 repeats. We believe our study is the first to demonstrate that SCA12 may not be as rare in some populations as previously thought.

Diagnostic test utilization in evaluation for resective epilepsy surgery in children

Epilepsy surgery is highly successful in achieving seizure freedom in carefully selected children with drug‐resistant focal epilepsy. Advances in technology have aided presurgical evaluation and increased the number of possible candidates. Many of the tests employed are resource intense, and in specific cases they may be unhelpful or have adverse effects. Some standardization of the evaluation process is thus considered timely. Given the lack of class 1 or 2 evidence defining the relative utility of each test in specific clinicopathologic cohorts, a set of expert recommendations was attempted using consensus among members of the Pediatric Epilepsy Surgery Task Force of the International League Against Epilepsy (ILAE) Commissions of Pediatrics and Diagnostics These recommendations aim to limit fringe over or underutilization of use while retaining substantial flexibility in the use of various tests, in keeping with most standard practices at established pediatric epilepsy centers.

Intra-operative electrocorticography in lesional epilepsy

Intra-operative electrocorticography (ECoG) is useful in epilepsy surgery to delineate margins of epileptogenic zone, guide resection and evaluate completeness of resection in surgically remediable intractable epilepsies. The study evaluated 157 cases (2000-2008). The preoperative evaluation also included ictal SPECT (122) and PET in 32 cases. All were lesional cases, 51% (81) of patients had >1 seizure/day and another 1/3rd (51) had >1/week. Pre and post resection ECoG was performed in all cases. A total of 372 recordings were performed in 157 cases. Second post-operative recordings (42) and third post-operative recordings (16) were also performed. Site of recordings included lateral temporal (61), frontal (39), parietal (37), hippocampal (16) and occipital (4). 129/157 cases (82%) showing improvement on ECoG, 30/42 cases showed improvement in 2nd post resection, 8/16 showed improvement in the 3rd post-operative ECoG. 116/157 (73%) patients had good outcome (Engel I and II) at follow up (12-94 months, mean 18.2 months). Of these, 104 patients (80%) showed improvement on post-operative ECoG. 12 had good outcome despite no improvement on ECoG. The improvement in ECoG correlated significantly with clinical improvement [Sensitivity: 100% (95% CI; 96-100%); specificity: 68.3% (95% CI; 51.8-81.4%); positive predictive value: 89.9% (95% CI, 83.1-94.3%); negative predictive value: 100% (95% CI, 85-100%)]. The level of agreement was 91.72% (kappa: 0.76). Concluding, pre and post resection ECoG correlated with its grade of severity and clinical outcome.

Sirtuin1: A Promising Serum Protein Marker for Early Detection of Alzheimer’s Disease

Sirtuin (SIRT) pathway has a crucial role in Alzheimer’s disease (AD). The present study evaluated the alterations in serum sirtuin1 (SIRT1) concentration in healthy individuals (young and old) and patients with AD and mild cognitive impairment (MCI). Blood samples were collected from 40 AD and 9 MCI patients as cases and 22 young healthy adults and 22 healthy elderly individuals as controls. Serum SIRT1 was estimated by Surface Plasmon Resonance (SPR), Western Blot and Enzyme Linked Immunosorbent Assay (ELISA). A significant (p<0.0001) decline in SIRT1 concentration was observed in patients with AD (2.27±0.46 ng/µl) and MCI (3.64±0.15 ng/µl) compared to healthy elderly individuals (4.82±0.4 ng/µl). The serum SIRT1 concentration in healthy elderly was also significantly lower (p<0.0001) compared to young healthy controls (8.16±0.87 ng/µl). This study, first of its kind, has demonstrated, decline in serum concentration of SIRT1 in healthy individuals as they age. In patients with AD and MCI the decline was even more pronounced, which provides an opportunity to develop this protein as a predictive marker of AD in early stages with suitable cut off values.

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.

Post-traumatic seizures—A prospective study from a tertiary level trauma center in a developing country

RATIONALE No large studies till date are available from India on post-traumatic seizures (PTS). METHODS This is a prospective observational study of 520 patients with traumatic brain injury (TBI) (July 2007-2008). Patients admitted after 24h of injury, with Glasgow coma scale (GCS)<or=4 were excluded. RESULTS At a median follow-up of 386 days, 59 (11.4%) patients developed PTS. Incidence of immediate, early and late onset seizure were 6.5%, 2.1% and 2.7% respectively. In children, incidence of PTS was 18.3%. On univariate analysis, females, of age <10 years, with associated medical problems and with delayed loss of consciousness and poor GCS (<9), following fall from height, had significantly higher odds of PTS. On multivariate analysis, the risk of PTS was 3.7 times higher in patients who had fallen from height, 4.4 times higher in associated medical problems, and 3.7 times higher in severe head injury (GCS<9) at presentation. PTS was associated with poor Glasgow outcome score and higher incidence of behavioral abnormality on follow up. 32% patient with PTS developed recurrent delayed seizures. Seizure recurrence was significantly higher in late onset PTS. PTS affected overall outcome of the patients in severe head injury. CONCLUSION The risk of PTS was higher in patients who sustained fall from height, in GCS<9, and associated medical problems. About 1/3rd of the patients with early PTS developed recurrent delayed seizures.

Memory and intelligence outcome following surgery for intractable temporal lobe epilepsy: relationship to seizure outcome and evaluation using a customized neuropsychological battery

The main objectives of this prospective study were to (1) assess memory and intelligence outcome following surgery for intractable temporal lobe epilepsy, (2) correlate this with seizure outcome and side of surgery, and (3) perform (1) and (2) using an indigenously developed battery customized to the Indian population. Prior to use in our epilepsy surgery program, the test-retest and interexaminer variance reliability of this battery had been established in both normal and cognitively compromised populations. The memory scores were overall rather than material-specific. The battery was administered to right-handed adults undergoing surgery for intractable temporal lobe epilepsy without any evidence of opposite temporal lobe abnormality, both presurgery and postsurgery at a mean follow-up of 8 months. Twenty-five consecutive patients were included; 13 underwent right and 12 underwent left temporal surgery. Seizure outcome was assessed using Engels classification. Among 13 patients who underwent right temporal surgery, although 4 patients with poor seizure outcome had insignificant changes in scores, 7 of 9 patients with good seizure outcome exhibited considerable (> 20% over preoperative) improvement in their memory and intelligence scores. Statistical analysis using Students t test and the Mann-Whitney test revealed that the patients who underwent right temporal surgery with good seizure outcome had significant improvement in both memory (P = 0.007) and intelligence (P = 0.043) scores compared with those with poor seizure outcome. In contrast, patients who underwent left temporal surgery had no significant change in cognitive scores irrespective of seizure outcome. Cognitive improvement seems to occur in patients with good seizure outcome following nondominant temporal lobe surgery for intractable epilepsy with no evidence of pathology in the opposite temporal lobe. The same finding was not observed in patients undergoing left temporal surgery.