Rn Bhattacharya

Risk Factors for Aneurysmal Subarachnoid Hemorrhage in an Indian Population

Background: Aneurysmal subarachnoid hemorrhage (aSAH) has a mortality rate as high as 50%. The prevalence of intracranial aneurysms from various parts of India varies from 0.75 to 10.3%, with higher numbers of cases being diagnosed due to the increasing age of the population and improvements in imaging techniques. However, little is known about the attributable risk factors of aSAH in the Indian population. Methods: Using a case-control study we estimated the risk of factors such as hypertension, cigarette smoking, alcohol consumption, diabetes mellitus and family history of aSAH in a South Indian population. The population-attributable risk (PAR) of smoking, hypertension and alcohol use was estimated for the South Indian as well as for the general Indian population. Results: Our results showed that cigarette smoking (OR, 3.59; p < 0.001) and a history of hypertension (OR, 2.98; p < 0.001) were significant risk factors associated with aSAH. When patients were classified by gender, it was observed that being a smoker and having hypertension increased the risk for aSAH by nearly fourfold in men. Among women, hypertension and older age were significant risk factors. The PAR estimates indicated that smoking (OR, 3.59; 95% CI, 2.13–6.06) and hypertension (OR, 2.98; 95% CI, 1.73–5.12) are significant risk factors. Conclusions: Hypertension and smoking may be causal risk factors which might also modify the effect of genetic factors that could increase susceptibility to aSAH in the Indian population. Since these risk factors are amenable to effective modification, our findings will be useful for a gender-specific management of aSAH.

Pathogenesis of intracranial aneurysm is mediated by proinflammatory cytokine TNFA and IFNG and through stochastic regulation of IL10 and TGFB1 by comorbid factors

BackgroundIntracranial aneurysm (IA) is often asymptomatic until the time of rupture resulting in subarachnoid hemorrhage (SAH).There is no precise biochemical or phenotype marker for diagnosis of aneurysm. Environmental risk factors that associate with IA can result in modifying the effect of inherited genetic factors and thereby increase the susceptibility to SAH. In addition subsequent to aneurismal rupture, the nature and quantum of inflammatory response might be critical for repair. Therefore, genetic liability to inflammatory response caused by polymorphisms in cytokine genes might be the common denominator for gene and environment in the development of aneurysm and complications associated with rupture.MethodsFunctionally relevant polymorphisms in the pro- and anti-inflammatory cytokine genes IL-1 complex (IL1A, IL1B, and IL1RN), TNFA, IFNG, IL3, IL6, IL12B, IL1RN, TGFB1, IL4, and IL10] were screened in radiologically confirmed 220 IA patients and 250 controls from genetically stratified Malayalam-speaking Dravidian ethnic population of south India. Subgroup analyses with genetic and environmental variables were also carried out.ResultsPro-inflammatory cytokines TNFA rs361525, IFNG rs2069718, and anti-inflammatory cytokine IL10 rs1800871 and rs1800872 were found to be significantly associated with IA, independent of epidemiological factors. TGFB1 rs1800469 polymorphism was observed to be associated with IA through co-modifying factors such as hypertension and gender. Functional prediction of all the associated SNPs of TNFA, IL10, and TGFB1 indicates their potential role in transcriptional regulation. Meta-analysis further reiterates that IL1 gene cluster and IL6 were not associated with IA.ConclusionsThe study suggests that chronic exposure to inflammatory response mediated by genetic variants in pro-inflammatory cytokines TNFA and IFNG could be a primary event, while stochastic regulation of IL10 and TGFB1 response mediated by comorbid factors such as hypertension may augment the pathogenesis of IA through vascular matrix degradation. The implication and interaction of these genetic variants under a specific environmental background will help us identify the resultant phenotypic variation in the pathogenesis of intracranial aneurysm. Identifying genetic risk factors for inflammation might also help in understanding and addressing the posttraumatic complications following the aneurismal rupture.

Role of Endothelial Nitric Oxide Synthase Gene Polymorphisms in Predicting Aneurysmal Subarachnoid Hemorrhage in South Indian Patients

Endothelial nitric oxide synthase (eNOS) gene polymorphisms have been implicated as predisposing genetic factors that can predict aneurysmal subarachnoid hemorrhage (aSAH), but with controversial results from different populations. Using a case-control study design, we tested the hypothesis whether variants in eNOS gene can increase risk of aSAH among South Indian patients, either independently, or by interacting with other risk factors of the disease. We enrolled 122 patients, along with 224 ethnically matched controls. We screened the intron-4 27-bp VNTR, the promoter T-786C and the exon-7 G894T SNPs in the eNOS gene. We found marked interethnic differences in the genotype distribution of eNOS variants when comparing the South Indian population with the reported frequencies from Caucasian and Japanese populations. Genotype distributions in control and patient populations were found to be in Hardy-Weinberg equilibrium. In patients, the allele, genotype and estimated haplotype frequencies did not differ significantly from the controls. Multiple logistic regression indicated hypertension and smoking as risk factors for the disease, however the risk alleles did not have any interaction with these risk factors. Although the eNOS polymorphisms were not found to be a likely risk factor for aSAH, the role of factors such as ethnicity, gender, smoking and hypertension should be evaluated cautiously to understand the genotype to phenotype conversion.

Bilateral thalamic glioma: Report of four cases and review of literature

Primary thalamic tumors are rare and bilateral thalamic tumors are even rarer. The incidence, clinical manifestations, natural history and prognosis of primary bilateral thalamic gliomas (PBTT) remain relatively obscure. In this article, four cases of bilateral thalamic gliomas are discussed and the available literature is reviewed. We conclude that primary bilateral thalamic tumors are distinct lesions, as proven by their specific neuroradiological and metabolic properties, unresponsiveness to radiotherapy and chemotherapy as well as a rapidly fatal clinical evolution. Early diagnosis and prompt therapy may delay the devastating effects of this tumor.

Medulloblastoma in children: Prognostic factors and predictors of outcome

Objective: To determine the relative contributions of clinical, radiological and histopatholgical predictors of survival in children with medulloblastoma (MB) and to compare it with their adult counterparts. Materials and Methods: Retrospective case record analyses of 79 children (<16 y) operated after Jan. 1990, who have completed at least 5 y of follow-up. The following variables were assessed by bivariate analysis: age, CT scan location of the lesion, brainstem invasion, extent of excision, histological subtype. Statistical analysis was performed using Chi-square test, Fischers test and Students t test. Results: Near-total to total excision could be achieved in 59 (74.6%) cases. Twenty-three patients (29.11%) required CSF diversion procedures. Histopathology revealed features of classical medulloblastoma in 63.2%, thermoplastic variant in 11% and glial differentiation in 25.3% of cases. Postoperative mutism was seen in 14 (17.72%) patients. All patients received adjuvant therapy. On follow-up, 34 patients were found to have posterior fossa recurrence and four patients were re-operated. An additional 17% of patients were found to have either spinal or supratentorial metastasis on follow-up. The overall 5-year recurrence-free survival rate was 19 (24.05%). Mortality was recorded in 23 patients and nearly 29 patients who were severely disabled on follow-up were referred to terminal care centres. Conclusion: In spite of recent advances in management, children with medulloblastoma still carry a poor prognosis. We observed poor outcome in children below 7 y of age. Vermian location had a better outcome in adults but not in children. Desmoplastic variant was observed to be a significant prognostic factor in paediatric, group while brain stem invasion carried poor prognosis for both.

Lack of association of Endoglin insertion polymorphism in intracranial aneurysm in South Indian population

Background : Endoglin , is a component of transforming growth factor-β complex. It is involved in vascular development and structural maintenance of the vessel wall. Conflicting reports on the association of a six base insertion polymorphism in intron 7 of the endoglin gene in intracranial aneurysms (IA) have been reported earlier. materials and Methods: A case-control study was designed to compare 102 South Indian patients with intracranial saccular aneurysms and 118 ethnically and geographically matched healthy controls. The frequency of the six base insertion polymorphism was assessed by heteroduplex analysis followed by direct sequencing. Results: Insertion allele count was 39 (19.1%) of 204 alleles in the patient group and 42 (17.8%) of 236 alleles in the control group. The INS allele frequency was similar to the frequency in Caucasian population, but it was significantly lower than the Japanese population ( P =0.01). There was also no relationship of this polymorphism in patients with single aneurysm (33/176 alleles) or those with multiple aneurysms (6/28 alleles). Conclusion: Six base insertion polymorphism in Endoglin gene was not found to be a risk factor for intracranial saccular aneurysms in the South Indian population. Ethnic-related differences were observed. This is the first report on any genetic mutation in intracranial aneurysms in Indian population.