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

BACKGROUND: Intracranial 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. METHODS: Functionally 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. RESULTS: Pro-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. CONCLUSIONS: The 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.

Association of Versican (VCAN) gene polymorphisms rs251124 and rs2287926 (G428D), with intracranial aneurysm.

Intracranial aneurysm (IA) accounts for 85% of Subarachnoid Hemorrhage (SAH) and is mainly caused due to the weakening of arterial wall. The structural integrity of the intracranial arteries is mainly influenced by the extracellular matrix (ECM) remodeling. The Proteoglycan Versican plays an important role in extracellular matrix assembly and plays a major role in the pathogenesis of IA. The linkage studies also indicated VCAN as a putative candidate gene for IA in the 5q22-31 region. Using a case-control study design, we tested the hypothesis whether the variants in VCAN gene, nonsynonymous variants in the coding region of Glycosaminoglycan α (GAG-α) and GAG-ß and two reported SNPs involved in splicing rs251124 and rs173686 can increase the risk of aSAH among South Indian patients, either independently, or by interacting with other risk factors of the disease. We selected 200 radiologically confirmed aneurysmal cases and 250 ethnically, age and sex matched controls from the Dravidian Malayalam speaking population of South India. The present study reiterated the earlier association of rs251124 with intracranial aneurysm (P = 0.0002) and also found a novel association with rs2287926 (G428D) in exon 7 coding for GAG-α with intracranial aneurysm (P = 0.0015). Interestingly, both these SNPs contributed to higher risk for aneurysm in males. In-silico analysis predicted this SNP to have the highest functional relevance in the gene which might have a potentially altered regulatory role in transcription and splicing. Using meta-analysis with available literature rs251124 was found to be the strongest intracranial aneurysm marker for global ethnicities. This study with a novel functional SNP rs2287926 (G428D) further substantiates the potential role of VCAN in the pathogenesis of IA.

Lack of association of lysyl oxidase (LOX) gene polymorphisms with intracranial aneurysm in a south Indian population.

Intracranial aneurysm (IA) accounts for 85 % of haemorrhagic stroke and is mainly caused due to weakening of arterial wall. Lysyl oxidase (LOX) is a cuproenzyme involved in cross linking structural proteins collagen and elastin, thus providing structural stability to artery. Using a case-control study design, we tested the hypothesis whether the variants in LOX gene flanking the two LD block, can increase risk of aSAH among South Indian patients, either independently, or by interacting with other risk factors of the disease. SNPs were genotyped by fluorescence-based competitive allele-specific PCR (KASPar) chemistry. We selected 200 radiologically confirmed aneurysmal cases and 235 ethnically and age and gender matched controls from the Dravidian Malayalam speaking population of South India. We observed marked interethnic differences in the genotype distribution of LOX variants when compared to Japanese and African populations. However, there was no significant association with any of the LOX variants with IA. This study also could not observe any significant role of LOX polymorphisms in influencing IA either directly or indirectly through its confounding factors such as hypertension and gender in South Indian population.

Primary myxopapillary ependymoma of the fourth ventricle with cartilaginous metaplasia: a case report and review of the literature.

Myxopapillary ependymoma (MPE), which is a benign histological subtype of ependymoma, is found predominantly in the cauda equina region. It occurs rarely in the brain and mostly as a metastatic deposit from a spinal lesion. The occurrence of primary intracranial MPE is exceptional, with only 11 cases reported to date. We report an additional case of intracranial MPE, which is the third reported case in the fourth ventricle. The tumor manifested in a 50-year-old lady, who presented with features of raised intracranial pressure. A gross total resection of the tumor was achieved. Histologically, the tumor had characteristic features of MPE with focal metaplastic cartilaginous deposit. On further evaluation, there was no evidence of a primary tumor in the spinal cord. Intracranial MPE needs further evaluation by craniospinal MRI to exclude an unrecognized primary in the spinal region, which could warrant surgical attention.

Supratentorial and cerebellar liponeurocytomas: report of four cases with review of literature.

Liponeurocytoma is not exclusive to the cerebellar or fourth ventricular location. Since its inclusion in the central nervous system tumor classification in 2000, six cases with similar radiological, histomorphological and immunohistochemical features have also been described in the lateral ventricles. In the present study, we report clinical, radiological and pathological findings of three supratentorial and one cerebellar liponeurocytoma from our records, evaluated with an extensive panel of immunohistochemistry, and review published cases in the literature. The immunohistochemical pattern of supratentorial and infratentorial liponeurocytomas are almost identical, which indicates that these tumors are homologous.

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.

A case of cerebral toxoplasmosis in a pregnant non-immunocompromised patient.

Cerebral toxoplasmosis, a disease of immunocompromised individuals, is rare in immunocompetent persons. We present a case of cerebral toxoplasmosis in a non-immunocompro-mised pregnant woman. Her imaging studies revealed a mass lesion involving the right basal ganglia, periventricular grey matter, midbrain and pons suggesting a neoplastic pathology along with hydrocephalus. She underwent an endoscopic third ventriculostomy and biopsy of the lesion. Postoperatively her consciousness improved as the hydrocephalus was relieved. After a thorough gynaecological examination she gave birth to a healthy child via normal vaginal delivery. The histopathology examination of biopsy suggested an inflammatory pathology. Serological studies for toxoplasmosis were positive. After 6 weeks of anti-toxoplasma treatment follow-up imaging showed a significant decrease in the size of the lesion.

Middle and posterior fossa aspergilloma.

BACKGROUND: Aspergilloma of the brain is a rare disease. Among its varied presentations, a solitary intracranial mass is very uncommon. A preoperative diagnosis of it is very difficult, but a perioperative squash smear/frozen section can identify the pathology. Because of its rarity in immunocompetent patients and the difficulty in preoperative diagnosis, we have illustrated this case and its presentation and management. METHODS: A 27-year-old man presented with an h/o right-sided weakness along with headache and ear discharge. A computed tomographic (CT) scan showed a large irregular, space-occupying lesion in the middle and posterior cranial fossa. He had a mastoidectomy done 3 years before for chronic suppurative otitis media. After a symptom-free interval of 1 year, he was investigated for severe earache on the same side. A CT scan at that time showed a space occupying mass in the right temporal bone and right inferior temporal lobe. A biopsy and histopathology of the lesion revealed a chronic granulomatous mass. He was started on antituberculous drugs and was on it for 7 months at the time of presentation. RESULTS: He underwent a suboccipital craniectomy and total excision of the mass. Postoperatively, his consciousness improved but began to deteriorate on the third postoperative day. A repeat CT scan showed hydrocephalus and total removal of the mass. An external ventricular drain was put and he was ventilated, but he died on the fourth postoperative day. Histopathology report came as aspergilloma. CONCLUSION: This report highlights the rare presentation of aspergilloma in an immunocompetent patient. It emphasizes the importance of suspecting this disease in such patients and the role of intraoperative squash smear preparations or frozen section in the diagnosis as routine diagnostic procedures that will help in early pharmacotherapeutic interventions in adjunct to surgery.