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INTRODUCTION: CD8 encephalitis is a relatively recently described condition in the setting of HIV infection. It is becoming increasingly recognised in recent years though is still likely underdiagnosed. METHODS: We present three cases of encephalitis in HIV-positive black African females initially presenting with neurological pathology. Two cases concern recent presentations of patients attending HIV services at a large tertiary referral hospital and the third case involves a retrospective analysis of an archived case. RESULTS AND DISCUSSION: MRI brain demonstrated periventricular white matter changes in 2 cases and a cerebellar lesion in the third case. CSF examination revealed lymphocytosis and elevated protein levels. CSF HIV viral load analysis showed viral escape along with new antiretroviral drug resistance mutations. CSF flow cytometry studies demonstrated a reversed CD4:CD8 ratio with a high CD8+ cells percentage. All patients had EBV DNA detected in their CSF. Brain biopsy in two patients confirmed CD8 encephalitis and also revealed isolated cells demonstrating EBV positivity by in-situ hybridization using EBER (Epstein-Barr virus-encoded small RNAs). Treatment with steroids and ART optimisation led to significant clinical and radiological improvements in all cases. DISCUSSION: CD8 encephalitis should be considered as a cause of neurological symptoms and confusion in the HIV-positive patient, particularly if poor ART adherence or viral resistance are suspected. Brain biopsy should be considered in HIV-positive patients with encephalopathy of uncertain cause. Early treatment with high-dose corticosteroids when suspecting this diagnosis is essential for a favourable outcome. The prognosis is variable but can be favourable even following severe encephalopathy. The presence of new INSTI mutations in the CSF but absent peripherally in two INSTI-era patients is a novel finding for this case series in the context of CD8 encephalitis. The role played by EBV in this disease remains unclear and warrants further investigation.
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Epigenetic silencing of O-6-methylguanine-DNA methyltransferase (MGMT) promoter via methylation in a glioblastoma (GBM), has been correlated with a more favourable response to alkylating chemotherapeutic agents such as temozolomide. The use of global methylation surrogates such as Long Interspersed Nucleotide Element 1 (LINE1) may also be valuable in order to fully understand these highly heterogeneous tumours. In this study, we analysed both original and recurrent GBMs in 22 patients (i.e. 44 tumours), for both MGMT and LINE1 methylation status. In the 22 patients: 14 (63.6%) displayed MGMT methylation stability in the recurrent GBM versus 8 (36.4%), with instability of methylation status. No significant differences in overall and progression free survival was evident between these two groups. LINE1 methylation status remained stable for 12 (54.5%) of recurrent GBM patients versus 9 (41%) of the patients with instability in LINE1 methylation status (p = 0.02), resulting in an increase in overall survival of the stable LINE1 group (p = 0.04). The results obtained demonstrated major epigenetic instability of GBMs treated with temozolomide as part of the STUPP protocol. GBMs appear to undergo selective evolution post-treatment, and have the ability to recur with a newly reprogrammed epigenetic status. Selective targeting of the altered epigenomes in recurrent GBMs may facilitate the future development of both prognostic biomarkers and enhanced therapeutic strategies.