Statistics from Altmetric.com
Editor,—We read with interest the article from Dr Garg.1 We are just finishing a case-control study about risk factors for new onset seizures among HIV infected patients. All HIV infected patients hospitalised between 1 January 1992 and 31 March 1999 entered the study. Those suffering from any type of recent onset seizure were included as “cases”. Two “controls” per case were randomly chosen matched by year of hospitalisation. Semiological type of seizure, CD4+ lymphocyte counts (dichotomised at 200 cells/ml), HIV infection clinical stage (dichotomising C v A or B),2 opportunistic HIV related central nervous system (CNS) diseases, CNS pathologies not related to HIV, age and sex, were registered.
Fifty four patients were included as cases. Their general clinical characteristics were in accordance with those of Garg's. Most of them had generalised tonic-clonic seizures (generalised 49, partial four, not classifiable one), and their causes, summarised in table 1, were mostly in relation to opportunistic HIV related CNS diseases (36/54 cases). Nevertheless, CNS pathologies not related to HIV or with no specific cause could be identified in a significant number of cases (8/54 and 10/54 respectively). Patients generally showed considerable immunosuppression (CD4+ counts <200 cells/ml in 93% of cases), and had previously suffered from other AIDS defining pathologies (86.5%).
We hypothesised that immunosuppression, HIV clinical stage, and CNS HIV related opportunistic diseases were independent seizure risk factors. Crude univariate and multivariate analyses were done by means of Fisher's exact test and logistic regression and the results, summarised in table 2, were expressed as odds ratios with the corresponding 95% confidence interval and Fisher's exact test or likelihood ratio p values (SPSS 8.0 for Windows).
Crude univariate analysis disclosed that immunosuppression, HIV clinical stage, and several CNS HIV related opportunistic diseases behaved as important risk factors, as well as CNS pathologies unrelated to HIV, analysed as a group, did. However, when dichotomised CD4+ lymphocytes counts, HIV clinical stage, and relevant CNS pathologies were simultaneously introduced, in conjunction with sex and age as potential confounders, in a logistic regression model, immunosuppression and HIV infection clinical stage lost all their influence, while the effect of most HIV related CNS opportunistic diseases was maintained or even enhanced, in the same way as occurred with CNS pathologies unrelated to HIV.
Neither immunosuppression nor HIV clinical stage behave as independent risk factors, and their apparent implications are explained through HIV opportunistic CNS pathologies. CNS toxoplasmosis and CNS lymphoma are very strong risk factors of new onset seizures in HIV infected patients. The role of multifocal progressive leukoencephalopathy and HIV unrelated pathologies, though not to be doubted, appear to be much smaller. The implication of HIV by itself appears weak, if at all, and the elucidation of its role would require further well designed cohort or case-control studies in which the diagnosis of HIV encephalopathy would be done on a neuropathological basis in cases as well as in controls, a condition very difficult to fulfil in common clinical practice.
The author responds:
I am grateful to Dr Gaspar and Dr Álvarez for their interest shown in my article. In their study Gaspar and Alvarez observed that HIV related CNS opportunistic infections (for example toxoplasmosis) and CNS lymphoma were strong risk factors of new onset seizures in HIV infected patients. An almost similar observation was made by Rothmanet al.1-1 In their study these authors tried to determine which neurological signs or symptoms were predictive of new focal lesions on a cranial computed tomography study in HIV infected patients,1-1 and 110 patients who had new or changed neurological signs or symptoms were subjected to cranial computed tomography. Twenty seven patients (24%) had focal cerebral lesions seen on computed tomography of which 19 (18%) were new lesions. New onset seizures were the most important clinical finding and were strongly associated with new abnormalities seen on computed tomography. In this study also the most common intracranial lesion among patients with CD4 counts l <200 cells/ml was toxoplasmosis, while cerebrovascular accidents (ischaemic or haemorrhagic) were most common in those with CD4 counts >200 cells/ml. So, I agree with Gaspar and Álvarez that HIV infected patients who have new onset seizures are more likely to have a definite focal abnormality, which in majority of cases are caused by readily treatable opportunistic CNS infections.
Another important point raised by Gaspar and Álvarez is about the role of direct HIV infection of the brain in the pathogenesis of new onset seizures in patients with AIDS. It has been suggested that in patients with seizures who have no definite identifiable disease of the brain, cerebral HIV infection seems to be the most likely cause of seizures. In a series by Wong et al 17 patients within the “non-identified” group (comprising of 32 patients) underwent postmortem examination of brain; only six of them had characteristic pathological changes suggestive of HIV encephalopathy.1-2 So, in all HIV infected patients with normal imaging studies and normal cerebrospinal fluid examination the seizures can not be attributed to HIV infection of brain. In a recent prospective study Pascual-Sedano et alreported that in the majority of such patients the new onset seizures were either because of antiviral drug toxicity or were related to some metabolic derangement.1-3 Even in patients with definite HIV encephalopathy whether seizures are caused by direct HIV infection of brain or some associated toxic/metabolic abnormality remains to be established. I agree with Gaspar and Álvarez that a well designed cohort or case-control study of neuropathologically proved HIV encephalopathy patients with seizures or without seizures is required to establish the role of direct HIV infection of brain in the aetiopathogenesis of new onset of seizures in these patients.
If you wish to reuse any or all of this article please use the link below which will take you to the Copyright Clearance Center’s RightsLink service. You will be able to get a quick price and instant permission to reuse the content in many different ways.