Several disorders may involve the leptomeninges in patients with advanced HIV-1 disease. The most important of these is infection by Cryptococcus neoformans. This condition may present subacutely with headache, nausea, vomiting, and confusion, just as in non-AIDS patients. However, importantly, in some patients initial symptoms can be remarkably mild, with only low-grade headache or fever. Likewise, the CSF findings may be bland, with few or no cells and little or no perturbation in either glucose or protein levels. For this reason the clinician should have a low threshold for lumbar puncture and should routinely examine CSF for Cryptococcus (India ink stain, cryptococcal antigen determination, culture). Initial treatment is usually gratifying, although continued chronic therapy is required.

The syndrome of aseptic meningitis, presumably relating to direct HIV-1 infection of the leptomeninges, may complicate advanced HIV-1 infection but most often develops in the period of transition to AIDS. Both acute and chronic forms are accompanied by headache and meningeal symptoms, whereas signs of meningeal irritation are more characteristic of the acute group. Cranial nerve palsies affecting the seventh and, less often, the fifth and eighth nerves may complicate the course.

The CSF shows a modest mononuclear pleocytosis, usually with normal glucose and mildly elevated protein. The presumption that this condition is due to direct HIV-1 infection of the meninges derives from the fact that the virus can be identified in the CSF and no other cause has been found. The syndrome itself is characteristically benign but may imply a poor prognosis in relation to impending progression to AIDS. The efficacy of antiretroviral or other therapies in this disorder has not been studied.

Other, less common meningeal disorders (including meningeal lymphoma, tuberculous meningitis, meningovascular syphilis) resemble their counterparts in the non-AIDS patient. A number of other conditions may present with symptoms resembling meningitis; for example, parenchymal brain diseases such as toxoplasmosis and primary CNS lymphoma may initially manifest with headache as an important symptom. More common, however, is the development of headache of uncertain cause. Although not well understood, this headache is not rare in late HIV-1 infection and at times can be a severe, debilitating problem. In some patients this headache may relate to systemic infection but in others the explanation is elusive and for this reason has been referred to as HIV headache.