INTRODUCTION

In their excellent review of the clinical issues of HIV-associated neurocognitive disorders (HAND), Davies and Brew extensively describe the changing issues of diagnosis and treatment in the combined antiretroviral therapy (cART) era, where we continue to see cognitive impairment in patients with HIV infection but with less progression, milder symptoms and more heterogeneity in presentation. In resource-limited settings, we still see classic AIDS dementia, with the characteristic subcortical triad of ‘memory, movement and mood’ similar to those in Huntington’s and Parkinson’s disease. Memory impairment, dysfunction tends to be in the form of slowed mental function and is characterized by impaired retrieval of information. Tests that require going from one mental task to another rapidly (such as the Trail Making B Test) are particularly impaired, as are rapid tasks requiring rapid cognitive and motor processing. The movement problems are often easiest to see in tasks of psychomotor speed such as the grooved pegboard, where the patients must rapidly manipulate small pegs into specially shaped holes in a particular orientation (one of the best screening tools for HIV dementia). The mood changes tend to be flattening of emotional responses (apathy) along with coarsening of personality. There is also a dramatic increase in the prevalence of major depression, which can be difficult to diagnose in the presence of the apathy, but is a critical diagnosis to make as treatment of depression dramatically improves the ability of demented patients to take medications and engage in care. Less common, but still seen occasionally, is AIDS mania, a particularly disabling mood syndrome that appears to be a form of organic bipolar disorder. In subtler forms, AIDS mania is characterized by insomnia, usually with the patients feeling that they do not need sleep, are irritable and disorganized. When it is more severe, it resembles the mania seen in idiopathic bipolar disorder, with euphoria, grandiosity and thought disorder, and can be accompanied by delusions, hallucinations and extreme agitation. This syndrome is rarely seen except in patients with advanced disease.

THE CHANGING PICTURE OF HAND

In populations where treatment of HIV is more available, HAND usually presents with milder symptoms and may be asymptomatic. Davies and Brew mention that the phenotype of cognitive impairment may be changing and becoming more ‘cortical’ rather than ‘subcortical’, meaning that as HIV populations age, there may be more Alzheimer’s disease-like elements to their dementia.

They point out the most important current questions that are controversial and problematic for clinicians. The first is that HAND can be stable (ongoing disease without progression), inactive (result of an earlier injury with no current central nervous system (CNS) inflammation), progressive or regressive and the course is changeable even with stable treatment. The science behind this is unclear. The presence of HIV in the blood or cerebrospinal fluid (CSF) makes disease more likely, but many patients do not have evidence of HIV in either compartment. Lower T-cell nadir, comorbid disease and, to a limited extent, time on treatment – all are predictive, but have limited clinical value in deciding on the next step. On the basis of these findings, screening for HAND and evaluation of adherence, viral load and probably CNS viral load are reasonable first steps. Some patients have CNS virus that has a different resistance pattern than the peripheral virus. This may be related to difference in penetration and drug levels in the CNS. Patients with continuing detectable virus, poor adherence or resistance are candidates for altered therapies and adherence interventions.

SCREENING

The second issue is how much resource should be devoted to screening and evaluation of asymptomatic HAND when it is unclear as to what should be done when we find it. Screening tools vary greatly in time burden, and a full diagnostic evaluation is time consuming and expensive. In resource-limited settings, clinical screening may be limited to physician examination. This issue is complicated by the lack of clear beneficial treatment for patients with mild disease. Use of antivirals predicted to have better CNS penetration based on scores developed (such as the CNS penetration–effectiveness (CPE) score) do not predict better outcomes nor do they predict a decrease in HAND when therapy is changed. This is because the events in the CNS are extremely complex.

MECHANISMS OF HAND

Factors that putatively increase cognitive impairment include HIV viral reproduction, direct toxicity of antivirals, inflammation due to immune activation (such as immune reconstitution syndrome (IRIS)), ageing, medical comorbidity, blood–brain barrier disruption, opportunistic infections and patient use of intoxicants. Factors that putatively decrease cognitive impairment include effective viral suppression, decreased immune activation, better adherence, better CNS penetration, early treatment, better treatment of comorbid disorders and longer treatment.