Prior to the introduction of HAART up to 20 % of patients with AIDS developed HIV dementia and it was associated with a high mortality rate with a mean survival of 6 months to 1 year after the development of dementia. Prior to HAART mild neurocognitive impairment was described in 30 % of patients with asymptomatic HIV disease and in up to 50 % of patients with AIDS defining illnesses. The incidence of HIV associated dementia has declined in the post-HAART era to approximately 2 %, however cognitive impairment continues to be an ongoing clinical issue despite good virological control of HIV. Prevalence rates of 20–50 % of HAND have been demonstrated in large prospective studies.

HIV is neuroinvasive, neurotropic and neurovirulent. HIV enters the brain through infected monocytes and lymphocytes. They are used as a “Trojan horse” mechanism to cross the blood brain barrier. HIV has been found in the cerebrospinal fluid (CSF) of patients during seroconversion, suggesting that HIV enters the CNS early in the course of infection. Neurons are not infected directly by HIV. Microglial cells and macrophages are the primary targets for productive HIV infection within the CNS as they both possess receptors for CD4 and CCR5. Microglia cells act as the brain’s native immune response cells. Astrocytes are also infected by HIV despite their lack of receptors for viral attachment but in a more restricted fashion.

HIV can cause an inflammatory reaction upon entry to the CNS which may be manifested by a T cell reaction with vasculitis and leptomeningitis. There is upregulation of MHC class II antigens, increased number of microglial cells found and increased production of cytokines. Perivascular microglia are likely involved early in infection and the parenchymal microglia become involved in the later stages of infection. The chemokine receptor CCR5 is the dominant receptor used within the brain. There is proliferation of astrocytes and intense perivascular lymphocytic and macrophagic infiltration has been seen at autopsy which has been postulated to be related to immune reconstitution inflammatory syndrome (IRIS).

The pathognomonic feature of HIV encephalitis (HIVE) on histological examination is the presence of multinucleated giant cells. These cells are the fusion of infected and uninfected microglia and macrophages and they stain positively for HIV antigens. Together they provide evidence of productive infection by HIV within the CNS. This pathological feature was present in 20–50 % of patients who had autopsies performed in the first 15 years of the HIV epidemic. HIVE has a predilection for the basal ganglia and white matter and affects the neocortical grey matter, cerebellum and brainstem to a lesser extent. Other pathological features of HIV include myelin pallor, axonal loss, microglial nodules and gliosis. There is also disruption of the blood brain barrier and apoptosis of astrocytes. This leads to dendritic and neuronal loss (Fig. 14.2; Table 14.2).

Risk factors include a low nadir CD4⁺ T-cell count, older age, substance abuse, lower educational level, co-infection with hepatitis C, CCR2 polymorphisms, the 2578G variant of CCL2 (MCP-1), TNF-α 308A allele and systemic features such as low haemoglobin, constitutional symptoms and a low body mass index. Apolipoprotein E status, particularly in older patients, has been associated with HAND in some studies.

HIV-associated dementia remains an independent predictor of time to death. Functional impairment in the areas of work assessment, finances, medication management, cooking and shopping has been demonstrated. Unemployment is higher.

Patients exhibited disturbance in cognitive, behavioural and motor function. Patients complained of forgetfulness, loss of concentration, difficulty recalling recent events and losing their train of thought. Motor symptoms included lower limb weakness, loss of balance and abnormal co-ordination. Apathy and social withdrawal were the most common behavioural symptoms. It was consistent with a subcortical dementia given the prominent psychomotor slowing and the absence of cortical signs such as aphasia and apraxia. The neuropathological findings supported this hypothesis given the predominance of white matter and subcortical nuclei pathology. One study demonstrated increased rates of neuropsychological impairment at each successive stage of HIV infection. The domains most often affected were attention, speed of information processing and learning efficiency and they suggested that this pattern was consistent with earliest involvement of subcortical or fronto-striatal brain systems.