Cognitive disorders

Acute changes in cognition – delirium

Sudden changes in cognitive function raise the possibility of a diagnosis of delirium. The cardinal signs of delirium are fluctuating conscious state, impaired concentration and disorientation in time or place. As the course of illness is variable there may be periods of lucidity. There may also be associated psychotic symptoms (hallucinations in any sensory modality or delusional ideas) that can be distinguished from other forms of psychotic illness on a temporal basis. Delirium is more likely to occur in the later stages of HIV infection but is not exclusively limited to this period. It is also common in hospitalised patients with rates of up to 22% described in inpatients with HIV infection.[34] A thorough medical assessment including corroborative history of substance abuse or withdrawal may help to clarify the aetiology.

The assessment of delirium includes documentation of cognitive changes both for diagnosis and monitoring progress (Table 3). Physical examination and investigation should be targeted towards likely causes. [35]

Table 3. Assessment of delirium

Physical examination

Evidence of head trauma.

Neurological examination for focal neurological signs, tremor and asterixis.

Ophthalmological examination.

Initial screen

FBE, ESR, CRP, liver and renal function, thyroid function, blood sugar; routine urinalysis.

Urine/serum drug screen: illicit drugs.

Medication level monitoring: lithium, anticonvulsants.

Chest X-ray

Investigations for HIV-related infections

Serum antibodies to Toxoplasma, cytomegalovirus, herpes simplex virus, Treponema pallidum (syphilis).

Serum cryptococcal antigen.

Blood culture.

Further investigations

Nutritional deficiency: B12, folate.

Pulse oximetry and blood gas analysis if clinically hypoxic.

CSF analysis for HIV RNA and opportunistic infections. Cerebral imaging: CT, MRI.


FBE = full blood examination; ESR = erythrocyte sedimentation rate; CT = computer tomography; MRI = magnetic resonance imaging; EEG = Electroencephalography; CSF = cerebrospinal fluid.

Treatment will be directed by the findings on investigation, but it is not uncommon to fail to discover a specific cause. General management includes environmental measures to increase the familiarity of the person’s environment such as adequate lighting, orientation cues and limiting the number of staff involved in patient interaction. Medication can be used to decrease agitation and maintain a regular sleep cycle. It is common practice to use antipsychotic medication in these circumstances, initially at low doses and titrated accordingly. Occasionally, parenteral medication may be required and it should be used judiciously. Benzodiazepine medication is indicated in delirium secondary to alcohol withdrawal but should be used cautiously in other circumstances. Benzodiazepines can cause significant interactions with antiretroviral medications and they have been associated with increased confusion, excessive sedation and ataxia.[36]

Chronic cognitive disorders in people with HIV infection

Cognitive difficulties are often associated with chronic HIV infection. HIV enters the CNS early in the course of acute infection, infecting predominantly microglia and perivascular macrophages. Over time progressive neuronal dysfunction and apoptosis ccurs,[37] producing evident deficits, especially in the subcortical regions and fronto-striatal pathways of the brain. The mechanisms of this damage is not fully understood but it may occur either due to the direct effect of viral replication and release of viral proteins by infected macrophages and microglia, or possibly secondary to inflammatory mediators released by activated macrophages and microglia over time.[38][39]

Clinical assessment of cognitive impairment in people with HIV infection should consider the range of common comorbidities that can affect cognitive performance, in addition to the direct effects of chronic HIV infection.[39] Common physical comorbidities that require consideration include ageing, previous acquired brain injuries, cardiovascular disease, diabetes, co-infection with hepatitis C virus and sleep disorders. Consideration should also be given to psychiatric illness, such as depression and schizophrenia, and substance abuse, which also may impact on cognitive performance. A history of previous HIV-related CNS disorders (HIV-associated neurocognitive disorder [HAND] and CNS opportunistic infections) before commencing antiretroviral therapy (ART) also increases the likelihood of HAND being present on assessment.[40]

The cognitive domains most typically involved in HAND are working memory, speed of information processing, attention and active information retrieval. People with mild impairments may report minor difficulties performing complex cognitive tasks in everyday life. In more moderate to severe cognitive impairment, clinically evident slowness and apathy may be present. In advanced cognitive impairment, people may exhibit disinhibited behaviour, apathy, slowness and grossly disturbed motor functioning.[40]

The use of ART has had a significant impact on reducing the morbidity and mortality associated with HIV infection and HAND. In spite of this effect, HIV infection continues to be associated with varying degrees of cognitive impairment. The Frascati criteria[41] are the current standard for consistently describing the categories of impairment based on a clinical assessment. These criteria divide impairment into three levels of severity based on a neuropsychological assessment:

  1. HIV-associated neurocognitive impairment (ANI)
  2. HIV-associated mild neurocognitive disorder (MND)
  3. HIV-associated dementia (HAD).

All three categories require impairments in cognitive function across two domains.  With performance at least one standard deviation below the mean compared to a normal population sample for ANI and MND. These two diagnoses differ on their level of impact on daily function with no impact in those with ANI and mild interference in function in those with MND. A diagnosis of HAD is made when cognitive performance in two domains is two standard deviations below demographically appropriate mean scores (see section on neurological disorders) and is associated with significant functional impairment.

With the widespread adoption of ART for HIV infection in developed countries, there has been a shift in the presentation of HAND. There has been a decline in the appearance of the more severe forms of impairments such as HAD, however more mild forms of HAND such as ANI and MND persist. The CHARTER study revealed that over half of ART-treated adults with HIV infection showed evidence of neuropsychological impairments. Most of these showed evidence of mild impairments consistent with ANI (33%) and MND (12%). Only 2% had severe impairments consistent with HAD.[42]

Treatment considerations should be sensitive to the patient’s care requirements and available community supports. Consideration of competence to make medical and lifestyle decisions and discussion of an appropriate proxy should be part of an overall treatment plan. It is thought that ART which better penetrates the CNS may improve some of the cognitive deficits associated with this pathology.[40] However, these improvements may only be modest and some patients remain severely impaired despite instigation of treatment.[43]