Dementia due to HIV disease.
- Clinical features
- Diagnosis and differential diagnosis
- Neuropsychological tests
- Brain imaging
- Cerebrospinal fluid analysis
- Course and prognosis
- Review of evidence
- Antiretroviral drugs
- Drugs under investigation
- Drugs for behavioural symptoms
- Advice about management
- Possible preventive measures
The first description of a syndrome consisting of cognitive, motor and behavioural disturbances in patients with AIDS was reported in 1986. (1) The syndrome was named ‘AIDS dementia complex'. A rating scale for the syndrome, ranging from 0 (normal) to 4 (endstage), was proposed by Price et al. (2) in 1988. In 1990, the World Health Organization introduced the term ‘HIV-associated dementia', (3) pointing out that subclinical or mild cognitive and/or motor dysfunctions without impairment of performance in daily living activities, corresponding to stages 0.5 and 1 on the scale of Price et al., cannot be subsumed under the term ‘dementia'. The expression ‘mild cognitive/motor disorder' was proposed for those conditions. The same distinction was made in 1991 by the American Academy of Neurology, (4) which identified an ‘HIV-associated dementia complex' and an ‘HIV-associated minor cognitive/motor disorder'.
This article covers the dementia syndrome associated with HIV infection. For minor cognitive/motor disorder, the reader is referred to Maj et al. (5)
The onset of HIV-associated dementia is usually insidious. Early cognitive symptoms include forgetfulness, loss of concentration, mental slowing, and reduced performance on sequential mental activities of some complexity (the subject misses appointments, or needs lists to recall ordinary duties; loses track of conversations or his or her own train of thought; needs additional time and effort to organize thoughts and to complete daily tasks). Early behavioural symptoms include apathy, reduced spontaneity and emotional responsivity, and social withdrawal (the subject becomes indifferent to his or her personal and professional responsibilities; his or her work production decreases, as well as the frequency of social interactions; the subject complains of early fatiguability, malaise, and loss of sexual drive). Depression, irritability or emotional lability, agitation, and psychotic symptoms may also occur. Early motor symptoms include loss of balance and co-ordination, clumsiness, and leg weakness; the subject is less precise in normal hand activities, such as writing and eating, drops things more frequently than usual, trips and falls more frequently than usual, and perceives the need to exercise more care in walking. (1,6)
Routine mental status tests, in this early stage, may be normal or show only slowing in verbal or motor responses and/or difficulty in recalling a series of objects after 5 min or more. Neurological examination may show tremor (best seen when the patient sustains a posture, such as holding the arms and fingers outstretched), hyperreflexia (particularly of the lower extremities), ataxia (usually seen only on rapid turns or tandem gait), slowing of rapid alternating movements (of the fingers, wrists or feet), frontal release signs (snout reflex, palmar grasp), dysarthria. Tests of ocular motility may show interruption of smooth pursuits, and slowing or inaccuracy of saccades.
In the late stages of the disease, there is usually a global deterioration of cognitive functions and a severe psychomotor retardation. Speech is slow and monotonous, with word-finding difficulties and possible progression to mutism. Patients become unable to walk, due to paraparesis, and usually lie in bed indifferent to their illness and their surroundings. Bladder and bowel incontinence are common. Myoclonus and seizures may occur. Pedal paraesthesias and hypersensitivity may appear, due to concurrent sensory neuropathy. The level of consciousness is usually preserved, except for occasional hypersomnolence.
The World Health Organization ( WHO) criteria for HIV-associated dementia (3) are as follows:
- The research criteria for dementia of the ICD-10 (7) are met, with some modifications: a.) decline in memory may not be severe enough to impair activities of daily living; b.) decline in motor function may be present, and is verified by clinical examination and, when possible, formal neuropsychological testing; c.) the minimum requested duration of symptoms is 1 month; d.) aphasia, agnosia and apraxia are unusual.
- Laboratory evidence for systemic HIV infection is present.
- No evidence of another aetiology from history, physical examination, or laboratory tests should be present (specifically, cerebrospinal fluid analysis and either CT or magnetic resonance imaging (MRI) should be done to exclude active central nervous system opportunistic processes).
The American Academy of Neurology criteria (4) require the following:
- Laboratory evidence for systemic HIV infection.
- Acquired abnormality in at least two of the following cognitive abilities (present for at least 1 month): attention/concentration, speed of processing of information, abstraction/reasoning, visuospatial skills, memory/learning, and speech/language.
- At least one of the following: a.) acquired abnormality in motor function or performance; b.) decline in motivation or emotional control or change in social behaviour.
- Absence of clouding of consciouness during a period long enough to establish the presence of (2).
- Absence of evidence of another aetiology. Both WHO and American Academy of Neurology criteria distinguish three levels of severity of the dementia syndrome (mild, moderate, and severe), on the basis of the degree of the impairment in activities of daily living.
Diagnosis and differential diagnosis
Neuropsychological examination supports the clinical diagnosis of HIV-associated dementia, by providing evidence of cognitive and motor dysfunction. Moreover, it may be useful in the differential diagnosis with a depressive syndrome.
The most prominent impairment is observed on tests of fine motor control (finger tapping, grooved pegboard), rapid sequential problem solving (trail-making A and B, digit symbol), visuospatial problem solving (block design), spontaneity (verbal fluency), and visual memory (visual reproduction). In contrast, naming and vocabulary skills are largely preserved even in the most advanced cases. This pattern has been regarded as consistent with the clinical picture of a ‘subcortical dementia'.
The signs that should alert to the possible presence of a depressive ‘pseudodementia' are as follows: (8)
- the intratest variability of performance (i.e. missing easy items and then correctly answering more difficult questions);
- mood-congruent complaints, which are at odds with objective performance (i.e. the subject complains of having difficulties with a test, whereas his or her performance is near perfect);
- responses of ‘I don't know' or giving up, which are followed by the correct answer, when the subject is further urged to respond.
It should be considered, however, that dementia and depression may coexist in HIV-seropositive subjects.
Brain imaging provides additional support to the diagnosis of HIV-associated dementia, especially by excluding central nervous system opportunistic processes, in particular cerebral toxoplasmosis and primary central nervous system lymphoma.
The predominant finding in HIV-associated dementia is cerebral atrophy; both CT and MRI demonstrate widened cortical sulci and, less commonly, enlarged ventricles. Furthermore, MRI frequently shows high-intensity signal abnormalities on the T 2-weighted image (diffuse widespread involvement, patchy localized involvement, focal distinct areas of involvement, or punctuate white-matter hyperdensities). These lesions are without mass effect and are most commonly located in the periventricular white matter and the centrum semiovale (less frequently, in the basal ganglia or in the thalamus).
As to differential diagnosis, both CT and MRI are able to demonstrate the multiple bilateral ring enhancing lesions that are characteristic of cerebral toxoplasmosis, and the contrast-enhancing mass lesions of primary central nervous system lymphoma.
Cerebrospinal fluid analysis
Cerebrospinal fluid analysis can support the clinical diagnosis of HIV-associated dementia, especially by excluding several central nervous system opportunistic infections, in particular cryptococcal meningitis.
The most frequent cerebrospinal fluid findings in HIV-associated dementia are the increase of total proteins and of the IgG fraction and index. A mononuclear pleocytosis may occur. The presence of the HIV core antigen p24 can be detected, although this finding is possible also in neurologically normal subjects. HIV RNA can be demostrated in the cerebrospinal fluid by using the polymerase chain reaction; the levels of HIV RNA in the cerebrospinal fluid correlate with the severity of dementia. (9) Increased cerebrospinal fluid levels of neopterin, b 2-microglobulin and quinolinic acid (non-specific markers of immune activation), as well as of several cytokines (interleukin 1b, interleukin 6, tumour necrosis factor-a), have been reported, but may be detected also during central nervous system opportunistic infections.
As to differential diagnosis, Indian ink staining, cryptococcal antigen titres, and fungal culture can be decisive for the identification of cryptococcal meningitis. Other central nervous system opportunistic infections that can be identified by cerebrospinal fluid analysis include central nervous system tuberculosis, cytomegalovirus encephalitis, and neurosyphilis.
Estimates of the prevalence and incidence of HIV-associated dementia vary widely, depending on the source from which patients are recruited and the criteria used for the diagnosis. (5)
A recent prospective study, carried out on a cohort of homosexual men in the United States, found that the diagnosis was made concurrently with that of the initial AIDS-defining illness in 3 per cent of cases, and that the incidence of the dementia syndrome during the first 2 years after the diagnosis of AIDS was 7 per cent per year, with 15 per cent of patients developing dementia during the course of the disease. (10)
Several risk factors for the development of HIV-associated dementia have been reported, including older age, decreased body mass, decrements in haematocrit, and a history of intravenous drug abuse. However, avalaible data are not consistent.
The pathogenesis of HIV-associated dementia is at present incompletely understood. In the brain, productive infection is almost exclusively restricted to macrophages and microglia. Neuronal injury (most probably apoptosis) is currently believed to be produced by toxic products released directly by HIV-infected macrophages and microglia or by activated astrocytes. Some of these factors have been identified: they include the platelet-activating factor, quinolinic acid, nitric oxide, and some metabolites of arachidonic acid, which are neurotoxic, and tumour necrosis factor-a, which is toxic for oligodendrocytes and can cause demyelination.
The strains of HIV which are isolated from the brain have in common the characteristic of infecting macrophages but not lymphocytes. This macrophage tropism corresponds to what was initially regarded as neurotropism. Macrophage tropism is related to a mutation in a specific region of gp120, the external glycoprotein of the virus. In the late stages of the infection, when active replication of the virus generates more mutants and the compromised immune system permits the escape of these mutants, the development of macrophage-trophic strains is more likely to occur, and this probably represents the limiting step for the occurrence of HIV encephalopathy and dementia. (11)
Course and prognosis
The course of HIV-associated dementia is variable, and no predictor of the pace of progression is currently available. The syndrome often progresses rapidly to severe deterioration and death, especially in patients with advanced systemic disease, but it may also have prolonged stable phases, or may fluctuate, with reversible deterioration occurring in concomitance with opportunistic infections. Death usually occurs as a result of inanition, aspiration pneumonia, or systemic opportunistic infections.
Review of evidence
Zidovudine is a reverse transcriptase inhibitor which crosses the blood–brain barrier and reaches effective concentrations in the cerebrospinal fluid. It is able to inhibit HIV replication in macrophages and seems to produce an improvement of the symptomatology in patients with HIV-associated dementia, although this effect appears to be transient (i.e. to dissipate after 6–12 months of treatment).
The only double-blind randomized controlled trial (12) comparing zidovudine with placebo in patients with HIV-associated dementia used high doses (either 1000 or 2000 mg/day) of the drug (the standard dosage is 500–600 mg/day). After 16 weeks of treatment, the combined average neuropsychological test z-scores showed a significant improvement in patients receiving zidovudine; the effect was significantly more pronounced in patients taking 2000 mg/day than in the 1000 mg/day group. The improvement was also significant after 32 and 64 weeks of treatment. Adverse side-effects were not documented.
In an open 12-month prospective trial, Tozzi et al. (13) used three different dosages of zidovudine (500, 750, or 1000 mg/day, depending on the haematological state) in 30 patients with HIV-associated dementia. An improvement in the stage of dementia was observed in 15 patients after 1 month and 25 patients after 6 months. Following an initial improvement, eight patients deteriorated in dementia staging after 6 to 12 months of treatment (five of them had received the dosage of 500 mg/day). Two patients dropped out because of adverse side-effects, eight developed haematological toxicity requiring temporary discontinuation of the drug, and five required a reduction of dosage due to bone marrow toxicity.
The decline after initial improvement of cognitive performance in AIDS patients after 6 to 12 months of treatment with zidovudine has been confirmed in other open trials. (14)
Among the other reverse transcriptase inhibitors, didanosine does not seem to have an impact on the progression of HIV-associated dementia, whereas no studies are available on the efficacy of zalcitabine, stavudine, or lamivudine. No trial has tested the efficacy of protease inhibitors; according to currently available evidence, these drugs do not reach effective concentrations in the cerebrospinal fluid.
Drugs under investigation
Drugs whose beneficial effect on cognitive performance in patients with HIV infection has been preliminarily documented in published studies include the monoamine oxidase inhibitor deprenyl (a putative antiapoptotic agent) and peptide T (a neurotrophic peptide). Other investigational drugs include memantine and nitroglycerin (which are N-methyl-D-aspartate receptor antagonists), nimodipine (a calcium-channel blocker) and pentoxifylline (an inhibitor of the production and activity of tumour necrosis factor-a). No published trial in patients with HIV-associated dementia is currently available for any of these drugs.
Drugs for behavioural symptoms
The psychostimulant methylphenidate (at doses ranging from 10 to 90 mg/day) has been repeatedly found to improve cognitive symptoms in patients with AIDS, producing relatively mild side-effects. The available studies, however, have several limitations, including small patient samples, open design, and inclusion of depressed patients. No systematic research has been conducted in patients with HIV-associated dementia.
Patients with AIDS, when treated with typical antipsychotic drugs for the presence of psychotic symptoms or behavioural dyscontrol, are particularly prone to develop extrapyramidal side-effects and neuroleptic malignant syndrome. According to preliminary research evidence, the atypical antipsychotic risperidone is well tolerated even by patients who had to stop standard neuroleptics due to extrapyramidal side-effects.
AIDS patients with depressed mood have been found to respond to tricyclic antidepressants and selective serotonin reuptake inhibitors as well as HIV-seronegative subjects. There is a preliminary evidence that SSRIs (or at least some of them) are better tolerated than tricyclic antidepressants, except in patients with diarrhoea. Current evidence does not support the idea that tricyclic antidepressants may worsen HIV-related cognitive impairment or precipitate delirium, although no specific study is available in patients with HIV-associated dementia.
Advice about management
At the present state of knowledge, patients with HIV-associated dementia should be treated with zidovudine. Although there is uncertainty about the most appropriate dosage, the standard doses of 500 to 600 mg/day should be tried first. If the patient does not respond, the dosage should be increased to 1500 or 2000 mg/day.
Psychosocial interventions should include maintenance of a structured daily schedule, titration of external stimuli, restriction to fa miliar environments, frequent orienting interactions with significant others, and monitoring of personal and financial affairs.
The care of patients with HlV-associated dementia will make increasing demands on health services, as well as on volunteer and community support systems. It is uncertain, at present, whether such care is best provided in specialized units (e.g. inpatient AIDS units), or within general psychiatric or medical services. Special management problems may arise when the behavioural disturbance (e.g. poor impulse control, sexual acting-out behaviour) is such as to constitute a risk for other patients or staff members. Placement of patients in the terminal stage of the disease may also represent a problem: the lack of appropriate options in the community may obstruct their timely and humane discharge from the hospital.
Possible preventive measures
Several studies suggest that long-term treatment with zidovudine may produce a prophylactic effect in symptomatic patients with HIV infection, reducing the risk for development of HIV-associated dementia. This effect, however, seems to be time limited: in a recent retrospective study carried out on a longitudinal cohort of 1109 patients with AIDS,(15) the use of zidovudine for a period of 6 to 18 months was associated with a reduced risk of dementia, whereas treatment for longer than 18 months was not beneficial.
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