Herbert B. Newton, MD, FAAN
DESCRIPTION
HIV dementia (i.e., AIDS dementia complex, HIV encephalopathy, HIV-1-associated cognitive/motor complex) is a syndrome of progressive deterioration of memory, cognition, behavior, and motor function in HIV-infected individuals during the late stages of the disease, when immunodeficiency is severe.
EPIDEMIOLOGY
Incidence/Prevalence
- Exact incidence and prevalence figures are not available. HIV dementia is the most common neurological complication of HIV infection and is estimated to have an overall incidence of 7.5–20% in retrospective studies. The incidence varies with CD4 counts: 7.3 cases/100 person years with CD4 counts less than 100, 3.0 cases/100 person years with CD4 counts between 101 and 200, 1.5 cases/100 person years with CD4 counts between 201 and 500, and 0.5 cases/100 person years with CD4 counts above 500. More recently, the incidence appears to be decreasing, most likely due to widespread use of highly active antiretroviral therapy (HAART).
- All races affected; most common in Caucasians and blacks. Any age can be affected; most common between 20 and 40 years of age. Both sexes can be affected; most often diagnosed in males.
RISK FACTORS
No specific risk factors have been identified other than diagnosis of HIV infection, low CD4 counts (i.e., less than 200/µL) and an advanced stage of disease, and lack of antiretroviral therapy.
Genetics
Genetic factors have not been identified.
GENERAL PREVENTION
Other than the use of HAART therapy, no other preventive measures are known.
PATHOPHYSIOLOGY/ETIOLOGY
HIV is neurotropic and can be cultured early from the nervous system. However, productive infection within neurons or astrocytes does not appear to be the major cause of HIV dementia or vacuolar myelopathy. Brain macrophages (i.e., microglia) can develop productive HIV infection and are the major vehicle for introducing the virus into the nervous system. Recent hypotheses suggest that neural injury and dysfunction may be due to an innocent-bystander effect. HIV does shed toxic substances, such as whole or fragmented gp120 envelope glycoprotein, which can cause neuronal death in vitro. In addition, other neurotoxic substances can be released in areas of productive infection and cause injury to neurons and astrocytes, such as tumor necrosis factor α, interleukin-1β, interleukin-6, and quinolinic acid. The proposed “final common pathway” of neurotoxicity is excessive stimulation of N-methyl-D-aspartate (NMDA) receptors. Overstimulation of NMDA receptors by gp120, quinolinic acid, and other substances could cause toxic build-up of intracellular calcium, thereby killing neuronal cells.
COMMONLY ASSOCIATED CONDITIONS
Vacuolar myelopathy
HISTORY
- Patients with HIV dementia demonstrate progressive dysfunction of memory, cognition, behavior, and motor function. During early stages of disease (stage 0.5, 1, 2), patients note difficulty with concentration, mild memory impairment, loss of mental agility, behavioral changes, and slowness of thinking. Mild motor dysfunction may affect strength, gait, balance, and coordination. The neurological examination often reveals subtle psychomotor slowing, mild memory deficits, reduced concentration, saccadic ocular pursuit movements, and soft motor signs (e.g., mild leg weakness, hyperreflexia, slowed rapid alternating movements, unsteady gait, tremor, frontal lobe release reflexes).
- In advanced stages of HIV dementia (stage 3, 4), patients develop progressively more severe neurological dysfunction with pronounced psychomotor slowing, reduced verbal output, apathy, confusion, disorientation, disinhibition, and reduced awareness of illness. Smooth-pursuit ocular movements become very saccadic, and frontal lobe release reflexes are common. Motor dysfunction becomes profound and may include ataxia, severe leg weakness and spasticity, hyperreflexia, Babinski's signs, tremor, myoclonus, and bowel and bladder incontinence.
- Vacuolar myelopathy usually develops as part of the motor component of HIV dementia, but can occur in isolation. It is clinically similar to subacute combined degeneration (i.e., vitamin B12 deficiency) and presents as a progressive myelopathy with spastic paraparesis, hyperactive reflexes, Babinski's signs, gait ataxia, tremor, and urinary incontinence. In some patients, a sensory level may be appreciated.
PHYSICAL EXAM
Progressive loss of memory and cognition, often with mild motor deficits, as outlined above.
DIAGNOSTIC TESTS AND INTERPRETATION
Lab
Initial Lab Tests
In general, HIV dementia is a diagnosis of exclusion after other infections, space-occupying lesions, and processes are ruled out. The most important tests will consist of blood counts (including CD4 counts to determine stage of HIV infection), infectious cultures of appropriate tissues, and serum antibody titers of various infectious agents. Other specific tests may be helpful in certain cases, such as Venereal Disease Research Laboratory test (VDRL) or vitamin B12 levels.
Imaging
Initial Approach
MRI, with and without administration of gadolinium, is the most sensitive technique to evaluate HIV patients with loss of memory and intellectual function. HIV dementia may demonstrate atrophy or scattered, nonenhancing, white-matter lesions, as well as ventricular enlargement. Similarly, progressive multifocal leukoencephalopathy (PML) presents with patchy, nonenhancing, periventricular white-matter lesions that slowly enlarge and coalesce. Cerebral toxoplasmosis usually demonstrates multiple ring-enhancing lesions with surrounding edema. Primary CNS lymphoma (PCNSL) presents as a solitary or multifocal lesion within the deep periventricular white matter that typically enhances with contrast. Mild edema and/or mass effect may be noted. Tuberculous or fungal abscesses cause ring-enhancing lesions with surrounding edema.
Diagnostic Procedures/Other
Lumbar puncture is often helpful and should at least include routine CSF studies, bacterial/fungal antigens, cytology, CSF bacterial/viral/fungal cultures, smear and culture for acid-fast bacilli, and VDRL. In addition, surrogate markers of immune activation should be ordered, such as β2-microglobulin, quinolinic acid, and neopterin. Electroencephalography can rule out subclinical seizure activity as a cause for cognitive deterioration. Neuropsychological testing can establish a pattern of memory loss and cognitive dysfunction, and provide a baseline for subsequent follow-up testing.
Pathological Findings
Neuropathological evaluation of patients with HIV dementia often reveals cortical atrophy and ventricular dilatation, as well as abnormalities of deep structures including the hemispheric white matter, basal ganglia, and thalamus, consistent with a subcortical dementing process. Histologically, there is diffuse white-matter pallor and vacuolation, astrocytic gliosis, and cortical neuronal loss. Regions of HIV encephalitis contain multiple foci of multinucleated giant cells, foamy macrophages, lymphocytes, and microglia. The characteristic histological findings of vacuolar myelopathy consist of spongiform (vacuolar) changes of the dorsal and lateral columns, in association with lipid-filled macrophages.
DIFFERENTIAL DIAGNOSIS
The differential diagnosis includes HIV-related and non-HIV-related diseases that can lead to deterioration of memory and cognition. HIV-related diseases to consider include PML, cerebral toxoplasmosis, PCNSL, bacterial or fungal abscess, and various toxic/metabolic encephalopathies.
MEDICATION
First Line
All patients should be evaluated for zidovudine or HAART, since this may delay the onset or reduce the severity of HIV dementia. HAART usually consists of a combination of two nucleoside reverse transcriptase inhibitors (e.g., zidovudine, didanosine, lamivudine) plus one protease inhibitor (e.g., indinavir, saquinavir). Several randomized, placebo-controlled trials have shown benefit of single-agent zidovudine (1,000 or 2,000 mg/day) for delaying the onset of HIV dementia, or improving neuropsychological test performance in affected patients. Treatment with HAART can induce an improvement in clinical grading of HIV dementia, as well as reduce brain metabolite abnormalities as shown by magnetic resonance spectroscopy.
Second Line
Nimodipine (calcium channel blocker) was evaluated in a placebo-controlled clinical trial. Although the results did show a trend towards an effect for nimodipine, it was not statistically significant. Similar results have been noted in clinical trials of deprenyl (monoamine oxidase B inhibitor and anti-apoptotic agent) and lexipafant (platelet-activating factor inhibitor). A new promising agent is memantine, which blocks ion channels associated with NMDA receptors and inhibits gp120-associated neuronal injury in vitro. Clinical trials using memantine in patients with HIV dementia have shown the drug to be well tolerated. Efficacy trials are ongoing.
ADDITIONAL TREATMENT
General Measures
Antiretroviral therapy should be maximized, if possible (i.e., zidovudine, HAART). Nutritional and metabolic deficiencies should be corrected, especially those that might impact neurological function (e.g., hyponatremia). All systemic infections should be diagnosed and treated.
Additional Therapies
Patients with HIV dementia may stabilize or improve slightly on antiretroviral therapy (zidovudine or HAART). Muscle relaxants such as baclofen may be helpful to reduce spasticity and muscle spasms in patients with advanced motor complications.
SURGERY/OTHER PROCEDURES
Biopsy may be required in rare cases to differentiate HIV dementia from other focal intracranial processes.
IN-PATIENT CONSIDERATIONS
Admission Criteria
Patients are generally admitted for acute neurological changes such as altered level of consciousness, confusion, focal or generalized weakness, seizure activity, headache, and focal neurological deficits (e.g., dysphasia, hemianopsia). Patients with persistent neurological deficits should be considered for rehabilitation.
Discharge Criteria
Will be variable, depending on the specific issue that caused the admission.
FOLLOW-UP RECOMMENDATIONS
Patient Monitoring
Follow-up of neurological status will be required, especially as patients enter more advanced stages of HIV dementia.
PATIENT EDUCATION
PROGNOSIS
The course and prognosis for HIV dementia is quite poor, since it occurs in patients with low CD4 counts and advanced disease. The 6-month cumulative mortality rate for stage 2–4 HIV dementia is 67%. However, the number of patients developing late-stage HIV dementia appears to be slowing with widespread use of HAART.
COMPLICATIONS
Potential for significant progressive loss of memory and cognition, along with motor deficits.
