AUTHOR AND EDITOR INFORMATION

Section 1 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Follow-up
• Miscellaneous
• Multimedia
• References

INTRODUCTION

Section 2 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Follow-up
• Miscellaneous
• Multimedia
• References

Background

Neurologic complications from the human immunodeficiency virus (HIV) may arise from HIV itself, opportunistic infections, tumors, or drug-related complications. HIV encephalopathy and AIDS dementia complex (ADC) are the neurologic complications that arise from primary HIV infection, others include vacuolar myelopathy, peripheral neuropathies, and polymyositis.

Several important terms exist concerning CNS conditions caused by HIV. HIV encephalopathy is part of the acute HIV syndrome during seroconversion. HIV-associated progressive encephalopathy (HPE) is a syndrome complex with cognitive, motor, and behavioral features seen in children. ADC, also known as HIV-associated dementia complex (HAD), is characterized by cognitive, motor, and behavioral features in adults, which usually develops in advanced AIDS when CD4⁺ lymphocyte counts fall below 200 cells/mm³. With the advent of highly active antiretroviral therapy (HAART), a less severe dysfunction, minor cognitive motor disorder (MCMD), has become more common than ADC.

ADC is more frequently associated with advanced age and lowCD4⁺ counts.

Pathophysiology

The mechanism by which HIV infection leads to ADC is likely multifactorial and is the subject of intense research. The following paradigms are supported by multiple studies.

• HIV neuroinvasion: HIV is thought to enter the brain via HIV-infected monocytes and other infected CD4⁺ cells, which then differentiate into macrophages. The virus replicates in these cells and can then, in theory, infect other cells, such as microglia, oligodendrocytes, astrocytes, and neurons; macrophages and microglia are the most common. In vitro models have shown that HIV may enter the CNS by transcytosis of endothelial cells.

• Cellular proteins: The widespread pathologic damage may occur via indirect cellular responses with the secretion of chemokines, proinflammatory cytokines, nitrous oxide, and other neurotoxic factors. These products are produced not only from the infected cells (macrophages, astrocytes, microglia), but also from noninfected activated cells. Recently, much attention has been placed on chemokines, such as CCL4 and CXCL12, and their respective chemokine receptors, CCR5 and CXCR4, which may affect many cellular processes including neuronal migration, apoptosis, and neurotransmitter regulation.

• HIV proteins (virotoxins): Damage to neurons may occur through the actions of specific HIV proteins, including gp120, gp41, Tat, Nef, Vpr, and Rev. These viral proteins may be directly toxic to neuronal cells or may cause damage by activating astrocytes, microglia and macrophages to release cytokines, chemokines, or neurotoxic substances. Studies in several transgenic mouse models indicate that expression of a single or multiple HIV genes leads to clinical and histologic abnormalities. By initiating feedback loops, virotoxins may amplify their toxicity and cause widespread damage.

• Autoimmune disease: CNS damage by humoral immune mechanisms, as evidenced by the presence of anti-CNS antibodies in AIDS patients with dementia, but not in those without dementia.

• Altered neurotransmitter release

• Increases in excitatory amino acids and free intracellular calcium

Frequency

United States

The Multicenter AIDS cohort Study prospectively followed 2734 American men with HIV. Before HAART (1990-1992), the incidence of HIV dementia was 21 cases per 1000 person-years; after the advent of HAART (1996-1998), this value decreased to 10.5 cases per 1000 person-years.

The frequency of HPE as an initial AIDS-defining illness in children is 12-67%. In untreated children, the prevalence of HPE is about 50%. In a recent study of HIV encephalopathy in children with HIV infection who are receiving HAART, the rate of active HPE in 2000 was 1.6% and the prevalence of arrested HPE was 10%. HPE relapse occurred in 23% of the sample group with previously arrested HPE.

International

The Australian AIDS surveillance data demonstrate a pre- to post-HAART decline in the incidence of ADC of 135 reported cases in 1993-1995 to 119 cases in 1996-2000. In the same intervals, its prevalence increased from 5.2% to 6.8% because ADC patients live longer with HAART. Not surprisingly, survival of those with ADC and advanced AIDS (CD4 count <100) increased from 5 months pre-HAART to 38.5 months post-HAART.

In a study of patients with HIV in a Ugandan clinic, the prevalence of ADC was 31%. If extrapolated to sub-Saharan Africa (26 million people with HIV out of 40.3 million people infected worldwide), ADC would be the most important cause of dementia under age 40.

Mortality/Morbidity

In one study (pre-HAART), the median survival after diagnosis of ADC was 6 months, or about 2 months less than the survival in AIDS patients without dementia. However, the advent of HAART has not only improved the prognosis of AIDS in general but may also reduce the incidence of ADC and lead to improvement in cognitive function in patients who already have ADC. About 10% of HIV-infected adults have ADC and 30% have MCMD. In children treated with HAART, HPE may be thought of as an infrequent and reversible complication of HIV.

Race

In a large US cohort, the likelihood of ADC was similar in white and nonwhite patients.

Sex

The sex distribution of ADC reflects that of HIV infection.

Age

Older patients have a higher likelihood of having ADC.

Drug use: Viral proteins Tat and gp120 have been shown to have synergistic neurotoxicity with cocaine and methamphetamine. IV drug users may have a higher likelihood of developing ADC.

Other: Poorer prognosis has been associated in patients with lower educational levels, lower CD4 counts and higher HIV RNA levels, anemia, low body mass index, and more constitutional symptoms.

CLINICAL

Section 3 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Follow-up
• Miscellaneous
• Multimedia
• References

History

ADC and HPE affect cognitive, behavioral, and motor function.

• Patients often present with the insidious onset of reduced work productivity, poor concentration, mental slowness, decreased libido, and forgetfulness.
• Apathy and withdrawal from hobbies or social activities are common and must be differentiated from depression.
• Rare features include sleep disturbances, psychosis (with mania), and seizures.
• Motor problems include imbalance, clumsiness, and weakness.
• Early signs and symptoms are subtle and may be overlooked.
• Later, these symptoms evolve into a global dementia with memory loss and language impairment. This can lead to a vegetative state.
• In MCMD, activities of daily living are only mildly impaired unlike ADC.
• Regarding HPE, in infants, characteristic features include decline in intellectual and motor milestones. In young children, the rate of acquisition of new skills decreases and impairment of fine motor ability and dexterity may be associated; they may also have feeding difficulties. In older children and adolescents, the presentation is similar to that of ADC in adults.

Physical

• The neuropsychological examination reveals features more suggestive of subcortical dementia, as seen in Parkinson disease, than of cortical dementia of the Alzheimer type.
• • Early on, neuropsychological examination reveals psychomotor slowing, memory loss, and word-finding difficulties. Subcortical involvement with impaired retrieval and manipulation of acquired knowledge is prominent.
  • Later, severe psychomotor retardation and language impairment become obvious, leading to akinetic mutism.

• Neurologic examination in adults
• • Early on, the neurologic examination may be normal or reveal subtle impairment of rapid limb and eye movements.
  • Later, frontal lobe release signs, tremor, hyperreflexia, clonus, spasticity, weakness, and poor coordination develop. These signs may reflect a concomitant vacuolar myelopathy.
  • The terminal stage of ADC, after progression over several months, includes severe psychomotor retardation and dementia, apraxia, paraparesis, and akinetic mutism. Death ensues within a few months of reaching this stage.
  • Seizures are rare and warrant exclusion of other conditions.

• Price and Brew in 1988 outlined a clinical staging of ADC, summarized by the following:
• • Stage 0 (normal): Mental and motor functions are normal.
  • Stage 0.5 (equivocal/subclinical): Symptoms may be absent, minimal, or equivocal, with no impairment of work or performance of activities of daily living (ADL). Mild signs (snout response, slowed ocular or extremity movements) may be present. Gait and strength are normal.
  • Stage 1 (mild): The patient is able to perform all but the more demanding aspects of work or ADL but has unequivocal evidence of functional, intellectual, or motor impairment. Signs or symptoms may include diminished performance on neuropsychological testing. Patient can walk without assistance.
  • Stage 2 (moderate): The patient is able to perform basic activities of self-care but cannot work or maintain the more demanding aspects of daily life. The patient is ambulatory but may require a single prop.
  • Stage 3 (severe): The patient has major intellectual incapacity (cannot follow news or personal events, cannot sustain complex conversation, considerable slowing of all outputs). Motor disability precludes walking unassisted (ie, without walker or personal support); walking usually slowed and accompanied by clumsiness of arms.
  • Stage 4 (end stage): The patient is in a nearly vegetative state. Intellectual and social comprehension and output are at a rudimentary level. The patient is nearly or absolutely mute. The patient is paraparetic or paraplegic with urinary and fecal incontinence.

• Neurologic examination in pediatric populations
• • In neonates, the physical examination findings are often normal.
  • Although the age of onset is usually in the first year of life, manifestations may not be noticeable until age 2-3 years. At this time, children may present with cognitive impairment, maskedlike facies, acquired microcephaly, and pseudobulbar and corticospinal tract signs.
  • Common findings in older children and adolescents are impaired attention, decreased linguistic and scholastic performance, psychomotor slowing, emotional lability, and social withdrawal. Examination findings are similar to those in adults with ADC.

DIFFERENTIALS

Section 4 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Follow-up
• Miscellaneous
• Multimedia
• References

Other Problems to be Considered

Metabolic encephalopathies
Depression
Psychoactive drugs
Attention deficit hyperactivity disorder

WORKUP

Section 5 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Follow-up
• Miscellaneous
• Multimedia
• References

Lab Studies

• Cerebrospinal fluid (CSF) is rarely completely normal and helps to exclude other etiologies of altered mental status.
• • CSF shows elevated protein (60%) and immunoglobulin G (80%).
  • Oligoclonal bands are sometimes present.
  • CSF is usually acellular, but a mononuclear pleocytosis is found in 25%.
  • HIV antibodies are present.
  • HIV frequently is cultured from CSF or detected by means of polymerase chain reaction (PCR). CSF testing of HIV PCR may be the best correlate of ADC.
  • Several cytokines, chemokines, and other soluble factors are increased, including beta-2 microglobulin, neopterin, and quinolinic acid.
  • Dopamine levels are reduced.

• Serum studies
• • Vitamin B-12 and folic acid levels should be determined and, if necessary, corrected (see Vitamin B-12 Associated Neurological Diseases.
  • In cases of borderline low B-12 levels, homocysteine and methylmalonic acid levels are better indicators of a deficiency.
  • An assay for anti-parietal cell or anti-intrinsic factor antibodies and a Schilling test may be indicated.

Imaging Studies

• These can support a diagnosis of ADC and rule out other neurologic opportunistic infections or neoplasms.
• Diffuse cortical atrophy is the most common finding on CT and MRI. Basal ganglia calcifications are seen in adults but are more common in children. Neuroimaging results may be normal in MCMD.
• MRI
• • Hyperintense lesions are noted in the periventricular white matter and centrum semiovale on T2-weighted images.
  • These lesions tend to be patchy in the early stages and diffuse as the disease progresses.
  • Differential diagnosis includes multiple sclerosis (MS) and small-vessel disease.

• Position emission tomography (PET) may reveal abnormalities in cortical metabolism. This method is not widely available and is most useful as a research tool.
• Single photon emission computed tomography (SPECT) may reveal abnormalities in cerebral blood flow. This method is most useful for research rather than as a routine diagnostic tool.
• Functional MRI studies are not yet widely available, but they may demonstrate abnormalities in regional brain activation during working memory tasks before mild dementia can be detected by clinical or neuropsychological evaluation.

Other Tests

• EEG reveals generalized slowing in the later stages of ADC.
• Neuropsychological testing has a place in diagnosis, management, and monitoring in both clinical settings and research settings.
• • Early in disease, impairment of working memory is noted in bedside testing such as digit and word reversals and serial sevens.
  • In advancing disease, tests that explore motor ability (ie, Finger Tapping Test, Grooved Pegboard Test), concentration (ie, Continuous Performance Test, Trail Making Test A and B), processing (ie, Trail Making Test A and B, Choice Reaction Time), memory/learning (ie, Weschler Memory Scale, California Verbal Learning Test), abstraction (ie, Wisconsin Card-Sorting Test), and speech/language (ie, Boston Naming Test, Verbal Fluency Test) may be helpful.
  • Formal neuropsychological testing results may be normal in MCMD.

Procedures

• Brain biopsy is not recommended for corroboration, but biopsy material obtained for other reasons may confirm this diagnosis.

Histologic Findings

The hallmark is HIV encephalitis in the white and subcortical gray matter. These changes are noted in 20-90% of patients. Some patients with ADC show only minimal changes. Atrophy is typically in a frontotemporal distribution. Diffuse myelin pallor may be present but is more commonly due to changes in the blood-brain barrier than to demyelination. Vacuolation may be observed.

Cortical neuronal loss is noted in 18-50% of patients. Subcortical neuronal loss (substantia nigra) is noted in 25%. Reduced synaptic density and dendritic arborization may be observed. Some neurons and astrocytes appear to die by apoptosis. Brain tissue may be infiltrated by microglia, macrophages, lymphocytes, and multinucleated giant cells. Activated glial cells are twice as numerous in brains of patients with AIDS as in brains of controls. Microgliosis may be diffuse or form clumps or nodules, often in a perivascular pattern in the white and subcortical gray matter. Infected cells are associated consistently with macrophages/microglia and endothelial cells. Less commonly observed are astrocytes and neurons with restricted expression of HIV genes.

TREATMENT

Section 6 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Follow-up
• Miscellaneous
• Multimedia
• References

Medical Care

Currently, HAART is the cornerstone of treatment for HIV-related cognitive disorders as defended by multiple randomized, placebo-controlled trials. Strategies for Management of Anti-Retroviral Therapy 2006 (SMART), a multicenter international trial and one of the largest HIV/AIDS treatment trials ever conducted, shows benefit of continuous treatment compared with episodic treatment. Case reports and small experimental studies have shown that stimulants and L-deprenyl may be helpful for attention and memory deficits. Research regarding n-methyl-D-aspartate (NMDA) antagonists, acetylcholine esterase inhibitors, antioxidants, and chemokine-receptor antagonists is in progress. At this time, no data support use of these latter interventions.

• Metabolic causes of cognitive decline, such as other infections, vitamin deficiencies, thyroid dysfunction, and liver and renal dysfunction, should be corrected in consultation with internal medicine specialists.


• HAART protects against, induces remission, and decreases incidence of ADC and HPE.
• • Early and continuous viral suppression with HAART is associated with improved performance on neuropsychological testing.
  
  
  • Antiretrovirals with good CSF penetration are the treatment of choice and include the following: lamivudine, stavudine, zidovudine, efavirenz, nevirapine, and indinavir.
  
  
  • When treatment fails and virologic rebound occurs, cognitive function deteriorates. Optimal doses in the presence of ADC remain unclear. If ADC develops during treatment with antiretroviral agents, additional or alternative agents should be tried.


• Sometimes, depression and behavioral disturbances such as hallucinations or delusions require pharmacotherapy. However, caution is required when patients with ADC are treated with psychoactive drugs, such as antidepressants, antiepileptics, neuroleptics, and anxiolytics, because of enhanced susceptibility to sedative properties and possible paradoxical reactions. Such symptoms should be treated cooperatively by specialists in internal medicine, neurology, and psychiatry. Furthermore, physicians must remember that many drugs can upregulate the metabolism of HAART drugs, thus reducing its bioavailability.

Consultations

Care of patients with ADC and HPE is usually carried out in collaboration with primary care physicians and infectious disease specialists. Sometimes, neuropsychological testing and psychiatric consultation are helpful.

Diet

In general, patients with AIDS should be encouraged to maintain a balanced diet. Often this requires input from a nutritionist.

Activity

Patients should be encouraged to remain as active as their underlying disease permits.

FOLLOW-UP

Section 7 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Follow-up
• Miscellaneous
• Multimedia
• References

Further Inpatient Care

• Depending on the severity and manifestations of ADC, patients may require nursing home placement.
• • The severely demented and emaciated patient is at risk for decubitus ulcers.
  • Psychotic features of ADC may require psychiatric consultation.
  • Although seizures are rare, their management is difficult, because several antiseizure drugs affect blood levels of antiretroviral drugs.

Further Outpatient Care

• Patients need close follow-up because of progressive dementia, unavoidable polypharmacy with possibly toxic drug levels (in particular free drug levels), and possible development of seizures and psychosis. Patients may become incapable of self-care and require hospice care.
• HIV RNA levels and CD4⁺ T-cell counts should be evaluated periodically to uncover clinical response and treatment resistance. HIV RNA serum levels generally reflect CSF levels until late in disease when different HIV strains may be present.

Prognosis

• The prognosis is guarded.
• HAART has reduced the incidence of ADC via suppression and reversal. However, given that HAART may not be completely effective in penetrating the BBB, low levels of HIV may continue to replicate, thereby increasing the incidence of MCMD. Although MCMD may be considered a chronic condition, it may progress to a more severe dementia.
• Use of HAART has made PHE infrequent and largely reversible. If control of the virus is lost, relapse may occur.
• In the pre-HAART era, CD4⁺ counts and HIV RNA load were the best predictors of morbidity and mortality of AIDS. In the post-HAART era, their value has diminished. In a study of 329 patients who were HIV positive with CD4⁺ counts of less than 200 or less than 300 with ADC, ADC was an independent predictor of time to death.

Patient Education

• For excellent patient education resources, visit eMedicine's Dementia Center, Immune System Center, and Sexually Transmitted Diseases Center. Also, see eMedicine's patient education articles Dementia Due to HIV Infection, Dementia Overview, and HIV/AIDS.

MISCELLANEOUS

Section 8 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Follow-up
• Miscellaneous
• Multimedia
• References

Medical/Legal Pitfalls

• Misidentifying a clinical presentation as ADC can delay the appropriate treatment of conditions such as toxoplasmosis or cytomegalovirus (CMV) encephalitis.
• Appropriate treatment may also be delayed by failure to check HIV status in any otherwise young, healthy individual with cognitive, behavioral, and/or motor changes.

MULTIMEDIA

Section 9 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Follow-up
• Miscellaneous
• Multimedia
• References

Media file 1:  HIV-1 encephalopathy and AIDS dementia complex. CT scan of the brain of a patient with AIDS dementia complex (ADC) shows diffuse atrophy and ventricular enlargement and attenuation of periventricular white matter.
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Media type:  CT

Media file 2:  HIV-1 encephalopathy and AIDS dementia complex. T2-weighted MRI shows ventricular enlargement and large areas of hyperintense signal in the subcortical white matter of both frontal lobes.
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Media type:  MRI

Media file 3:  HIV-1 encephalopathy and AIDS dementia complex. Photomicrograph from a patient with AIDS dementia complex (ADC) shows perivascular and parenchymal infiltrates of lymphocytes and macrophages. These often form microglial nodules. Image contributed by Dr Beth Levy, Saint Louis University School of Medicine, St Louis, Missouri.
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Media type:  Photo

Media file 4:  HIV-1 encephalopathy and AIDS dementia complex. Photomicrograph from patient with AIDS dementia complex (ADC) illustrates the intense astrogliosis that is characteristic of HIV encephalitis. Image contributed by Dr Beth Levy, Saint Louis University School of Medicine, St Louis, Missouri.
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Media type:  Photo

Media file 5:  HIV-1 encephalopathy and AIDS dementia complex. Multinucleated giant cells, as shown here, are a hallmark of HIV encephalitis and harbor the virus. Image contributed by Dr Beth Levy, Saint Louis University School of Medicine, St Louis, Missouri.
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Media type:  Photo

REFERENCES

Section 10 of 10

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Follow-up
• Miscellaneous
• Multimedia
• References

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Article Last Updated: May 8, 2007