eMedicine Specialties > Psychiatry > Psychosomatic

Dementia Due to HIV Disease

Soma Sahai-Srivastava, MD, Director of Neurology Ambulatory Care Services, LAC and USC Medical Center; Assistant Professor, Department of Neurology, University of Southern California
Arousiak Varpetian, MD, Assistant Professor of Clinical Neurology, Department of Neurology, University of Southern California Keck School of Medicine; Clinical Director, Rand Schrader Neurology Clinic (Los Angeles County-University of Southern California HIV Clinic)

Updated: Jan 2, 2009

Introduction

Background

Physicians frequently encounter neurologic and psychiatric complications in patients with human immunodeficiency virus (HIV) infection. This is not surprising since the HIV virus enters the central nervous system (CNS) early in the course of the infection. Prior to the advent of highly active antiretroviral therapy (HAART), dementia was a common source of morbidity and mortality, usually observed in the late stages of AIDS, and was seen in up to 50% of patients prior to their death.¹  In 1986, the term AIDS dementia complex (ADC) was introduced to describe a unique constellation of neurobehavioral findings.^2,3  ADC is now considered a single entity with a broad and varied spectrum of clinical manifestations and severity.⁴

Globally, 33.2 million people were estimated to be living with HIV/AIDS in 2007.² Of those people, only 2 million have access to HAART because they live in developed countries.

In the United States, more than 1 million people are estimated to live with HIV.¹ With the changing face of AIDS and HIV infection, a geographical difference in how ADC presents is now clear. HAART has brought dramatic changes in the lives of patients and divided the disease into "have" and "have nots." On one hand, in developed countries like the United States, having an HIV-infected patient present for the first time with a full-blown ADC picture is rare; on the other hand, in countries like Africa where HAART is not available, this scenario is still the norm.

Pathophysiology

HIV enters the CNS by infecting macrophages and monocytes that then cross the blood brain barrier, carrying the virus with them. Immunohistochemistry studies show that the virus is most densely located in the basal ganglia, subcortical regions, and frontal cortex. Pathological changes at autopsy are also predominantly subcortical, involving the deep gray (ie, basal ganglia, thalamus) and white matter regions. Infected macrophages or microglial cells then elaborate proinflammatory⁶ diffusable cellular neurotoxins, including tumor necrosis factor-alpha (TNF-alpha), cytokines, interleukins, chemokines, nitric oxide, and excitatory amino acids. These neurotoxic agents create an inflammatory environment by activating uninfected microglia and then proceed to injure surrounding astrocytes and neurons. HIV does not directly infect the neuron, but the neuron is damaged by the effects of various proinflammatory neurotoxins.

Using immunohistochemical techniques, many HIV viral products have been implicated in HIV dementia. The basal ganglia show the highest immunostaining by the HIV p24 antigen. Some studies show that gp41 expression in the basal ganglia and frontal lobes correlates significantly with the severity of dementia. Other viral proteins, including tat and gp120, are present in abundance in the brains of patients with HIV dementia. gp120 causes neuronal death in vitro and is accompanied by the opening of calcium channels in the neuronal membrane.

A lot of research and interest has been generated in the role of p53 (tumor suppressor transcription factor)⁷ , which appears to have multiple roles in the pathogenesis of the disease. HIV proteins tat and gp120 cause microglia to release factors that promote neuronal p53 activation. All 3 cell types in the brain (microglia, astrocytes, and neurons) accumulate p53, causing cell cycle arrest; in neurons, this ultimately induces apoptosis and cell death by oxidative injury and DNA damage.⁸

In summary, both viral (eg, gp120, gp41, tat) and host cell products (eg, TNF-alpha, cytokines, interleukins, quinolates, nitric oxide, platelet-activating factors) can either amplify or directly contribute to neuronal injury.^9,10 However, the presence of macrophages and microglia correlate better with clinical dementia than with the amount of HIV-infected cells in the brain, as determined by gp41-positive cells.¹¹

Frequency

United States

The annual incidence of HIV dementia in the Western world prior to HAART was 7%, with a cumulative risk of 5-20%.¹²  With HAART, the incidence of HIV dementia started declining initially, but has begun increasing again. The incidence of HIV-1 encephalopathy has been increasing in the post–HAART era. The prevalence of the disorder is now increasing; the cumulative incidence is 25-38% and the prevalence is around 37%.¹²  Milder forms of ADC affect an additional 30-40% of patients. In the post-HAART period, rapidly progressive dementia is less commonly a presentation, and chronic and fluctuating forms of HIV dementia are more common.

In 4-15% of patients, ADC is the presenting clinical manifestation of HIV disease.¹²  The multicenter AIDS cohort study found a rate of HIV dementia of less than 1% in asymptomatic seropositive patients.¹³

Mortality/Morbidity

ADC causes a significant increase in the overall morbidity due to AIDS.

• The increase in morbidity results from a combination of factors, including the increased number of hospitalizations, increased duration of hospital stays, and decreased life expectancy compared with AIDS patients who do not have dementia. In the pre-HAART era, AIDS patients who had untreated ADC had an average life span of 6 months, which was significantly less than that for AIDS patients without dementia. This has now increased to 38 months for ADC patients in the Western hemisphere who have been on a stable regimen of HAART.¹²
• The overall psychosocial and emotional burden on the family and friends of such patients is tremendous, far beyond that of a cognitively intact patient with AIDS.
• Patients with cognitive difficulties have problems with compliance and adherence to their medication regimen. Because of their neuropsychiatric problems, these patients are likely to be less inhibited and are more prone to HIV-related risk behavior like unprotected intercourse, and they therefore pose a greater risk of transmission of the virus.  

Comorbidities

• Hepatitis C virus: HIV infection and hepatitis C virus infection affect disease progression of each other. HIV-1 infection accelerates the progression of HCV-associated liver fibrosis. Infection with multiple genotypes of HCV can accelerate the progression of HIV disease.¹⁴
• CMV: This virus is the most commonly found co-infection in HIV-1 infected patients at autopsy. Wohl et al studied CMV-seropositive patients and concluded that CMV DNA was an independent predictor of death, aside from the well-known predictors, CD-4 count and HIV-plasma load. In the HAART era, CMV encephalopathy has decreased in incidence.¹⁵
• Neurosyphilis: The course of neurosyphilis is shortened, and it is more aggressive and difficult to treat in HIV patients.

Race

HIV has a high incidence and prevalence in the African-American community, which is reflected in the race distribution of ADC.

Sex

Some data suggest that female gender may be a risk factor of HIV dementia.¹⁶  Some studies have found that women with HIV may have a more rapid progression of neurologic symptoms and signs.^17,12

Age

The Multicenter AIDS Cohort Study reported that older age was associated with more rapid progression to dementia and death.¹⁸ Becker et al reported that the prevalence of cognitive disorders in those who are HIV positive and older than 50 years was significantly greater than in younger patients.¹⁹

Clinical

History

See Nosology in Background.

Physical

The examination includes a full Mental Status Examination (MSE), a general neurologic examination, and a general physical examination. The patient should then be referred to a neuropsychologist for complete neuropsychological testing addressing specific domains as suggested above.

• Some patients with HIV can become depressed, suicidal, and homicidal. Therefore, a thorough psychiatric assessment should also be performed at each visit.
• In the early stage, findings from the MSE and the general neurologic examination are normal. MSE findings are abnormal if the patient exhibits inattention, impaired concentration (eg, digit span, serial 7' s), memory loss (eg, recalling 3 objects at 5 min), slowed verbal responses, and a blunted affect.
• In the more severe form of HIV-associated dementia complex, the neurologic examination shows frontal release signs, slowed rapid movements, antisaccadic eye movements, incoordination, abnormal gait, hyperreflexia, hypertonia, extensor-plantar response weakness, and peripheral neuropathy.³ Cortical signs, including apraxia, aphasia, and agnosia, typically are absent.
• In the late stages of the disease, patients also may have quadriparesis or paraparesis, myoclonus, and incontinence.²⁰

Causes

• Several risk factors for ADC have been identified, including low weight, anemia, constitutional symptoms, low CD4 count, and high plasma HIV-RNA load.
• The prevalence of ADC increases 3-fold with a CD4 count of less than 200/µL and increases 7-fold with a CD4 count of less than 100/µL.
• Patients with concomitant hepatitis C virus (HCV) have a worse cognitive status than those without.
• A recent report implicated apolipoprotein E4 as a risk factor for the development of dementia.

Differential Diagnoses

Other Problems to Be Considered

Medication adverse effects: Antiretroviral medications can sometimes have neurocognitive side effects (eg, efavirenz therapy can result in depression, insomnia, and decreased neuropsychological testing).²¹

Immune reconstitution inflammatory syndrome (IRIS): Clinical worsening may be observed in patients with HIV soon after initiation of HAART therapy due to mounting of a significant inflammatory response. This is seen even while patients’ CD4 count improves and viral load dramatically decreases. IRIS may actually worsen ADC and PML.²² ADC and IRIS can be distinguished by the speed of onset: ADC is subacute to chronic whereas IRIS can be more acute to subacute. ADC occurs in the setting of untreated progressive AIDS whereas IRIS begins with the start of treatment. Distinguishing between the 2 is important because the treatment is different. ADC requires HAART with high penetration into CNS. IRIS should be treated with steroids depending on its severity.

A 40-year-old woman presented with confusion, decline in memory without any focal findings, and dehydration. She was diagnosed with HIV 3 months prior and started on HAART medication 1 month prior when she had no cognitive symptoms. The MRI shows atrophy and white matter hyperintensity on T2 not involving U-fibers. CSF studies were negative for demyelinating disease, JC virus DNA, cryptococcal antigen, and CMV IgG and IgM. Confusion eventually improved with hydration, but on follow-up 2 months later, she still had significant cognitive deficits and needed assistance from family in instrumental activities of daily living.

Workup

Laboratory Studies

• HIV antibody and Western blot testing as well as viral load and CD4 count
• Draw peripheral blood for syphilis serology testing, vitamin B-12 and folate levels, thyroid studies, routine electrolyte levels, BUN/creatinine determination, and a drug screen to effectively exclude other metabolic and infectious etiologies.²³
• TB testing/screening

Imaging Studies

• In the early stages, neuroimaging study findings may be entirely normal.
• CT scanning of the brain can reveal brain atrophy, ventricular enlargement, and increased white matter signal in later stages.
• MRI is the first-choice neuroimaging modality. An MRI of the brain must be performed to exclude other CNS causes of dementia, including toxoplasmosis, progressive multifocal leukoencephalopathy, and cerebral lymphoma. In the late stages of AIDS dementia complex (ADC), MRI findings typically show diffuse nonenhancing white matter, hyperintensity, cerebral atrophy, and ventricular enlargement. The degree of cerebral atrophy correlates with the symptoms and progression of ADC.
• Positron emission tomography (PET) scanning and functional nuclear MRI reveal decreased metabolism in the thalamus and basal ganglia in the early stages of ADC. PET scanning can be particularly useful in very difficult cases to help exclude CNS lymphoma, which shows increased uptake, whereas the lesions of AIDS dementia do not.
• Proton magnetic resonance spectroscopy (MRS) is a functional imaging technique that measures brain metabolites. In persons with ADC, neuronal injury is confirmed by finding lower N -acetyl aspartate (NA) levels (a marker of neuronal metabolism) in the frontal white matter. In the basal ganglia and white matter, where gliosis and inflammatory changes are noted, the level of choline-containing metabolites, which is a marker of glial metabolism, is increased. In the future, proton MRS could be used to follow the effectiveness of CNS-targeted therapies for ADC.
• Chang et al recently showed that even in the asymptomatic stage, metabolite changes are seen by MRS in the basal ganglia and frontal white matter. In the absence of clinically recognizable symptoms, elevated glial marker, myoinositol to creatinine ratio (MI/Cr), is seen in the white matter, indicating early HIV brain disease. Patients with ADC have elevated MI/Cr and choline to creatinine ratio (Cho/Cr) in basal ganglia and white matter, relative to the asymptomatic group. However, compared with controls, patients with ADC have decreased NA/Cr ratio, which is a neuronal marker. The decreased NA/Cr ratio in ADC is more profound in younger subjects. This indicates that in older individuals, the metabolic changes seen may be a combination of age and HIV infection.^24,25

A 22-year-old woman who was infected with HIV from a perinatal blood transfusion, presented with bilateral leg weakness. Brain MRI showed atrophy and minimal white matter hyperintensity. Thoracic and lumbar MRI showed no abnormalities. The radiological diagnosis was HIV-encephalitis. The weakness in the legs did not change over the next 4 years. Despite treatment with HAART, cognitive changes developed 4 years later. The patient died of intracranial hemorrhage due to blood dyscrasia at the age of 25.

A 22-year-old woman who was infected with HIV from a perinatal blood transfusion, presented with bilateral leg weakness. Brain MRI showed atrophy and minimal white matter hyperintensity. Thoracic and lumbar MRI showed no abnormalities. The radiological diagnosis was HIV-encephalitis. The weakness in the legs did not change over the next 4 years. Despite treatment with HAART, cognitive changes developed 4 years later. The patient died of intracranial hemorrhage due to blood dyscrasia at the age of 25.

A 22-year-old woman who was infected with HIV from a perinatal blood transfusion, presented with bilateral leg weakness. Brain MRI showed atrophy and minimal white matter hyperintensity. Thoracic and lumbar MRI showed no abnormalities. The radiological diagnosis was HIV-encephalitis. The weakness in the legs did not change over the next 4 years. Despite treatment with HAART, cognitive changes developed 4 years later. The patient died of intracranial hemorrhage due to blood dyscrasia at the age of 25.

Candida, GMS stain.

Cerebritis.

Pontine hemorrhage.

Other Tests

• Electroencephalogram
  • Patients with subclinical seizures may present with symptoms that mimic dementia. Consider performing an EEG to help exclude this type of pseudodementia.
  • EEG findings may be normal in early dementia or may demonstrate diffuse slowing. However, this finding is nonspecific and is present in persons with dementia from any cause (even metabolic); therefore, it does not help in making an etiologic diagnosis.
• Neuropsychological testing
  • This type of testing can be used for early screening of asymptomatic high-risk patients (eg, those with high viral load and low CD4 count²⁶ ) and for follow-up evaluations of patients with ADC.
  • In the early stages of the disease, MSE findings may be entirely normal. In such cases, neuropsychological testing is especially useful and can help detect mild early cognitive abnormalities. Performing this test can help quantify and determine the specific pattern of the cognitive abnormality.
  • Specialists use several neuropsychiatric screening techniques; the most widely accepted is the HIV dementia scale. The scale consists of 4 subsets that target memory (eg, recall, registration), psychomotor speed, constructional ability, and concentration. A total of 12 points can be earned, and a score of fewer than 6 points is considered abnormal. The test takes 10 minutes to administer and can be given by a nonneurologist. These tests are useful diagnostic adjuncts, but the results cannot solely determine the presence of ADC.
• Combination screening: The Memorial Sloan-Kettering rating scale is used for clinical staging of ADC from 0 (normal) to 4 (end stage). It combines functional ability results with the findings from neuropsychological testing. Currently, it is used mostly as a research instrument.

Procedures

Lumbar puncture and cerebrospinal fluid (CSF)

• CSF studies, including cryptococcal antigen, CSF Venereal Disease Research Laboratory (VDRL) test, fluorescent treponemal antibody-absorption test (FTA-abs), and cytomegalovirus polymerase chain reaction (PCR) test help exclude CNS infection. Depending on the clinical picture, PCR studies may also be obtained for herpes simplex and varicella zoster viruses and JC virus (the causative agent of progressive multifocal leukoencephalopathy [PML]).
• Patients with ADC usually have a mild elevation of CSF protein levels and, in the cell count, increased total immunoglobulin fraction and intrathecal synthesis of anti-HIV immunoglobulin G, with the detection of oligoclonal bands in as many as 35% of cases.
• These CSF abnormalities are nonspecific and are often present in neurologically asymptomatic patients with HIV.
• HIV-1 virus is present in CSF in the absence of neurologic abnormalities. CSF HIV RNA levels do not correlate with neuropsychological impairment; rather, plasma levels are a better correlation.
• CSF markers are helpful in early dementia, when the diagnosis may be confusing. CSF markers, including neopterin, quinolinic acid, certain cytokines (eg, TNF-alpha, interleukin 1, interleukin 6), and antibodies to gp120 (eg, HIV viral envelope protein), correlate with the severity of dementia, but are only research tools and therefore not widely available. CSF beta-2 microglobulin, an immune activation marker, is a more specific CSF marker and has a positive predictive value of 88% if levels are higher than 3.8 mg/dL. CSF beta-2 microglobulin levels were twice as high in patients who cognitively improved with HAART than in those who did not, indicating that CNS inflammation plays a major role in reversible neurocognitive deficits.
• Some studies have shown the association of plasma TNF-alpha and CSF macrophage chemoattractant protein 1 (MCP-1) with ADC.²⁷
• Patients with HIV dementia have elevated levels of certain matrix metalloproteins in the CSF, but the clinical significance of these metalloproteins is unclear.

Histologic Findings

Gross brain specimens show white matter pallor and microglial nodules. Microscopically, ADC is typically associated with a triad of multinucleate giant cells, microglial nodules, and perivenular inflammation. Severe ADC is characterized microscopically by microgranulomatous foci of multinucleate giant cells, initially in the white matter and later in the gray matter. Reactive gliosis is also observed, in which an increase occurs in both the number and size of astrocytes, associated with infiltration by monocytes.

Treatment

Medical Care

The standard of care for a patient with AIDS is to use 3 or more antiretroviral agents. Triple therapy has been shown to improve neurologic outcome when compared with dual or single treatment regimens. The routine use of HAART has changed the epidemiology of HIV dementia in the Western hemisphere.²⁸ HAART regimens can reverse some of the neurologic deficits of HIV-D, with patients showing improvements in motor and psychomotor speed. This improvement was independent of CNS penetration of specific antiretroviral drugs. Multiple studies have shown that patients on HAART show partial reversals of neuropsychological deficits and significant improvement, which is sustained, whereas patients not on HAART steadily decline.²⁹

Several cohort studies have shown that treatment with multiple antiretroviral agents is superior to either no treatment or monotherapy in patients with AIDS dementia complex (ADC).^30,12  This finding is based on clinical follow-up of patients with neuropsychological testing. ADC is clearly an indication for HAART, regardless of the combination of antiretroviral agents used. The Strategies for Management of Anti-Retroviral Therapy (SMART) study showed that it is better to follow HIV plasma viral load and consistently keep it suppressed than to adjust therapy based on peripheral CD4 counts.^31,32

More than 20 antiretroviral medications are used to treat HIV. Most of them have poor CSF-to-plasma drug ratios, indicating poor CNS penetration. Exceptions include stavudine, abacavir, nevirapine, and zidovudine (ZDV). However, whether this translates into poor drug levels in CNS tissue, and whether drug penetrance is clinically important remains unclear. One study showed that patients treated with a HAART regimen containing multiple drugs with good CNS penetrance did not experience improved outcomes compared with patients treated with a HAART regimen composed of a single drug with good CNS penentrance.³³  In the absence of more data, no general recommendation exists to change a patient’s therapy of HAART to higher penetrance based on their cognitive status.¹³  

ZDV is the most studied antiretroviral medication.³⁴ Since its initial introduction in 1987, several studies have consistently shown that ZDV reduces the rate of HIV dementia from greater than 53% to 10%.³⁵ It improves radiologic, neuropsychologic, and clinical findings in patients with ADC. However, adding ZDV, which is the drug with the best CSF penetrance, to an immunologically and virologically effective regimen does not improve the clinical efficacy of the HAART combinations.
 
Researchers are studying several experimental therapies (eg, memantine, nimodipine, delavirdine, peptide T, lexipafant). These therapies are either neuroprotective agents or they attempt to block the release of neurotoxic agents by macrophages or platelets. Several of these protocols are undergoing clinical trials.

Consultations

• Specialist (infectious diseases or general practice physician) with expertise in HIV: An HIV treatment expert should treat all patients with ADC with a HAART regimen that is clinically, virologically, and immunologically effective.
• Psychiatrist
  • Patients with ADC commonly exhibit agitation, anxiety, fatigue, depression, and other psychiatric manifestations. Mania and psychosis have been described as presenting symptoms or complications of ADC.
  • Consultation with a psychiatrist may be required to discuss appropriate use of antidepressants, antipsychotics, or stimulants.
  • Psychotherapy may be helpful for patients with mild-to-moderate dementia to help them understand, mourn, and adapt to this new impairment in functioning.
  • Neurologist with expertise in neurobehavior: As the population of patients with HIV ages, dementia is a risk because it occurs late in life. A neurologic workup by a neurologist specializing in neurobehavioral disorders may help to sort out the etiology of cognitive impairment. Older patient with HIV may develop Parkinson’s disease, frontotemporal dementia, Lewy body dementia, or Alzheimer’s disease unrelated to HIV.
• Rehabilitation therapist
  • The care of patients with ADC is best accomplished with a team approach.
  • Both the physical and occupational therapist play a vital role in trying to maximize the functional capacity of the patient.

Diet

• Nutritional therapies
  • Nutritional therapies may be considered as potential interventions in the follow-up care for patients with cognitive motor symptoms associated with HIV infection.
  • Oxidative free-radical scavengers, such as vitamin E, the experimental antioxidant OPC-4117, and the trace mineral and antioxidant selenium, may prove therapeutically useful.

Medication

HIV infection is significant in the pathogenesis of ADC. Initiate antiretroviral therapy for untreated patients, and optimize therapy for patients currently on antiretroviral therapy. For further information on antiretroviral therapy, see the eMedicine article HIV Infection, Antiretroviral Therapy.

Follow-up

Further Inpatient Care

Once the diagnostic workup is completed, patients can receive follow-up care in an outpatient setting. Patients with advanced dementia may need supportive inpatient care.

Further Outpatient Care

• Systemic virologic suppression is associated with cognitive improvement, which may reflect a decrease in the CNS viral load.
• Neuropsychological testing is a more sensitive method of following cognitive changes than a simple neurologic examination. Serial testing should be performed at regular intervals to monitor for improvement in scores and responses to therapy.
• Radiologic follow-up with serial neuroimaging (ie, MRI) at regular intervals is a useful follow-up tool. These test results show decreased brain atrophy and improvement in white matter changes if the patient is responding to antiretroviral therapy.
• Nutritional therapies may be considered as potential interventions for the cognitive motor symptoms associated with HIV infection. Oxidative free-radical scavengers, such as vitamin E, the experimental antioxidant OPC-4117, and the trace mineral and antioxidant selenium, may prove therapeutically useful.

Inpatient & Outpatient Medications

Antiretroviral medications should be continued indefinitely in essentially all cases.

Deterrence/Prevention

Aggressive early treatment of patients with HIV disease with antiviral medications and early suppression of viral replication results in successful control of infection and prevents most of the devastating consequences of HIV dementia. Several studies have shown that early and aggressive treatment of HIV infection decreases the rate of dementia from greater than 50% to 10%.

Complications

Adverse effects from medications and drug interactions are the most common complications.

Prognosis

• ADC has a variable progression.³⁶ Typically, without treatment, the disease has a rapid progression over a few months, with a mean survival rate of 3-6 months. The survival rate has increased from 5 months in 1993-94 to 38.5 months in the 1996-2000 period.¹²  The prevalence is increasing, but presentation is now milder. Predictors of rapid neurologic progression prior to HAART were psychomotor slowing, injection drug use, and low CD4 counts. Co-infection with hepatitis C is another marker of worse prognosis. Cognitive improvement is observed in patients with ADC after the initiation of HAART. Sevigny et al have shown a significant and independent association of HIV-associated dementia with time to death. HIV-associated dementia is a significant risk factor for death. Poor medication adherence may be a factor. Plasma and CSF MCP-1 levels were also associated with time to death.²⁷
• Advanced HIV disease with high viral load or low CD4 count, poor health with anemia and wasting disease carry a poor prognosis.
• Include cognitive screening tests in routine examination of patients, especially with those at high risk such as those who are older or who have high plasma HIV RNA levels, low CD4 counts or HCV, and poor baseline cognitive status.
• The development of dementia is usually delayed until severe immunodeficiency develops. This finding is interesting because HIV invades the brain early in its course. ADC may remain static or may fluctuate. ADC may improve with medical therapy, or it may worsen abruptly with severe metabolic disorders (eg, hypoxemia, pneumonia) and then improve with the resolution of the metabolic disorders. Some studies report that older age, a lower CD4 cell count, decreased hemoglobin level, reduced platelet count, and thrush are related to rapid disease progression. One study showed that injection drug use and the presence of psychomotor slowing are associated with rapid progression of the dementia.

Patient Education

• Educate the patient at an early stage, and discuss future medicolegal implications of dementia. A patient should be strongly encouraged to prepare a living will or to assign power of attorney.
• Educate patients and families about the persistent dangers of the transmission of HIV. The following Web sites can be referenced for further information.
  • Centers for Disease Control and Prevention -HIV and Its Transmission
  • National Institutes of Health -HIV Infection and AIDS: An Overview
  • UCSF Center for HIV Information -HIV Transmission and Prevention in Adolescents
• Education of family members, friends, and caregivers of a patient with HIV dementia is of great importance. HIV dementia is a multifaceted problem, and caregivers should know about the complications, including psychiatric complications. Often, friends and family need counseling and support to deal with this chronic and difficult condition.
• 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

Medicolegal Pitfalls

• Failure to exclude all other infectious etiologies because dementia due to HIV disease is a diagnosis of exclusion.
• Importantly a healthcare provider needs to discuss issues like a living will and durable power of attorney in managing health care for the patient with HIV. Patients should be strongly encouraged to prepare a living will or assign power of attorney early in their disease process. In cases where HIV-associated dementia is established, addressing issues of competence to make medical decisions is also important.
• Healthcare providers need to address several issues of critical importance with regard to a neurocognitively impaired patients with HIV infection.
  • Patients may at times reject treatment offered by a physician, even at the risk of remaining ill. A person’s right to autonomy cannot be challenged, provided that he or she has the competence to understand the risks and benefits of the treatment offered. Competent to consent to medical treatment is defined as the “mental capacity necessary to comprehend the risks and benefits of a proposed medical treatment and its alternatives.” The only exception to this situation would be a medical emergency in which the hospital or physician may obtain consent from a surrogate, a close family member, or a spouse. The healthcare provider may then render care to the patient in his or her best interest and treat the medical emergency.
  • In a psychiatry setting, competence is considered as “the ability to understand and appreciate those duties to society owed by an ordinary citizen to reasonable prudence and care.” This is pertinent for the patients with HIV-associated dementia who, due to their severe neurocognitive impairment, may be unable to provide for themselves and may endanger themselves or others. California’s Welfare and Institutions Code, Section 5150, allows the custodial detention and involuntary hospitalization persons believed to be disabled due to their mental condition such that they pose a grave danger to themselves or to others.
  • Only a county mental health professional psychiatric crisis team, state-designated mental health professional, or peace officer can authorize involuntary hospitalization. Within 72 hours, the patient must be evaluated for mental capacity and grave disability. Grave disability is determined by the ability of the person to provide basic food, clothing, and shelter for him or herself. If the patient is determined to be gravely disabled, the hold can be extended for 14 days and the superior court can be petitioned for appointment of a conservator.
  • In late-stage, HIV-associated dementia, and earlier as well, the ability to safely operate a motor vehicle may be jeopardized. The clinician has a duty to advise both the patient and the Department of Motor Vehicles that it is unsafe for the patient to drive. Some patients may have severe sensory loss related to HIV-associated peripheral neuropathy and thus may be unsafe to drive on that basis. The healthcare provider's direct responsibility is to report such patients to the Department of Motor Vehicles as potentially unsafe to be driving.³⁷

Multimedia

Media file 1: A 40-year-old woman presented with confusion, decline in memory without any focal findings, and dehydration. She was diagnosed with HIV 3 months prior and started on HAART medication 1 month prior when she had no cognitive symptoms. The MRI shows atrophy and white matter hyperintensity on T2 not involving U-fibers. CSF studies were negative for demyelinating disease, JC virus DNA, cryptococcal antigen, and CMV IgG and IgM. Confusion eventually improved with hydration, but on follow-up 2 months later, she still had significant cognitive deficits and needed assistance from family in instrumental activities of daily living.

Media file 2: A 22-year-old woman who was infected with HIV from a perinatal blood transfusion, presented with bilateral leg weakness. Brain MRI showed atrophy and minimal white matter hyperintensity. Thoracic and lumbar MRI showed no abnormalities. The radiological diagnosis was HIV-encephalitis. The weakness in the legs did not change over the next 4 years. Despite treatment with HAART, cognitive changes developed 4 years later. The patient died of intracranial hemorrhage due to blood dyscrasia at the age of 25.

Media file 3: A 22-year-old woman who was infected with HIV from a perinatal blood transfusion, presented with bilateral leg weakness. Brain MRI showed atrophy and minimal white matter hyperintensity. Thoracic and lumbar MRI showed no abnormalities. The radiological diagnosis was HIV-encephalitis. The weakness in the legs did not change over the next 4 years. Despite treatment with HAART, cognitive changes developed 4 years later. The patient died of intracranial hemorrhage due to blood dyscrasia at the age of 25.

Media file 4: A 22-year-old woman who was infected with HIV from a perinatal blood transfusion, presented with bilateral leg weakness. Brain MRI showed atrophy and minimal white matter hyperintensity. Thoracic and lumbar MRI showed no abnormalities. The radiological diagnosis was HIV-encephalitis. The weakness in the legs did not change over the next 4 years. Despite treatment with HAART, cognitive changes developed 4 years later. The patient died of intracranial hemorrhage due to blood dyscrasia at the age of 25.

Media file 5: Candida, GMS stain.

Media file 6: Cerebritis.

Media file 7: Pontine hemorrhage.

Media file 8: Spinal cord infarction.

References

1. Ances BM, Ellis RJ. Dementia and neurocognitive disorders due to HIV-1 infection. Semin Neurol. Feb 2007;27(1):86-92. [Medline].

2. UNAIDS and WHO. 2007 AIDS epidemic update. UNAIDS. Available at http://data.unaids.org/pub/EPISlides/2007/2007_epiupdate_en.pdf. Accessed 3/25/08.

3. Navia BA. Clinical and biologic features of the AIDS dementia complex. Neuroimaging Clin N Am. Aug 1997;7(3):581-92. [Medline].

4. Nomenclature and research case definitions for neurologic manifestations of human immunodeficiency virus-type 1 (HIV-1) infection. Report of a Working Group of the American Academy of Neurology AIDS Task Force. Neurology. Jun 1991;41(6):778-85. [Medline].

5. Antinori A, Arendt G, Becker JT, Brew BJ, Byrd DA, Cherner M. Updated research nosology for HIV-associated neurocognitive disorders. Neurology. Oct 30 2007;69(18):1789-99. [Medline].

6. Brabers NA, Nottet HS. Role of the pro-inflammatory cytokines TNF-alpha and IL-1beta in HIV-associated dementia. Eur J Clin Invest. Jul 2006;36(7):447-58. [Medline].

7. Garden GA, Morrison RS. The multiple roles of p53 in the pathogenesis of HIV associated dementia. Biochem Biophys Res Commun. Jun 10 2005;331(3):799-809. [Medline].

8. Nardacci R, Antinori A, Kroemer G, Piacentini M. Cell death mechanisms in HIV-associated dementia: the involvement of syncytia. Cell Death Differ. Aug 2005;12 Suppl 1:855-8. [Medline].

9. Di Rocco A, Werner P. Hypothesis on the pathogenesis of vacuolar myelopathy, dementia, and peripheral neuropathy in AIDS. J Neurol Neurosurg Psychiatry. Apr 1999;66(4):554. [Medline].

10. Swingler S. Pathogenic mechanisms of neuronal damage in the AIDS dementia complex. Mol Pathol. Apr 1997;50(2):72-6. [Medline].

11. Tan SV, Guiloff RJ. Hypothesis on the pathogenesis of vacuolar myelopathy, dementia, and peripheral neuropathy in AIDS. J Neurol Neurosurg Psychiatry. Jul 1998;65(1):23-8. [Medline].

12. McArthur JC. HIV dementia: an evolving disease. J Neuroimmunol. Dec 2004;157(1-2):3-10. [Medline].

13. Sacktor N, Lyles RH, Skolasky R, Kleeberger C, Selnes OA, Miller EN, et al. HIV-associated neurologic disease incidence changes:: Multicenter AIDS Cohort Study, 1990-1998. Neurology. Jan 23 2001;56(2):257-60. [Medline].

14. Goodkin K, Aronow A, Baldwin G, Molina R, Zheng, W, et al. HIV-1 associated neurocognitive disorders in the HAART era. In: The Spectrum of Neuro-AIDS Disorders. Washington DC: ASM Press; 2008.

15. Wohl DA, Zeng D, Stewart P, Glomb N, Alcorn T, Jones S. Cytomegalovirus viremia, mortality, and end-organ disease among patients with AIDS receiving potent antiretroviral therapies. J Acquir Immune Defic Syndr. Apr 15 2005;38(5):538-44. [Medline].

16. Stern Y, McDermott MP, Albert S, Palumbo D, Selnes OA, McArthur J. Factors associated with incident human immunodeficiency virus-dementia. Arch Neurol. Mar 2001;58(3):473-9. [Medline].

17. Liu X, Marder K, Stern Y, Dooneief G, Bell K, Todak G. Gender Differences in HIV-Related Neurological Progression in a Cohort of Injecting Drug Users Followed for 3.5 Years. J NeuroAIDS. 1996;1(4):17-30. [Medline].

18. Farinpour R, Miller EN, Satz P, Selnes OA, Cohen BA, Becker JT. Psychosocial risk factors of HIV morbidity and mortality: findings from the Multicenter AIDS Cohort Study (MACS). J Clin Exp Neuropsychol. Aug 2003;25(5):654-70. [Medline].

19. Becker JT, Lopez OL, Dew MA, Aizenstein HJ. Prevalence of cognitive disorders differs as a function of age in HIV virus infection. AIDS. Jan 1 2004;18 Suppl 1:S11-8. [Medline].

20. Skolnick AA. Protease inhibitors may reverse AIDS dementia. JAMA. Feb 11 1998;279(6):419. [Medline].

21. Blanch J, Martínez E, Rousaud A, Blanco JL, García-Viejo MA, Peri JM. Preliminary data of a prospective study on neuropsychiatric side effects after initiation of efavirenz. J Acquir Immune Defic Syndr. Aug 1 2001;27(4):336-43. [Medline].

22. Vendrely A, Bienvenu B, Gasnault J, Thiebault JB, Salmon D, Gray F. Fulminant inflammatory leukoencephalopathy associated with HAART-induced immune restoration in AIDS-related progressive multifocal leukoencephalopathy. Acta Neuropathol. Apr 2005;109(4):449-55. [Medline].

23. Lee PL, Yiannoutsos CT, Ernst T, Chang L, Marra CM, Jarvik JG, et al. A multi-center 1H MRS study of the AIDS dementia complex: validation and preliminary analysis. J Magn Reson Imaging. Jun 2003;17(6):625-33. [Medline].

24. Chang L, Lee PL, Yiannoutsos CT, Ernst T, Marra CM, Richards T, et al. A multicenter in vivo proton-MRS study of HIV-associated dementia and its relationship to age. Neuroimage. Dec 2004;23(4):1336-47. [Medline].

25. Chang L, Ernst T, Leonido-Yee M, Walot I, Singer E. Cerebral metabolite abnormalities correlate with clinical severity of HIV-1 cognitive motor complex. Neurology. Jan 1 1999;52(1):100-8. [Medline].

26. Glass JD, Wesselingh SL. Viral load in HIV-associated dementia. Ann Neurol. Jul 1998;44(1):150-1. [Medline].

27. Sevigny JJ, Albert SM, McDermott MP, Schifitto G, McArthur JC, Sacktor N, et al. An evaluation of neurocognitive status and markers of immune activation as predictors of time to death in advanced HIV infection. Arch Neurol. Jan 2007;64(1):97-102. [Medline].

28. Chang L, Ernst T, Leonido-Yee M, Witt M, Speck O, Walot I, et al. Highly active antiretroviral therapy reverses brain metabolite abnormalities in mild HIV dementia. Neurology. Sep 11 1999;53(4):782-9. [Medline].

29. Sacktor NC, Skolasky RL, Lyles RH, Esposito D, Selnes OA, McArthur JC. Improvement in HIV-associated motor slowing after antiretroviral therapy including protease inhibitors. J Neurovirol. Feb 2000;6(1):84-8. [Medline].

30. Evers S, Grotemeyer KH, Reichelt D, Luttmann S, Husstedt IW. Impact of antiretroviral treatment on AIDS dementia: a longitudinal prospective event-related potential study. J Acquir Immune Defic Syndr Hum Retrovirol. Feb 1 1998;17(2):143-8. [Medline].

31. Sacktor N, Skolasky RL, Tarwater PM, McArthur JC, Selnes OA, Becker J, et al. Response to systemic HIV viral load suppression correlates with psychomotor speed performance. Neurology. Aug 26 2003;61(4):567-9. [Medline].

32. Brew BJ, Gonzalez-Scarano F. HIV-associated dementia: an inconvenient truth. Neurology. Jan 30 2007;68(5):324-5. [Medline].

33. Evers S, Rahmann A, Schwaag S, Frese A, Reichelt D, Husstedt IW. Prevention of AIDS dementia by HAART does not depend on cerebrospinal fluid drug penetrance. AIDS Res Hum Retroviruses. May 2004;20(5):483-91. [Medline].

34. Harrison MJ. Guidelines for management of HIV-associated dementia, myelopathy, neuropathy and myopathy. Int J STD AIDS. Jul 1998;9(7):390-3. [Medline].

35. Dana Consortium on Therapy for HIV Dementia and Related Cognitive Disorders. Clinical confirmation of the American Academy of Neurology algorithm for HIV-1-associated cognitive/motor disorder. The Dana Consortium on Therapy for HIV Dementia and Related Cognitive Disorders. Neurology. Nov 1996;47(5):1247-53. [Medline].

36. Bouwman FH, Skolasky RL, Hes D, Selnes OA, Glass JD, Nance-Sproson TE, et al. Variable progression of HIV-associated dementia. Neurology. Jun 1998;50(6):1814-20. [Medline].

37. Sahai-Srivastava S. Medico-legal issues in HIV/AIDS in the 21st century. In: Goodkin EK, et al. The Spectrum of Neuro-AIDS Disorders: Pathophysiology, Diagnosis and Treatment. Washington, DC: ASM Press; 2008.

38. Mancall EL, Munsat TL. The neurologic complications of AIDS. In: Continuum: Lifelong Learning in Neurology. Vol 6. Baltimore, Md: Lippincott Williams & Wilkins; 2000:30-64.

39. Marder K, Albert SM, McDermott MP, McArthur JC, Schifitto G, Selnes OA, et al. Inter-rater reliability of a clinical staging of HIV-associated cognitive impairment. Neurology. May 13 2003;60(9):1467-73. [Medline].

40. Simpson DM, Berger JR. Neurologic manifestations of HIV infection. Med Clin North Am. Nov 1996;80(6):1363-94. [Medline].

Keywords

AIDS dementia complex, ADC, subacute HIV encephalitis, AIDS-related dementia, HIV-related dementia, AIDS-induced dementia, HIV-induced dementia, viral dementia, virus-induced dementia, multinucleate giant cell encephalitis, HIV-1-associated cognitive/motor complex, AIDS encephalopathy, HIV dementia, HIV encephalopathy, dementia, mental illness, psychosis, subcortical dementia, depression

Contributor Information and Disclosures

Author

Soma Sahai-Srivastava, MD, Director of Neurology Ambulatory Care Services, LAC and USC Medical Center; Assistant Professor, Department of Neurology, University of Southern California
Soma Sahai-Srivastava, MD is a member of the following medical societies: American Academy of Neurology, American Headache Society, and American Medical Association
Disclosure: Nothing to disclose.

Coauthor(s)

Arousiak Varpetian, MD, Assistant Professor of Clinical Neurology, Department of Neurology, University of Southern California Keck School of Medicine; Clinical Director, Rand Schrader Neurology Clinic (Los Angeles County-University of Southern California HIV Clinic)
Arousiak Varpetian, MD is a member of the following medical societies: American Academy of Neurology and American Medical Association
Disclosure: Nothing to disclose.

Medical Editor

Ronald A Greenfield, MD, Professor, Department of Internal Medicine, Section of Infectious Diseases, University of Oklahoma College of Medicine
Ronald A Greenfield, MD is a member of the following medical societies: American College of Physicians, American Federation for Medical Research, American Society for Microbiology, Central Society for Clinical Research, Infectious Diseases Society of America, Medical Mycology Society of the Americas, Phi Beta Kappa, Southern Society for Clinical Investigation, and Southwestern Association of Clinical Microbiology
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Managing Editor

Eduardo Dunayevich, MD, Adjunct Assistant Professor, Department of Psychiatry, University of Cincinnati; Clinical Research Physician, Neuroscience, Lilly Research Laboratories
Eduardo Dunayevich, MD is a member of the following medical societies: American Psychiatric Association
Disclosure: Nothing to disclose.

CME Editor

Harold H Harsch, MD, Program Director of Geropsychiatry, Department of Geriatrics/Gerontology, Associate Professor, Department of Psychiatry and Department of Medicine, Froedtert Hospital, Medical College of Wisconsin
Harold H Harsch, MD is a member of the following medical societies: American Psychiatric Association
Disclosure: lilly Honoraria Speaking and teaching; Forest Labs Honoraria Speaking and teaching; AstraZeneca Honoraria Speaking and teaching; Pfizer Grant/research funds Speaking and teaching; Northstar Grant/research funds Research; Novartis Grant/research funds research; Pfizer  Speaking and teaching; Sanofi-avetis Grant/research funds research; Otsuke Grant/research funds reseach; GlaxoSmithKline Grant/research funds research

Chief Editor

Stephen Soreff, MD, President of Education Initiatives, Nottingham, NH; Faculty, Metropolitan College of Boston University, Boston, MA
Stephen Soreff, MD is a member of the following medical societies: American College of Mental Health Administration and American Psychosomatic Society
Disclosure: Nothing to disclose.

The authors and editors of eMedicine gratefully acknowledge the contributions of previous author Brenda Jones, MD to the development and writing of this article.

Hetal Modi, MBBS for help in typing and researching this article.

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