HIV-Associated Dementia and Other Neurocognitive Disorders

Background

HIV is a neurotropic virus that directly invades the brain shortly after infection. HIV replicates in brain macrophages and microglia, causing inflammatory and neurotoxic host responses. HIV may cause cognitive, behavioral, and motor difficulties. These difficulties may range in severity from very mild to severe and disabling; if moderate or severe, they constitute minor cognitive motor disorder (MCMD) or HIV-associated dementia (HAD), respectively. These conditions are distinguished from the milder cognitive changes seen in some people with HIV infection by the greater impact and duration of the functional deficits. MCMD is thought to involve neuronal cell dysfunction, whereas HAD often involves actual cell death.

A note on nomenclature: There have been multiple shifts in the nomenclature used to describe HIV-associated neurocognitive disorders. The most recent proposed system, published in the journal Neurology in 2007, suggests three categories: asymptomatic neurocognitive impairment (ANI), mild neurocognitive disorder (MND), and HAD. However, the diagnoses of ANI and MND require neuropsychological testing that is more likely to be available in research settings as opposed to clinical settings. This chapter will therefore address the clinical diagnoses of MCMD and HAD.

Both MCMD and HAD are AIDS-defining conditions (listed as "Encephalopathy, HIV related" in the classification system used by the U.S. Centers for Disease Control and Prevention), and are risk factors for death. Neurocognitive disorders associated with HIV are among the most common and clinically important complications of HIV infection. However, they are diagnoses of exclusion, and other medical causes must be ruled out.

Risk factors for developing an HIV-associated neurocognitive disorder include the following:

• Older age
• Female gender
• More advanced HIV disease (including CD4 count <100 cells/µL, wasting)
• High plasma HIV RNA (viral load)
• Comorbid conditions (especially anemia and infection with cytomegalovirus, human herpesvirus 6, and JC virus)
• History of injection drug use (especially with cocaine)
• History of delirium

The use of effective antiretroviral therapy (ART) that maintains the plasma HIV RNA at undetectable or low values is the best way to prevent and treat HIV-related neurocognitive disorders. Thus, it is essential to choose an ART regimen that takes into consideration resistance testing and adherence issues.

Minor Cognitive Motor Disorder

MCMD is characterized by mild impairment in functioning and may escape diagnosis by the clinician. The course and onset of MCMD can vary dramatically. The more demanding the activities of a particular individual, the more likely that person would be to notice the difficulties. MCMD does not necessarily progress to dementia.

HIV-Associated Dementia

HAD is characterized by symptoms of cognitive, motor, and behavioral disturbances. There is often a progressive slowing of cognitive functions, including concentration and attention, memory, new learning, sequencing and problem solving, and executive control. HAD also can present with behavioral changes, which mainly take the form of apathy, loss of motivation, poor energy, fatigue, and social withdrawal. Motor changes, including slowing, clumsiness, unsteadiness, increased tendon reflexes, and deterioration of handwriting may occur.

S: Subjective

If a neurocognitive disorder is suspected, obtain a history of the patient's symptoms (see below). Whenever possible, obtain a parallel history of the patients past history and recent mental status changes from significant others or caretakers.

Patient self-reports of cognitive problems and bedside cognitive status tests may be insensitive, particularly to subtler forms of impairment.

To help clarify factors that may be causing the changes in mental status, inquire about the following:

• Acuity of onset
• Recent changes or events
• Medications, particularly new medications
• Drug and alcohol use
• Symptoms of opportunistic illnesses, other infections
• HIV history, including duration, CD4 cell count, HIV viral load, history of ART
• History of other medical and psychiatric disorders

Ask about the following symptoms:

O: Objective

• Check temperature and other vital signs (MCMD and HAD are not associated with fever).
• Perform a complete physical examination with special attention to signs of opportunistic illnesses.
• Perform a thorough neurological examination, including funduscopy. Rule out focal neurologic deficits.
• Perform Mini-Mental State Examination (note that this is not sensitive for HIV-associated neurocognitive disorders; negative results do not rule out these conditions).
• Consider a neuropsychological screening test such as the Modified HIV Dementia Scale (see Figure 1). Others are noted in "Laboratory and Diagnostic Evaluation," below.

A: Assessment

A differential diagnosis includes the following medical conditions, which may present with cognitive changes or delirium:

• Substance use: intoxication or withdrawal from alcohol, opioids, stimulants, etc.
• Psychiatric disorders, especially major depression
• Metabolic or systemic disorders, including hepatic encephalopathy, vitamin B12 or folate deficiency, uremia, endocrine disorders (e.g., hypogonadism)
• Central nervous system (CNS) opportunistic infections, such as cytomegalovirus encephalitis, cryptococcal meningitis, tuberculous meningitis, CNS toxoplasmosis, and progressive multifocal leukoencephalopathy (PML)
• Systemic infections
• Brain tumors, including CNS lymphoma and metastatic disease
• Other causes of cognitive impairment and dementia (e.g., neurosyphilis, substance-induced dementia, vascular dementia, brain injury, Alzheimer disease, and hydrocephalus)
• Medication adverse effects: antiretroviral (ARV) medications (especially efavirenz), psychotropic medications, interferon, anticholinergics, and others
• Poisoning with toxic substances

P: Plan

Laboratory and Diagnostic Evaluation

A change in the mental status of an HIV-infected person should prompt a thorough search for underlying biological causes. As noted above, HIV-related neurocognitive disorders are diagnoses of exclusion, and other causes of the patient's symptoms should be ruled out.

Perform the following tests:

• Laboratory tests: Complete blood count, electrolytes and creatinine, liver function, thyroid function, vitamin B12, rapid plasma reagin (RPR) or Venereal Disease Research Laboratory (VDRL).
• Toxicology tests if substance use is suspected (e.g., opioids, ethanol, amphetamines).
• Brain imaging studies (computed tomography [CT] scan or magnetic resonance imaging [MRI]); rule out space-occupying masses and other lesions; cortical atrophy may be seen in advanced HAD; this finding is not specific.
• Cerebral spinal fluid (CSF) tests if CNS infection is suspected.
• Consider tests for neurocognitive impairment as noted in the table below; most of these can be found on the website of the New York State Department of Health AIDS Institute.
• Refer to an HIV-experienced neuropsychologist, neurologist, or psychiatrist, if available.

Treatment

There are no specific treatments for HIV-associated neurocognitive disorders, but ART may reverse the disease process, and a number of therapies may be helpful. The treatment of MCMD and HAD ideally utilizes a multidisciplinary approach that may involve HIV specialists, neurologists, psychiatrists, psychologists, nurse practitioners, social workers, and substance-use counselors.

Neurocognitive impairment in patients with HIV infection often is multifactorial. In addition to treating HIV-associated neurocognitive disorders themselves, it is important to correct, as much as possible, all medical conditions that may adversely affect the brain (e.g., psychiatric comorbidities, endocrinologic abnormalities, adverse medication effects). For patients using alcohol or illicit or nonprescribed drugs, implement strategies to reduce their use; these agents can further impair cognition.

Pharmacologic Management of HIV-Associated Neurocognitive Disorders

• ART: Maximal suppression of HIV replication via ART may partially or fully reverse HIV-associated neurocognitive disorders, and ART is the treatment of choice for both treatment and prevention of HIV-associated neurocognitive disorders, including dementia. In general, ART regimens that effectively suppress HIV RNA in the serum also suppress HIV in the CNS. However, ARV medications vary in their ability to penetrate the blood-brain barrier and, therefore, in their ability to act directly on the HIV in the CNS. Limited data suggest that using ARVs with good CNS penetration may be important in treating or preventing neurocognitive disorders, and some experts recommend the use of these ARVs, if otherwise appropriate, for patients with HIV dementia. ARVs with the best CNS penetration include the nucleoside reverse transcriptase inhibitors (NRTIs) abacavir, emtricitabine, and zidovudine (AZT, ZDV); the nonnucleoside reverse transcriptase inhibitor (NNRTI) nevirapine; the protease inhibitors (PIs) indinavir/ritonavir and lopinavir/ritonavir; and the CCR5 antagonist maraviroc. There currently is no role for testing levels of HIV RNA in the CSF outside research settings.
• Stimulants: Stimulant medications (e.g., methylphenidate, dextroamphetamine) have been used as palliative agents to help manage symptoms of fatigue, decreased concentration, and memory deficits among patients with MCMD and HAD. Starting dosages of both is 5 mg/day; maximum dosage is 60 mg/day. The response to stimulants is idiosyncratic and varies from patient to patient; begin with the lowest dose of 5 mg QAM and titrate upward as needed. If BID dosing is required as a result of afternoon fatigue, the afternoon dose should be taken before 2 pm to prevent interference with sleep. Consider referral to a psychiatrist or neurologist for evaluation and initiation of treatment; after a stable dosage is achieved, treatment may be continued. These medications should be used with caution for patients who have a history of stimulant abuse.
• For comorbid depression, consider prescribing antidepressant medications as for other medically ill HIV-infected patients (see chapter Major Depression and Other Depressive Disorders).
• Antipsychotic medications may be useful in treating agitation and hallucinations but should be used for patients with dementia only when nonpharmacologic measures are insufficient for patient management; consult with a psychiatrist. All antipsychotic medications increase the risk of death in elderly patients with dementia. Start antipsychotic medications at the lowest possible dosage and increase slowly as needed.
• Many agents are being studied for either their neuroprotective effects or their therapeutic effects on HIV-associated neurocognitive disorders. The data are not sufficient at present to make specific recommendations. Patients with dementia often are sensitive to medication side effects; follow closely.
• Benzodiazepines have been shown to increase confusion and decrease concentration, and generally should be avoided.

Nonpharmacologic Management of MCMD and Mild HAD

• Encourage patients to remain appropriately active
• Explain the benefits of structured routines
• Encourage good nutrition
• Use strategies to minimize use of alcohol and illicit drugs
• Use memory aids such as lists
• Simplify complex tasks, especially drug regimens
• When giving instructions, do the following:
  • Repeat information
  • Write instructions to provide structure for patients and caregivers
  • Ask patients to express the information and instructions in their own words
• Adherence to medical regimens, including ART, often is particularly difficult for patients with neurocognitive disorders. Encourage use of medication adherence tools such as pill boxes, alarms, and, if available, packaged medications (e.g., blister packs) or prefilled medi-sets. Encourage patients to enlist adherence support from family members and friends.
• Cognitive skills building can be helpful (e.g., reading, solving puzzles, intellectual conversation).

Nonpharmacologic Management of Moderate to Severe HAD

The strategies noted above should be utilized, but additional measures are needed.

Management of patients with severe or late-stage HAD requires an evaluation of their safety and a determination of the environment and level of supervision that are needed. The clinician should attend to the following:

• Help determine whether patients can be left alone at home or whether doing so would present the risk of them wandering away or sustaining an injury in the home (e.g., from the use of an appliance such as the oven).
• For patients who cannot be left alone at home, assess options for support (e.g., help from family members or paid home attendants).
• Utilize fall prevention strategies.
• For patients who smoke, decide whether smoking can be done safely; if smoking is deemed unsafe, consider smoking cessation programs or supervision.
• If lesser measures fail, explore options for placement in a skilled nursing facility.

Additional helpful strategies for managing patients who are confused, agitated, or challenged by their experience include the following:

• Keep their environments familiar to the extent possible (e.g., in terms of objects, people, locations).
• Redirect or distract patients from inappropriate behavior.
• Remain calm when patients become confused or agitated; refrain from confronting an agitated patient; reorient confused or agitated patients.
• Provide a clock and calendar in the room to help keep patients oriented to time and to day of the week.
• Provide lighting that corresponds with day and night.
• Emphasize routines.
• Ensure that patients who require eyeglasses or hearing aids wear them to help lessen confusion and disorientation.
• Prepare patients for any planned changes.
• Ensure that patients are receiving their prescribed medications.
• Protect wandering patients.
• Supervise any cigarette smoking.
• Offer activities that keep their minds alert.
• Educate family members about the nature of dementia and methods for helping patients maintain activities of daily living.
• Suggest that patients or their family members make arrangements for financial, health, and other matters in the event they become unable to make decisions about their affairs (e.g., advance health care directives, durable powers of attorney, wills).

Patient Education

• Advise patients that ART can be effective in preventing and treating HIV-related neurocognitive impairment.
• Inform patients and family members of the many other strategies may aid in managing neurocognitive impairment. Such strategies may help patients maintain the highest possible level of skills and independence.
• Family members and significant others can be important sources of support (e.g., by providing assistance with medication adherence).
• Advise patients with advanced HAD that placement in a residential facility may be the best option for ensuring their safety.

References

• American Academy of Neurology. 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. 1991 Jun;41(6):778-85.
• Antinori A, Arendt G, Becker JT, et al. Updated research nosology for HIV-associated neurocognitive disorders. Neurology. 2007 Oct 30;69(18):1789-99.
• Brew B, Pemberton L, Cunningham P, et al. Levels of human immunodeficiency virus type 1 RNA in cerebrospinal fluid correlate with AIDS dementia stage. J Infect Dis. 1997 Apr;175(4):963-6.
• Cherner M, Cysique L, Heaton RK, et al.; HNRC Group. Neuropathologic confirmation of definitional criteria for human immunodeficiency virus-associated neurocognitive disorders. J Neurovirol. 2007;13(1):23-8.
• Cohen MA, Gorman JM. Comprehensive Textbook of AIDS Psychiatry. New York: Oxford University Press; 2008.
• Evers S, Rahmann A, Schwaag S, et al. Prevention of AIDS dementia by HAART does not depend on cerebrospinal fluid drug penetrance. AIDS Res Hum Retroviruses. 2004 May;20(5):483-91.
• McArthur JC, McClernon DR, Cronin MF, et al. Relationship between human immunodeficiency virus-associated dementia and viral load in cerebrospinal fluid and brain. Ann Neurol. 1997 Nov;42(5):689-98.
• New York State Department of Health AIDS Institute. Mental Health Care for People with HIV Infection: Clinical Guidelines for the Primary Care Practitioner. Accessed June 21, 2012.
• Power C, Selnes OA, Grim JA, et al. HIV dementia scale: a rapid screening test. J Acquir Immune Defic Syndr Hum Retrovirol. 1995 Mar 1;8(3):273-8.
• Price RW, Epstein LG, Becker JT, et al. Biomarkers of HIV-1 CNS infection and injury. Neurology. 2007 Oct 30;69(18):1781-8.
• Rippeth JD, Heaton RK, Carey CL, et al.; HNRC Group. Methamphetamine dependence increases risk of neuropsychological impairment in HIV infected persons. J Int Neuropsychol Soc. 2004 Jan;10(1):1-14.
• Schifitto G, Navia BA, Yiannoutsos CT, et al.; Adult AIDS Clinical Trial Group (ACTG) 301; 700 Teams; HIV MRS Consortium. Memantine and HIV-associated cognitive impairment: a neuropsychological and proton magnetic resonance spectroscopy study. AIDS. 2007 Sep 12;21(14):1877-86.
• Shiu C, Barbier E, Di Cello F, et al. HIV-1 gp120 as well as alcohol affect blood-brain barrier permeability and stress fiber formation: involvement of reactive oxygen species. Alcohol Clin Exp Res. 2007 Jan;31(1):130-7.
• U.S. Department of Health and Human Services. Guidelines for the Use of Antiretroviral Agents in HIV-1-Infected Adults and Adolescents. March 27, 2012.