Clinical Manual for Management of the HIV-Infected Adult
2006 Edition

Section 8: Neuropsychiatric Disorders

HIV-Associated Dementia and Minor Cognitive Motor Disorder

Background

The HIV virus is neurotropic and directly invades brain tissue shortly after infection. Accordingly, HIV may cause cognitive difficulties, including HIV-associated dementia (HAD), also called AIDS dementia complex (ADC). In the United States in past years, HAD was the most common neurologic complication of AIDS, affecting 40-60% of all AIDS patients. In recent years, the incidence of HAD has declined, probably because of the use of potent combination antiretroviral therapy (ART). Other HIV-related opportunistic infections of the central nervous system (CNS) (eg, toxoplasmosis, cytomegalovirus encephalitis) and malignancies (eg, lymphoma) have declined in frequency even more sharply than HAD. The fact that HAD has not declined as much as other HIV-related CNS disease suggests that the CNS may be an important reservoir for HIV and that current antiretroviral medications do not protect the CNS as well as they protect the rest of the body. The HIV viral load in the CNS is correlated with cognitive decline; however, it is not correlated with plasma viral load and cannot be estimated from plasma viral load.

The American Psychiatric Association describes dementia as "an organic mental disorder defined as a loss of intellectual abilities of sufficient severity to interfere with social or occupational functioning." The clinical presentation of dementia varies. Patients may develop ambulation or gait problems, mania, panic, psychosis, social isolation, or anxiety. Dementia is progressive but with a variable course; some patients have a rapid progression, whereas others have a slow decline in function. Many patients with HIV-related neurocognitive impairments are acutely aware of their deterioration and may develop an adjustment disorder characterized by profound fear, anxiety, or depression.

Some HIV-infected patients may develop a milder form of cognitive disorder, called minor cognitive motor disorder (MCMD), which is not necessarily an early stage of dementia. The distinction between MCMD and dementia is important and may have a major psychological impact on the patient.

Manifestations of Dementia

Early manifestations of dementia may include the following:

• Decreased attention or concentration
• Reduced speed of information processing
• Psychomotor slowing
• Impaired executive functioning (eg, abstraction, divided attention, shifting cognitive sets)

Late manifestations may include:

• Visuospatial difficulties
• Language problems
• Apraxias

S: Subjective

The patient complains of, or a care giver reports, the following:

• Impairment in memory (short-term and long-term), abstract thinking, judgment, and higher cortical functioning
• Personality changes that interfere with relationships
• Inability to carry out normal social or occupational functions
• Some patients experience only minor forgetfulness and diminished visual or motor skills

History

Take a thorough history, including the following:

• Medications
• Approximate onset of symptoms
• Drug and alcohol use
• Symptoms of opportunistic infections
• Pain
• HIV history, including duration, opportunistic illnesses, and CD4 levels
• Common manifestations (see above)

O: Objective

Perform the following tests:

• Check temperature and other vital signs, and perform a thorough physical examination to determine potentially reversible causes such as opportunistic infections.
• Perform a thorough neurologic examination, including funduscopic exam. Check symmetry of brow wrinkling, eyelid closure, and pupil size. Perform Romberg and other tests to rule out focal neurologic deficits.
• Check gait by asking the patient to walk rapidly, turn, and stop. Ask the patient to walk on heels and tiptoes. Test steadiness of gait with eyes open and closed. Ask the patient to stand from a squatting position without assistance.
• Perform a complete minimental status examination. As a quick screen, ask the patient to write his or her name, date, and location; to spell "world" backwards; to perform memory-object recall of 3 objects after 5 minutes; and to make change from a dollar.

A: Assessment

Partial Differential Diagnosis

• Other CNS conditions, such as toxoplasmosis, fungal infection, Mycobacterium avium complex (MAC), lymphoma, cytomegalovirus ventriculitis or encephalitis, normal-pressure hydrocephalus, neurosyphilis, tuberculosis, or Cryptococcus neoformans. Many of these are treatable.
• Depression, which can present as cognitive impairment.
• Other medical causes, such as nutritional deficiencies (eg, vitamin B12), metabolic disorders (eg, hypothyroidism), toxins (eg, chronic alcohol use), or infections (eg, tertiary syphilis).
• Delirium, which is an acute manifestation of cognitive impairment with inability to maintain attention. Delirium can be due to many medical conditions, but is also commonly caused by medications, including those with anticholinergic adverse effects, such as amitriptyline (Elavil), promethazine (Phenergan), prochlorperazine (Compazine), and diphenhydramine (Benadryl). An anticholinergic delirium is characterized by visual or tactile hallucinations, confusion, and sometimes agitation. Other medications that may cause delirium include prednisone, meperidine (Demerol), lithium (at toxic levels, which may occur in a stable patient with a serious opportunistic infection or dehydration), agonist-antagonist analgesics such as pentazocine (Talwin), and short-acting benzodiazepines such as midazolam (Versed) and triazolam (Halcion).
• Intoxication or withdrawal.

Mild Manifestations: HIV-Associated Minor Cognitive Motor Disorder

At least 2 of the following symptom should be present:

• Impaired attention, concentration, or memory
• Mental and psychomotor slowing
• Personality changes

Rule out other causes.

Severe Manifestations: HIV-Associated Dementia

Signs will include the following:

• Acquired cognitive abnormality in 2 or more domains, causing functional impairment
• Acquired abnormality in motor performance or behavior
• No clouding of consciousness or other confounding cause (eg, CNS infections, psychopathology, drug abuse)

Table 1 describes the states of HAD.

Table 1. Stages and Characteristics of HIV-Associated Dementia

Stage Characteristics Stage 0 (normal) Normal mental and motor function Stage 0.5 (subclinical) Equivocal symptoms of cognitive or motor dysfunction; no impairment of work or activities of daily living (ADL) Stage 1 (mild) Evidence of intellectual or motor impairment, but able to perform most ADL Stage 2 (moderate) Unable to work, but can manage self-care Stage 3 (severe) Major intellectual incapacity or motor disability Stage 4 (end-stage) Nearly vegetative

Source: Bartlett JG, Gallant JE. 2005-2006 Medical Management of HIV Infection. Baltimore: Johns Hopkins University Division of Infectious Diseases; 2005. Available online at hopkins-aids.edu/mmhiv/order.html.

P: Plan

• Check thyroid function, vitamin B12, folate, rapid plasma reagin (RPR), blood chemistries and electrolytes, liver function tests (LFTs), complete blood count (CBC), and testosterone level.
• Order computed tomography (CT) scan or magnetic resonance imaging (MRI). (Cortical atrophy, similar to that seen in Alzheimer dementia, may be visible in very late stages of HAD.) Rule out masses and space-occupying lesions.
• Check cerebrospinal fluid (CSF): In patients with HAD, the CSF will show increased protein and mononuclear pleocytosis. It may be valuable to check the HIV viral load in the CSF, because sometimes the CSF viral load is high regardless of the plasma viral load; this may explain the patient's central deficits.
• Perform an electroencephalogram (may show mild, nonspecific slowing).
• Refer the patient to a psychiatrist and neurologist for further evaluation and neuropsychological testing.

Treatment

Pharmacotherapy

ART may be helpful in treating MCMD and HAD and should be recommended for all patients, unless there are contraindications. The ability of particular antiretroviral drugs to penetrate the blood-brain barrier may be less important to treatment success than the overall potency of the regimen and the ability of the patient to adhere to it.

Studies from the 1980s showed that zidovudine monotherapy was beneficial in patients with HAD, so some clinicians include it in the ART regimen for anyone with neurocognitive impairment. Others suggest using at least 2 drugs that cross the blood-brain barrier (eg, zidovudine, stavudine, abacavir, lamivudine, and nevirapine). Efavirenz, didanosine, and lamivudine cross to a lesser degree. As a class, protease inhibitors (PIs) have poor blood-brain barrier penetration. Nevertheless, patients have shown neurocognitive improvement while taking PI-containing regimens, perhaps because of indirect effects on HIV activity in the CNS.

Treat depressive symptoms with low dosages of selective serotonin reuptake inhibitors (SSRIs) (see chapter Depression for details).

Antipsychotic medications may be useful in treating agitation and hallucinations, but patients with these conditions are often extremely sensitive to anticholinergic adverse effects and extrapyramidal symptoms. Newer neuroleptic or antipsychotic agents, such as olanzapine and risperidone, have lower rates of significant side effects compared with older drugs. The starting dosage of olanzapine is 2.5 mg orally at bedtime; that for risperidone is 0.5-1 mg orally at bedtime. Note that these drugs may interact with antiretroviral medications, especially ritonavir, and can cause weight gain and other metabolic adverse effects. Avoid benzodiazepines, which tend to increase confusion and decrease concentration. Consult with a knowledgeable psychiatrist or pharmacist.

Psychostimulants such as methylphenidate (Ritalin) and dextroamphetamine (Dexedrine) have been used to improve attention, concentration, and psychomotor function. Dosages of methylphenidate start at 5 mg for a test dose, then 2.5-5.0 mg twice daily, increasing by doses of 5 mg every other day until the desired effect is achieved. Usual dosages are in the range of 20-30 mg per day. Monitor blood pressure, heart rate, and symptoms of restlessness, agitation, nausea, and psychosis. No data are available regarding the use of atomoxetine (Strattera) to improve attention and concentration in patients with HAD.

Psychosocial interventions

For a patient who is knowledgeable about HIV, a dementia workup or diagnosis often precipitates a crisis, with an increased risk of suicide. Carefully screen for depression and suicidality, and treat these if they develop.

Behavioral management strategies may assist the patient with early manifestations of dementia to continue living with some degree of independence and safety in the home. Memory aids such as posted notes, calendars, alarmed pill-boxes, and other environmental cues may help.

It is critical to enlist the support of family members and significant others at an early stage of the illness. Because the disease is frightening and may be progressive, the patient and members of the support system need assistance in anticipating and planning for the future. Plans for assisted living or other in-home custodial care should be made early. Severe or late dementia causes fear, misunderstanding, and frustration for both the patient and care givers. All involved will require help from visiting nurses, social workers, hospice workers, and physicians. Recommend the preparation of an advance directive for the patient with early manifestations of dementia.

Patient Education

• Patients should maintain their support system as much as possible.
• Refer patients to a support group or an HIV-experienced counselor who can respond to their fears and concerns.
• ART has helped some people with HAD. Patients who are candidates for ART, should find someone to help with their antiretroviral medications, if at all possible. Enlist family members or roommates to help the patient take the medications as scheduled. Educate them about adverse effects, and whom to call with problems and questions.
• Teach patients to use cues (eg, notes, calendars, alarms) to help themselves keep track of medicines, appointments, social events, and other important activities. Help them identify ways to make the house safer and to maintain as much functionality and dignity as possible.

References

• Bartlett JG, Gallant JE. 2005-2006 Medical Management of HIV Infection. Baltimore: Johns Hopkins University Division of Infectious Diseases; 2005. Available online at hopkins-aids.edu/mmhiv/order.html.
• McArthur JC, Hoover DR, Bacellar H, et al. Dementia in AIDS patients: incidence and risk factors. Multicenter AIDS Cohort Study. Neurology. 1993 Nov;43(11):2245-52.
• McDaniel JS, Purcell DW, Farber EW. Severe mental illness and HIV-related medical and neuropsychiatric sequelae. Clin Psychol Rev. 1997;17(3):311-25.
• McGuire D. Neurologic Manifestations of HIV. In: Peiperl L, Coffey S, Volberding PA, eds. HIV InSite Knowledge Base[textbook online]; San Francisco: UCSF Center for HIV Information; June 2003. Available online at hivinsite.ucsf.edu/InSite?page=kb-04-01-02. Accessed February 7, 2006.
• Neuenburg JK, Brodt HR, Herndier BG, et al. HIV-related neuropathology, 1985 to 1999: rising prevalence of HIV encephalopathy in the era of highly active antiretroviral therapy. J Acquir Immune Defic Syndr. 2002 Oct 1;31(2):171-7.
• Price RW. AIDS Dementia Complex. In: Peiperl L, Coffey S, Volberding PA, eds. HIV InSite Knowledge Base[textbook online]; San Francisco: UCSF Center for HIV Information; June 1998. Available online at hivinsite.ucsf.edu/InSite?page=kb-04-01-03. Accessed February 7, 2006.
• Price, RW. Management of the Neurologic Complications of HIV-1 Infection and AIDS. In: Sande MA, Volberding PA, eds. The Medical Management of AIDS, 6th ed. Philadelphia: WB Saunders; 1999:217-240.
• Sacktor N, Skolasky RL, Tarwater PM, et al. Response to systemic HIV viral load suppression correlates with psychomotor speed performance. Neurology. 2003 Aug 26;61(4):567-9.