HIV-Associated 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.

The American Academy of Neurology (AAN) recognizes three categories of HIV-associated neurocognitive disorder (HAND) (see Table 1, below).

  • Asymptomatic neurocognitive impairment (ANI) is determined by neurocognitive testing and is not apparent clinically.
  • Mild neurocognitive disorder (MND) is a diagnosis of exclusion; it may be made clinically if neurocognitive testing is not available, and it involves mild functional impairment.
  • HIV-associated dementia (HAD) involves moderate to severe functional impairment.

[In the Diagnostic and Statistical Manual of Mental Disorders (DSM-5) section on cognitive disorders, MND correlates with mild neurocognitive disorder, and HAD with major neurocognitive disorder.]

Both MND 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 they 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 of <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

With the advent of ART, HAD prevalence has declined and MND prevalence has increased. As people with HIV live longer and become older, the risk of developing cognitive impairment increases. The use of effective antiretroviral therapy (ART) that maintains the plasma HIV RNA at undetectable or low values is important for preventing and treating HIV-related neurocognitive disorders. In people with neurocognitive impairment, however, there may be some benefit in using antiretroviral (ARV) agents that penetrate the CNS. However, recent research suggests that neuroinflammation rather than the HIV viral load in the CNS is primarily responsible for cognitive impairment in HIV-infected individuals. In choosing an ART regimen, it is important to take into consideration resistance testing, CNS penetration, and adherence issues.

Minor Neurocognitive Disorder

MND is characterized by mild impairment in functioning and may escape diagnosis by the clinician. The onset and course of MND can vary dramatically. The more demanding the activities of a particular individual, the more likely that person would be to notice the difficulties in functioning.

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 patient's 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. Often, other people may observe changes in the person's behavior or mood that indicate some change in cognitive functioning.

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

Table 1. AAN Criteria for HIV-Associated Neurocognitive Disorder

HIV-Associated Asymptomatic Neurocognitive Impairment (ANI)

  • Acquired impairment in cognitive functioning, involving at least two ability domains, documented by performance of at least 1 SD below the mean for age-education-appropriate norms on standardized neuropsychological tests. The neuropsychological assessment must survey at least the following abilities: verbal/language; attention/working memory; abstraction/executive; memory (learning; recall); speed of information processing; sensory-perceptual, motor skills.
  • The cognitive impairment does not interfere with everyday functioning.
  • The cognitive impairment does not meet criteria for delirium or dementia.
  • There is no evidence of another preexisting cause for the ANI.

Mild Neurocognitive Disorder (MND)

  • Acquired impairment in cognitive functioning, involving at least two ability domains, documented by performance of at least 1 SD below the mean for age/education-appropriate norms on standardized neuropsychological tests. The neuropsychological assessment must survey at least the following abilities: verbal/language, attention/working memory, abstraction/executive, memory (learning and recall), speed of information processing, sensory-perceptual and motor skills.
  • The cognitive impairment produces at least mild interference in daily functioning (at least one of the following):
    • Self-report of reduced mental acuity, inefficiency in work, homemaking or social functioning
    • Observation by knowledgeable others that the individual has undergone at least mild decline in mental acuity with resultant inefficiency in work, homemaking, or social functioning
  • The cognitive impairment does not meet criteria for delirium or dementia.
  • There is no evidence of another pre-existing cause for the mild neurocognitive disorder. If the individual with suspected mild neurocognitive disorder also satisfies criteria for a severe episode of major depression with significant functional limitations or psychotic features, or substance dependence, the diagnosis of mild neurocognitive disorder should be deferred to a subsequent examination conducted at a time when the major depression has remitted or at least 1 month after cessation of substance use.

HIV-Associated Dementia (HAD)

  • Marked acquired impairment in cognitive functioning, involving at least two ability domains; typically the impairment is in multiple domains, especially in the learning of new information, slowed information processing and defective attention/concentration. The cognitive impairment must be ascertained by neuropsychological testing with at least two domains being 2 standard deviations or greater below that of demographically corrected means.
  • The cognitive impairment produces marked interference with day-to-day functioning (work, home life and social activities).
  • The pattern of cognitive impairment does not meet criteria for delirium.
  • There is no evidence of another, pre-existing cause for the dementia (e.g., other CNS infection, CNS neoplasm, cerebrovascular disease, pre-existing neurologic disease or severe substance abuse compatible with CNS disorder).

Adapted from Antinori A, Arendt G, Becker JT, et al. Updated research nosology for HIV-associated neurocognitive disorders. Neurology. 2007 Oct 30;69(18):1789-99.

Additionally, the AAN specifies that, for patients with severe depression or substance dependence who are suspected of having HAD, the neurocognitive assessment should be deferred until the depression or substance use is in remission.

Although the AAN criteria include assessment via neuropsychological testing, in the absence of such testing, it is acceptable to make a presumptive diagnosis of MND or HAD on the basis of clinical signs and symptoms once all other possible causes of changes in mental function have been ruled out.

O: Objective

  • Check temperature and other vital signs (MND 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), International HIV Dementia Scale, or the Montreal Cognitive Assessment. 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: 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 at www.hivguidelines.org/clinical-guidelines/hiv-and-mental-health.
  • Refer to an HIV-experienced neuropsychologist, neurologist, or psychiatrist, if available.
Figure 1. Modified HIV Dementia Scale
Maximum ScoreScoreExercise

Maximum score: 12 points; a score of <7.5 points suggests possible HAD (note, this test is not specific)

Adapted from McArthur JC. Minor cognitive motor disorder: Does it really exist? Hopkins HIV Rep. Nov 1996;8(4):8.

N/AN/AMemory/Registration: State four words for the patient to recall (dog, hat, green, peach), pausing 1 second between each. Then ask the patient to restate all four.
6(   )

Psychomotor Speed: Ask the patient to write the alphabet in upper case letters horizontally across the page; record time: seconds.

≤21 sec = 6

21.1 - 24 sec = 5

24.1 - 27 sec = 4

27.1 - 30 sec = 3

30.1 - 33 sec = 2

33.1 - 36 sec = 1

> 36 sec = 0

4(   )Memory Recall: Ask the patient to restate the four words from Memory/Registration above. Give one point for each correct response. For words not recalled, prompt with a "semantic" clue, as follows: animal (dog); piece of clothing (hat), color (green), fruit (peach). Give 1/2 point for each correct after prompting.
2(   )Construction: Copy the cube below; record time: seconds.
(<25 sec = 2; 25 - 35 sec = 1; >35 sec = 0)

line drawing of cube

TestNotes
HIV Dementia Scale
  • Screens for the memory and attention deficits and psychomotor slowing that are typical of HAD
  • Requires training to administer and, therefore, may not be ideal for a clinic setting
Modified HIV Dementia Scale
  • Designed specifically for use by non-neurologists and, therefore, may be more useful than the HIV Dementia Scale for a primary care setting
  • Requires approximately 5 minutes to administer
  • See Figure 1, above
Mental Alternation Test
  • Useful for assessing patients with early dementia, who will show impairments in timed trials
Memorial Sloan-Kettering (MSK) Scale
  • Can be used for assessing severity
  • Combines the functional impact of both cerebral dysfunction (dementia) and spinal cord dysfunction (myelopathy); the two entities can be separated and staged independently
Trail Making Test, Parts A and B (from the Halstead-Reitan Neuropsychological Battery)
  • May be used as a screening tool, but results require interpretation by a neuropsychologist
  • May be used at the bedside to track a patient's response to ART over time
Grooved Pegboard (dominant and nondominant hand)
  • May be used as a screening tool and does not require literacy

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 MND and HAD ideally utilizes a multidisciplinary approach that may involve HIV specialists, neurologists, psychiatrists, psychologists, nurse practitioners, social workers, substance-use counselors, case managers, and others.

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. The integrase inhibitor raltegravir has reasonably good CNS penetration. 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 MND 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 p.m. 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 MND 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 patients' 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 that 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.

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