Mental Health Guidelines Committee, September 2007
HIV enters the central nervous system (CNS) soon after initial infection and is responsible for a range of neuropsychiatric complications. Although HIV is neuroinvasive, it does not directly infect neurons. The major brain reservoirs for HIV infection and replication are microglia and macrophages. Astrocytes can be infected but are not a site of active HIV replication. Accordingly, HIV-associated neurologic complications are indirect effects of viral neurotoxins (viral proteins gp120 and tat) and neurotoxins released by infected or activated microglia, macrophages, and astrocytes.
In addition to HIV-associated dementia (HAD), other HIV-associated neuropsychiatric complications include the following:
- Minor cognitive motor disorder, which differs from HAD in severity and degree of functional disability but may progress to HAD
- Neurobehavioral impairments (e.g., apathy, depression, anxiety/agitation, sleep disturbance, hypomania)
- Myelopathy, which is functional disturbance and/or pathologic change to the spinal cord
- Aseptic meningitis
Despite the decreasing incidence of HAD in recent years, cognitive impairment is the most common CNS complication in people with HIV/AIDS. Delirium is the most common cognitive disorder in hospitalized patients with AIDS. The prompt diagnosis of cognitive impairment/dementia and delirium may significantly decrease morbidity and mortality.
Greater degree of immunodeficiency and age are significant risk factors for HAD. However, the incidence of HAD has decreased since the introduction of HAART. After initiation of HAART, some people with HAD have shown marked improvement in cognitive status. This has been postulated to be due to an improvement in immune status, as evidenced by increased CD4 cell count and a decrease in plasma viral load and cerebral spinal fluid (CSF) viral load. Early studies [1-3], particularly in the pre-HAART era, have indicated that CSF HIV viral load correlates with severity of cognitive dysfunction, particularly in patients whose CD4 count is <200 cells/mm3. At this time, measurement of viral load in CSF is predominantly a research tool, rather than routine standard of care.
HAD produces a highly variable clinical course and a spectrum of signs and symptoms, ranging from subtle cognitive and motor impairments to profound dementia. Common early symptoms include word-finding difficulty, forgetfulness, psychomotor slowing, and diminished writing or visual/motor skills. Simple strategies, such as written reminders, can be used to compensate for early deficits. Clinical manifestations of HIV-associated dementia include the following:
- Apathy (depression-like features)
- Mania, new-onset psychosis
- Psychomotor retardation (slowed speech or response time)
- Personality changes
- Social withdrawal
- Lack of visuospatial memory (misplacing things)
- Lack of visuomotor coordination
- Difficulty with complex sequencing (difficulty in performing previously learned complex tasks)
- Impaired concentration and attention
- Impaired verbal memory (word-finding ability)
- Mental slowing
- Unsteady gait, loss of balance
- Leg weakness
- Dropping things
- Tremors, poor handwriting
- Decline in fine motor skills
Common psychiatric symptoms include depressed mood and hypomania (see Depression and Mania Guideline). Some patients experience a gradual mental decline, whereas others deteriorate rapidly over a relatively short period of time. Seizures, global cognitive deterioration, mutism, incontinence, and severe confusion are common clinical features of late-stage HAD.
Differential diagnosis of symptoms presenting as possible HAD includes the following:
- Systemic/metabolic/endocrine disease
- Cytomegalovirus encephalitis
- Cryptococcal meningitis
- Tuberculous meningitis
- CNS toxoplasmosis
- Progressive multifocal leukoencephalopathy (PML): Cognitive impairment may occur as an accompanying feature of a depressive episode. The term pseudodementia is used to describe this clinical presentation, which resolves with appropriate treatment of the depressive disorder.
- HIV minor cognitive motor disorder
- Tumors: CNS lymphoma, Metastatic disease
- Primary psychiatric illness: B12 deficiency, anemia, thyroid disease, Addison’s disease
- Substance withdrawal or intoxication: Chronic methamphetamine, alcohol, opioids, chronic cannabis
- Medications: Psychotropic, ARVs, drug-drug interactions
Substance use disorders/intoxication, CNS opportunistic infections, and malignancies should always be included in the differential diagnosis, particularly when cognitive changes are acute and/or progress rapidly. Although computed tomography (CT) and magnetic resonance imaging (MRI) scans may be nonspecific, they are useful to exclude other CNS disorders. MRI is preferable to CT. Magnetic resonance spectroscopy (MRS) and positron emission tomography (PET) have been used to evaluate HAD, but they are primarily used in research settings at this time.
When early-stage HAD is suspected, the usual screening tests used for cognitive disorders are of limited value, including abbreviated forms of the mental status examination such as the Folstein Mini-Mental State Exam. Although not effective for identifying early-stage cognitive dysfunction, the following tests have been used to identify and stage HAD (see Mental Health Screening Tools)
- HIV Dementia Scale: screens for the memory and attention deficits and psychomotor slowing that are typical of HIV dementia; 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 ideal than the HIV Dementia Scale for the clinic setting; requires approximately 5 minutes to administer.
- 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; it combines the functional impact of both cerebral (dementia) and spinal cord (myelopathy) dysfunction. 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. However, it may be used at the bedside to track a patient’s response to ARV treatment over time (to order the test, see http://www.mcssl.com/store/reitan-neuropsychology-laboratory).
In addition to screening tests, reports from caregivers or family members may also be useful when assessing patients for possible symptoms of HAD.
Psychiatric consultation may assist in differentiating between HAD and pseudodementia associated with depression and between HAD and cognitive impairment attributable to mania, psychosis, delirium, substance use, or psychotropic or HIV-related medications. Neuropsychological testing may also be helpful with diagnostic assessment.
In centers with neuro-AIDS expertise, the treatment of HAD is a multidisciplinary approach that involves infectious disease specialists, neurologists, and psychiatrists. A psychologist, nurse practitioner, or social worker may also help with behavioral strategies for the management of patients with HAD.
Three therapeutic modalities exist for management of patients with HAD:
- ARV therapy
- Pharmacologic treatment of symptoms
- Nonpharmacologic management
The MSK scale may be useful in developing a management plan and determining the level of assistance a patient may need.
Antiretroviral drugs: Early, small studies have shown that HAART that includes drugs that penetrate the blood-brain barrier, particularly zidovudine, lead to improvement and, at the very least, to a partial return of functioning in patients previously diagnosed with HAD. However, more recent data suggest that when HAART results in viral suppression, it will improve patients’ cognitive performance, independently of its theoretical ability to efficiently cross the blood-brain barrier . Therefore, it is probable that if viral load is suppressed systemically, it will be suppressed in the CNS. Accordingly, the prevailing goal may be to achieve viral suppression, rather than using a regimen that is superior only in crossing the blood-brain barrier. Future research may help elucidate the optimal ARV regimens for treatment of HAD.
Pharmacologic treatment of symptoms: Patients with HAD may also benefit from psychotropic medications used to target specific symptoms, such as psychomotor slowing, agitation, anxiety, depression, mania, and psychosis. However, HIV-infected patients are more likely than the non-infected population to develop extrapyramidal side effects with antipsychotic agents and hepatotoxicity with drugs that are metabolized primarily by the liver. In addition, drug-drug interactions between PIs and/or non-nucleoside reverse transcriptase inhibitors (NNRTIs) with psychotropic drugs may lead to increases in adverse drug reactions.
Patients with HAD may lose decision-making capacity due to either acute illness, such as delirium, or progression of underlying cognitive deficits. Loss of decision-making capacity may be either temporary and reversible or permanent. Determination of a patient’s ability to make decisions about his or her treatment should always refer to a specific clinical situation, for example, the capacity to refuse a lumbar puncture. Clinically, determination of decisional capacity may arise more often with regard to a patient’s capacity to refuse a medical procedure or treatment. Therefore, attention to both advance directives and family involvement may be particularly important in the management of patients with HAD.
In the nonpharmacologic management of patients with HAD, clinicians should do the following:
When giving instructions:
- Simplify complex tasks, especially drug regimens
- Suggest use of pill boxes, diaries, and time tables
- Repeat information
- Write instructions to provide structure for patient and caregiver
When presented with patients who are confused, agitated, or challenged by their experience:
- Maintain orientation cues, and structure activities appropriately
- Try to keep the environment familiar and prepare patients for change
- Redirect or distract patients from inappropriate behavior
- Maintain calm when patients become confused or agitated and refrain from confronting an agitated patient
- Depending on the severity of the case, explain the benefits of structured routines and activities, such as attending day programs, church, and family gatherings and spending time outdoors
Because the term dementia and the awareness of cognitive decline can be frightening to HIV-infected patients and to their families, educating patients and their families is crucial.
- Marshall D, Brey R, Butzin C, et al. CSF changes in a longitudinal study of 124 neurologically normal HIV-1 infected U.S. Air Force personnel. J Acquir Immune Defic Syndr 1991;4:777-781.
- 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;42:689-698.
- Brew B, Pemberton L, Cunningham P, et al. Levels of HIV-1 RNA correlated with AIDS dementia. J Infect Dis 1997;175:963-966.
- 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;20:483-491.
Delirium Associated with HIV
Delirium is the most common neuropsychiatric complication in hospitalized patients with AIDS. Delirium may be life-threatening and requires immediate medical attention. Occasionally, patients may present with early signs of delirium in the primary care setting. Thus, it is essential that clinicians be able to recognize the signs and symptoms and refer patients to the hospital immediately. In these cases, the clinician should then contact the emergency department to follow-up with the disposition of the patient.
The following patients are at risk for developing delirium:
- Those in advanced stages of immunosuppression
- Those with a history of opportunistic infections, substance use, head/brain injuries, or episodes of delirium
- Those with HAD or infections and malignancies of the CNS
The hallmarks of delirium are an impairment of consciousness, with a reduced ability to focus or sustain or shift attention, and changes in cognition or development of perceptual disturbances that are not explained by a preexisting dementia. These disturbances may develop over a short period of time, and the symptoms may fluctuate in severity. Delirium is generally a direct physiologic consequence of a medical condition.
Clinical Manifestations of Delirium in HIV-Infected Patients
- Impairment of memory, orientation, prefrontal “executive” functions: Difficulty with abstraction and/or sequential thinking; impaired temporal memory; impaired judgment
- Disturbances in thought and language: Decreased verbal fluency
- Disturbances in perception: Hallucinations (primarily visual); illusions (misinterpretation of visual cues, e.g., mistaking shadows for people)
- Disturbances in psychomotor function: Hypoactive, hyperactive, mixed hypo- and hyperactive
- Disturbances in sleep-wake cycle: Daytime lethargy, nighttime agitation
- Delusions (usually paranoid but more disorganized than those seen in psychoses)
- Affective lability
- Neurologic abnormalities: Tremors, ataxia, myoclonus, cranial nerve palsies, asterixis, cerebellar signs, nystagmus
Delirium is often difficult to diagnose. When patients appear hypoactive, depression is a frequent misdiagnosis for delirium. Possible causes of delirium are listed below. Clinicians should maintain a high index of suspicion for delirium related to CNS infections and substance use in HIV-infected patients. It is important to note that the combination of HIV infection and methamphetamine use is associated with significant brain structure alternations  and cognitive impairment .
Possible causes of delirium:
- Metabolic abnormalities
- Almost all HIV-related and psychotropic medications
- Methamphetamine use
- Alcohol intoxication and withdrawal
- CNS infections and malignancies
Treatment of delirium in patients with HIV/AIDS is based on the same principles used for treatment of delirium in patients with other medical illnesses. Correcting the underlying conditions that have led to delirium is the primary treatment. Symptoms such as confusion or agitation can be treated by using low doses of neuroleptics (e.g., haloperidol or risperidone). If symptoms of agitation put the patient or others at risk and are not controlled by low doses of antipsychotics, adding low doses of lorazepam may achieve sedation. Psychiatric consultation may be helpful in management.
- Jernigan TL, Gamst AC, Archibald SL, et al. Effects of methamphetamine dependence and HIV infection on cerebral morphology. Am J Psychiatry2005;162:1461-1472.
- Rippeth JD, Heaton RK, Carey CL, et al. Methamphetamine dependence increases risk of neuropsychological impairment in HIV infected persons. J Int Neuropsychol Soc 2004;10:1-14.
Mental Health Guidelines Committee, September 2007
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Delirium Associated with HIV