Neurologic Complications in AIDS

Bruce A. Cohen

I. GENERAL CONSIDERATIONS

The nervous system is involved early in the course of HIV infection and may produce the presenting clinical manifestations. Early natural history studies found neurologic symptoms and signs in 40% to 70% of patients during the course of the disease, whereas autopsy series demonstrated neuropathologic changes in 90% to 100% of persons with AIDS, affecting all levels of the neuraxis. These neurologic manifestations can result from effects of HIV itself or from opportunistic processes. Acute meningitis, meningoencephalitis, or polyneuritis can mark HIV seroconversion. Subsequently, neuropathy, encephalopathy, myelopathy, and myopathy can occur. Opportunistic illnesses (OI) of the CNS occur in conjunction with marked immune suppression.

Current therapeutic advances with combinations of antiretroviral agents known as highly active or combination antiretroviral therapy (HAART/cART) have had a profound effect on the frequency of both HIV-induced and opportunistic CNS disease. Neurologic complications continue to occur, however; as presentations in persons not known to have HIV infection, and among those who fail cART because of nonadherence or the emergence of resistant HIV strains. Recently, it has become apparent that subtle neurologic manifestations of HIV infection occur in patients on cART, including individuals who appear to be responding to treatment with suppression of systemic disease markers and symptoms. More common conditions causing neurologic complications in AIDS are listed in Table 44.1, although numerous case reports identify a wider spectrum of possible complicating infections.

Some general considerations helpful in approaching HIV+ patients with neurologic disease are listed below:

The imaging modality of choice in HIV-related CNS disease is MRI; however, particular imaging patterns may be nonspecific.

Multiple pathologic conditions in the CNS may occur concurrently in patients with profound immune suppression.

Most OIs appear with significant immune suppression as reflected by CD4+ lymphocyte counts of 200 per mm³ or less.

Neurologic manifestations of OIs in patients with AIDS can be subtle and lack classic disease features seen in other settings.

Specific diagnosis of OIs requires confirmation by culture, or demonstration of genetic material in CSF or biopsied tissue. Empiric therapy based on a presumptive diagnosis is appropriate in some circumstances; however, the absence of a typical treatment response should be prompt early further evaluation.

HIV-associated cognitive deficits are becoming more subtle in the era of successful cART and may occur in patients who appear to have successful control of systemic disease.

Not all neurologic symptoms occurring in HIV+ patients result from HIV or associated opportunistic processes, particularly when the HIV infection appears to be wellcontrolled. Such patients are subject to all of the common neurologic conditions that affect other populations.

Treatment strategies in AIDS are continuously evolving, particularly cART regimens.

II. CONDITIONS ATTRIBUTED TO HIV INFECTION

A. HIV-asssociated neurocognitive disorders (HAND).

HIV-associated dementia (HAD; HIV dementia, AIDS dementia complex, and HIV encephalopathy) occurred in
up to 20% of patients in the pre-cART era, usually after marked immune suppression developed, with progressive and disabling impairments in cognition, motor function, and behavior. Since the widespread use of cART, these forms of severe dementia are seen much less frequently. However, subtle forms of measurable cognitive impairment persist and may be increasing in prevalence as a consequence of longer survival and independent evolution of HIV in the relatively sequestered CNS. Three categories have been proposed to describe the current spectrum of HAND (Table 44.2):

Asymptomatic neurocognitive impairment (ANI). Individuals with acquired subclinical impairments in at least two cognitive domains on neurocognitive testing, without delirium, symptomatic complaints, or impaired daily activities.

Mild neurocognitive disorder. Individuals with clear sensorium and with acquired impairments in at least two cognitive domains causing at least mild interference with daily activities.

HAD. Individuals with clear sensorium and with more severe acquired impairments in at least two cognitive domains sufficient to produce marked interference with daily activities.

A recent study employing neurocognitive testing found that 69% of patients with HIV infection taking cART and without detectable virus in the blood or cognitive complaints had subtle cognitive impairments. Of 27% with cognitive complaints, 84% had HAND. Another recent study found HAND in 22% of a large cohort taking cART. Studies have demonstrated discordant presence of HIV in CSF despite absence of virus in blood, and specific HIV viral strains found in CSF, which vary from those found in plasma, and which may have different antiretroviral resistance patterns.

TABLE 44.1 Entities Causing Neurologic Complications in AIDS

Encephalopathy			Lymphoma
Diffuse			Tuberculosis
	HIV		Toxoplasmosis
	PML		Vitamin B₁₂ deficiency
	CMV		Nocardia asteroides
	VZV		Pyogenic abscess
	Syphilis	Meningitis
	Toxoplasmosis		HIV
	Aspergillosis		Cryptococci
	Toxic (medications)		Syphilis
Metabolic (e.g., hypoxia and sepsis)			Tuberculosis
Focal			Lymphoma
	Toxoplasmosis		CMV
	PML		HSV
	Lymphoma		VZV
	Cryptococci		Other fungi
	CMV	Neuropathy
	HSV		HIV
	VZV		Toxic (e.g., dideoxynucleosides)
	Syphilis		CMV
	Tuberculosis		Lymphoma
	Fungal abscess		Syphilis
	Nocardia asteroides		Vitamin B₁₂ deficiency
	Pyogenic abscess	Myopathy
Myelopathy			HIV
	HIV		Toxic (zidovudine)
	CMV		Toxoplasmosis
	HSV		Pyogenic
	VZV		CMV
	Syphilis
Abbreviation: HSV, herpes simplex virus.

TABLE 44.2 Criteria for HAND

A. HIV-associated ANI
	Acquired impairment in cognitive functioning involving at least two ability domains
	Cognitive impairment does not interfere with daily functioning
	Criteria for dementia or delirium are not present
	No evidence for an alternative etiology for the ANI
B. HIV-associated MND
	Acquired impairment in cognitive functioning involving at least two ability domains
	Cognitive impairment produces at least mild interference in function at work, home or in social activities
	Criteria for dementia or delirium are not present
	No evidence for an alternative etiology for the MND
C. HAD
	Acquired impairment in cognitive functioning involving at least two ability domains
	Marked interference in function (e.g., inability to work, manage affairs, etc.)
	Criteria for delirium not present (clear sensorium)
	No evidence of another cause for the dementia
Abbreviation: MND, mild neurocognitive disorder. Adapted from Antinori A, Arendt G, Becker JT, et al. Updated research nosology for HIV-associated neurocognitive disorders. Neurology. 2007;69:1789-1799.

Comorbid conditions may contribute to cognitive impairment in HIV-infected patients including concurrent hepatitis C virus infection, CNS active medications, substance use, and age-related cognitive changes. cART may alter lipid metabolism with accelerated atherosclerosis increasing the risk of cerebrovascular disease with related cognitive deficits.

The pathogenesis of HAD is not well-understood. Pre-cART autopsy studies demonstrated multinucleated giant cells containing HIV, myelin pallor, microglial nodules, and loss of neurons and synaptic density. cART era studies have found less significant correlations between the first three elements and clinical impairments. Neurons are not infected by HIV and die in locations remote from the perivascular macrophages and microglia that harbor the virus. Indirect neurotoxicity resulting from soluble factors released by infected cells causing activation of inflammatory mechanisms and disruption of critical trophic influences which culminate in neuronal apoptosis and neurite damage are pathogenic hypotheses that are currently favored.

1. Clinical features.

A clinical triad of cognitive impairment, behavioral changes, and motor impairment characteristic of HAD was described early in the AIDS pandemic. Cognitive features include slowness of thought processing, perseveration, impairments of complex attention, and impaired recall of acquired memories. Behavioral features include apathy, withdrawal from social interaction, and depression. Uncommonly, mania or atypical psychoses occur. Motor features include hyper-reflexia, hypertonia, ataxia, and tremors, typically affecting the legs initially but also involving fine motor coordination of the upper extremities. Extrapyramidal features including bradykinesia, facial masking, rigidity, and postural instability may be seen.

In cART treated patients, these features are attenuated and the temporal course is prolonged. Psychomotor slowing, lassitude, and mild extrapyramidal or fine motor impairments are most commonly seen. The impact can be significant nonetheless, both on the more demanding aspects of daily activities and by altering adherence to cART regimens resulting in loss of viral suppression. Individuals may have mild cognitive abnormalities on testing but no apparent changes in daily functioning. Performance fluctuation on cognitive tests is seen in more mildly affected individuals with some improving and others evolving to more severe impairments.

2. Diagnosis.

A clear sensorium is a requisite for the diagnosis. Evidence of functional impairment often comes to attention from impaired work performance or reports from a companion who assumes responsibility for handling funds and documents. Withdrawal from social activities is common, and depression may be a comorbid feature. A cognitive screening protocol employing the trailmaking and digit symbol tests has been used with reasonable sensitivity in large clinical trials and can be done quickly
as part of a routine examination. OIs (see the following sections) must be excluded with MRI and CSF analysis, and comorbid metabolic conditions, medications with CNS effects, and influences of recreational drugs or alcohol should be excluded.

MRI in HAND may be normal, demonstrate atrophic changes, or reveal a confluent symmetric leukoencephalopathy. CSF is normal or shows mild-to-moderate protein elevation. In the cART era, many patients with asymptomatic or mild impairments are not severely immune suppressed. Neurocognitive measures are sensitive but must be compared with appropriate normative populations with similar age, educational level, ethnicity, and gender. Depression can be evaluated with instruments such as the Beck depression screening test.

3. Therapy.

Antiviral agents. Zidovudine, in high doses, which inhibits HIV reverse transcriptase and penetrates into CSF reasonably well, was the first antiretroviral agent shown in a controlled prospective trial to have efficacy in HAD, as measured by serial cognitive testing. Currently, cART therapy with combinations of anti-nucleosides, nonnucleoside reverse transtriptase inhibitors, protease inhibiting agents, and integrase inhibitors has been associated with a marked reduction in the frequency of HAD. Optimal suppression of HIV viral load should be sought as measured by highly sensitive plasma assays. CSF viral load should also be assessed including individuals with HAND despite undetectable HIV in plasma.

There is no established optimal cART regimen for HAND; however, antiretroviral resistance testing of recovered virus from blood and CSF can aid in the selection of a cART regimen. Although conflicting reports exist regarding the value of selecting agents with higher CSF penetration, such as stavudine, zidovudine, abacavir, efavirenz, nevirapine, and indinavir for combination regimens, or the use of CSF HIV viral load suppression as a marker of treatment efficacy, these measures are often employed, particularly in patients with worsening cognition. New strategies targeting mediators of neurotoxicity are being explored and a search for reliable and timely surrogate markers of CNS disease is an area of current active research. Individuals who qualify should be offered the option of such clinical trials when available.
Supportive therapy.

Apathy and withdrawal can be managed with modafenil 200 to 400 mg daily (not an FDÀ approved indication) or methylphenidate at 5 to 10 mg two or three times a day.

Depression is usually managed with selective serotonin reuptake inhibitors such as fluoxetine or others. Tricyclic antidepressants such as nortriptyline at initial dosages of 25 mg at bedtime, increasing in 25-mg increments every 1 to 2 weeks (or similar agents at comparable doses) are alternatives; however, anticholinergic effects of these drugs can precipitate delirium.

Seizures occur with increased frequency in HIV-infected patients. Because of potential interactions with antiretroviral agents, nonenzyme-inducing anticonvulsants, which are not metabolized by the cytorchrome P-450 system, such as leviracetam, lamotrigine, gabapentin, or pregabalin are preferred.

Supervision. Progression of HIV-associated cognitive change results in loss of ability to manage personal business and financial affairs. Provisions for assistance and ultimately legal transfer of decision-making powers for both financial and health care decisions, and advance health care directives, should be arranged. Assistance in the home may be needed for the provision of meals and facilitation of personal care. Residence in a sheltered facility can be considered when the need for assistance precludes independent living.

4. Outcome.

cART has reduced the severity and mortality of HAND; however, by prolonging survival of patients with HIV infection, it may also lead to an increase in prevalence of cognitive impairment. The natural history of HAND in the era of successful cART is currently evolving.

B. HIV myelopathy.

Neuropathologic evidence of myelopathy has been found at autopsy in up to half of patients with AIDS, although it affects fewer patients clinically. In the cART era, the frequency appears to be decreasing. Vacuolar changes with foamy macrophages are found predominantly in the myelin of the dorsal and lateral columns of the thoracic spinal cord, resembling changes seen in subacute combined degeneration (see Chapter 45).
Signs of active HIV infection such as microglial nodules and infected macrophages are not associated. The specific cause is unknown; however, a deficiency of transmethylation pathways has been hypothesized.

Rarely, an acute self-limited meningomyelitis has been reported as a seroconversion reaction to HIV.

1. Clinical features.

Insidiously progressive spastic paraparesis and sensory ataxia with neurogenic bladder dysfunction are typical of vacuolar myelopathy.

2. Diagnosis

is made on the clinical features once other causes of chronic myelopathy have been excluded, particularly vitamin B₁₂ (cobalamin) deficiency, syphilis, human T-cell lymphotropic virus type I infection, and indolent OIs. Myelopathy resulting from recreational inhalation of nitrous oxide or toluene can mimic vacuolar myelopathy. MRI of the spinal cord can be normal or reveal atrophy or nonspecific intramedullary T2 signal abnormalities. CSF should be obtained to exclude other conditions.

3. Therapy.

Only gold members can continue reading. Log In or Register to continue