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HIV-1 AND INFECTIONS OF THE CENTRAL NERVOUS SYSTEM

HIV-1 AND INFECTIONS OF THE CENTRAL NERVOUS SYSTEM

Meningitis
Space-occupying Lesions in the Brain
Encephalopathy
Bibliography

Neurologic disorders are common in persons infected with the human immunodeficiency virus type 1 (HIV-1). Indeed, at autopsy, 70% to 80% of patients with AIDS have pathologic findings in the central nervous system (CNS), including infections, neoplasms, and degenerative conditions of uncertain etiology, such as vacuolar myelopathy; furthermore, diseases within the CNS have become major immediate causes of death in patients with AIDS.
The high prevalence and variety of diseases affecting the CNS is a consequence of the direct involvement of the brain by HIV-1 as well as the profound immunosuppression that occurs as the systemic retroviral illness progresses. Because the spectrum of problems involving the CNS is broad and because many of these conditions respond to specific therapies, the evaluation of the HIV-1–infected patient with neurologic symptoms or signs must be systematic, expeditious, and thorough. This chapter focuses on the prevalent infectious syndromes that involve the meninges and brain. Although the common CNS syndromes are discussed as distinct clinical entities, it must be emphasized that the patient with advanced HIV-1 disease can present with multiple disorders; for example, patients with AIDS can experience cryptococcal meningitis and cerebral toxoplasmosis concurrently.
Meningitis
A neurotropic retrovirus, HIV-1 appears to invade the CNS during the primary infection. The virus has been isolated from the cerebrospinal fluid (CSF) of adults with acute HIV-1 infection and from those with AIDS, and HIV-1 RNA has been detected by polymerase chain reaction (PCR) in the CSF of most patients at all stages of the disease. In addition, HIV-1 has been detected in a number of CNS cell populations, including endothelial cells, macrophages, and microglial cells. Finally, HIV-1 DNA has been found in the brains of about 50% of patients with asymptomatic infection and 100% of patients with AIDS.
Patients with acute HIV-1 infection can present with fever, malaise, myalgias, arthralgias, headache, and photophobia; on occasion, an acute encephalopathy dominates the clinical picture. The CSF abnormalities in patients with acute HIV-1 infection include a lymphocytic pleocytosis (<200 cells per cubic millimeter) and an elevated protein concentration. Thus, the possibility of HIV-1 infection should be considered in the adult who has aseptic meningitis and risk factors for infection with the virus (a history of IV drug use, homosexuality, or heterosexual promiscuity). In the patient with aseptic meningitis and risk factors, PCR or another assay to detect HIV-1 RNA in serum should be performed, and HIV-1 serologies should be obtained 1 and 3 months following the episode to detect seroconversion. The symptoms in patients with acute HIV-1 meningitis usually resolve within 4 weeks. Of note, some patients can experience a chronic meningitis syndrome, apparently caused by HIV-1.
Many patients with latent-stage (asymptomatic) HIV-1 infection have abnormal CSF profiles, typically a lymphocytic pleocytosis (60 mg/dL); these CSF abnormalities may or may not be accompanied by clinical evidence of meningitis. The CSF of patients with AIDS is characterized by an elevated protein level but no pleocytosis. Because of the high prevalence of abnormal spinal fluid findings in this patient population, the results of the CSF analysis must be interpreted with caution in patients who have an enigmatic neurologic process.
Patients with HIV-1 infection are at risk to experience meningitis caused by a variety of microbes, and reports of infection with bacteria (Streptococcus pneumoniae, Listeria monocytogenes), spirochetes (Treponema pallidum), mycobacteria (Mycobacterium tuberculosis, Mycobacterium avium-intracellulare), and fungi (Cryptococcus neoformans, Histoplasma capsulatum, Coccidioides immitis) have appeared in the medical literature. In addition, lymphomatous meningitis can develop in these patients as a complication of a systemic lymphoma. Accordingly, the appropriate microbiologic, serologic, or cytologic tests should be performed in the HIV-infected patient with an acute or chronic meningitis syndrome and epidemiologic, clinical, or laboratory evidence of one of these conditions. Of note, PCR of the CSF for the detection of M. tuberculosis DNA appears to be a very rapid, sensitive, and specific assay for establishing a diagnosis of tuberculous meningitis.
Although uncommonly, HIV-1–infected patients can present with acute syphilitic meningitis or meningovascular syphilis, a dramatic manifestation of neurosyphilis. In addition, these patients are at risk to experience asymptomatic neurosyphilis. Because the spinal fluid Venereal Disease Research Laboratory (VDRL) test in the setting of HIV-1 infection can be nonreactive, the possibility of neurosyphilis should be considered in the patient with positive peripheral blood serologies [VDRL, rapid plasma reagin (RPR)] and compatible cellular and biochemical CSF findings; for example, in one report of 11 patients with oligosymptomatic or asymptomatic neurosyphilis, the CSF VDRL assay was determined to be 100% specific but only 33% sensitive. In any case, T. pallidum can be recovered from the CSF in 20% to 25% of adults with primary or secondary syphilis, and so the potential for relapse within the CNS exists in penicillin-treated, HIV-positive patients. Finally, the utility of T. pallidum DNA PCR in the CSF remains under investigation.
C. neoformans, a fungus found in bird excreta and soil throughout the United States, is the most common cause of nonviral meningitis in patients infected with HIV-1. Before the widespread use of fluconazole, cryptococcal meningitis was reported in about 10% of patients infected with AIDS; the prevalence appears substantially lower at present. Often the initial manifestation of the underlying retroviral disease, cryptococcal meningitis is usually seen in HIV-1–infected patients whose CD4-cell counts are below 100/mm3. The illness presents as a subacute or chronic meningitis syndrome with fever, lethargy, nausea, headache, and nonfocal findings on neurologic examination; papilledema can be present. Results of computed tomography (CT) and magnetic resonance imaging (MRI) are usually normal. The CSF findings are variable, but a pleocytosis, a depressed glucose concentration (hypoglycorrhachia), and an elevated protein level are characteristic; however, in patients with advanced retroviral disease, the spinal fluid cell count, glucose level, and protein level can all be normal. Fortunately, cryptococcal antigen is detectable in the CSF and serum in more than 90% of patients, typically at high titer (>1:1,024). Spinal fluid cultures will reveal the presence of the fungus in virtually all patients, and blood cultures will be positive in 50% to 60% of cases. Higher-dose amphotericin B (0.7 mg/kg per day) with or without flucytosine (100 mg/kg per day) appears to be the treatment of choice for the initial 2 weeks of therapy; fluconazole or itraconazole can be utilized for consolidation therapy. However, some authorities recommend that fluconazole alone be employed as initial therapy in patients with mild disease. Liposomal amphotericin B has also been shown to be effective as initial therapy for crytococcal meningitis, and the use of the agent might be considered in patients who cannot tolerate amphotericin B. In any case, primary therapy for cryptococcal meningitis should be continued until the CSF cultures are sterile. Of note, because of defects in the mechanisms through which the polysaccharide is eliminated, cryptococcal antigen can remain detectable for extended periods of time.
Because relapse occurs in 40% to 60% of treated patients, lifelong suppressive therapy (secondary prophylaxis) is required, and fluconazole (200 mg orally per day) should be used for this purpose. Finally, low-dose fluconazole (200 mg orally thrice weekly) represents effective primary prophylaxis for the infection, and the antifungal should be given to patients with AIDS whose CD4-cell counts are below 100/mm3.
Space-occupying Lesions in the Brain
HIV-1–infected patients frequently present with abnormal findings on the neurologic examination and parenchymal lesions revealed by CT of the brain. Although a number of diseases can result in space-occupying lesions in the brain, the most common entities are toxoplasmosis and lymphoma. Pyogenic brain abscesses, cryptococcomas, tuberculomas, Kaposi’s sarcoma, and even cytomegalovirus (CMV) infection are rare causes of intracerebral masses in these patients.
A protozoan pathogen, Toxoplasma gondii is capable of causing single or multiple cerebral abscesses. The disease usually results from the reactivation of viable organisms encysted in extraneural sites during the primary infection. The risk for cerebral disease approaches 10% among persons with HIV-1 infection who have serologic evidence of prior infection with T. gondii; indeed, toxoplasmosis is the most common cause of intraparenchymal brain lesions in HIV-1–infected patients. The problem is usually seen in persons with CD4-cell counts below 100/mm3.
Most patients with cerebral toxoplasmosis present with focal neurologic problems, such as aphasia, hemiparesis, and complete hemiplegia, that evolve during 1 to 2 weeks; headache, fever, seizures, and changes in mental status also occur. In other patients, toxoplasmosis can present as an acute confusional state, with or without focal findings; these patients can have a diffuse necrotizing encephalitis rather than focal lesions. CT with contrast material will demonstrate single or multiple enhancing lesions in virtually all patients; the lesions are most commonly seen in the region of the basal ganglia or at the junction of the gray and white matter in the cerebral hemispheres. Although the test is not often required, MRI can detect lesions not visualized by CT; with MRI, multiple abscesses will be detected in more than 80% of patients. Toxoplasma serologies are positive in more than 95% of patients with CNS infection. Because the CSF changes are nondiagnostic, the standard analysis of CSF has been considered rarely helpful in the management of these patients; however, PCR of the CSF to detect T. gondii DNA may prove to be a very useful assay. In any case, because the intracranial pressure of patients with intracerebral mass lesions can be increased, a lumbar puncture in this setting does carry a risk for herniation.
Primary lymphoma of the CNS, which has been associated with the Epstein-Barr virus, is the lesion most frequently confused with toxoplasmosis. Although rare in the general population, the disease occurs in about 5% of patients with AIDS; most persons with the malignancy have a CD4-cell count below 50/mm3. In contrast to patients with toxoplasmosis, those with CNS lymphoma tend to present without focal neurologic signs but with a slowly evolving encephalopathy that is characterized by apathy and an altered mental status; nevertheless, the overlap in the clinical manifestations of the two diseases is great. Unfortunately, the anatomic location and CT appearance of toxoplasmosis and lymphoma are similar. Equally important, in up to 40% of patients, the malignancy is multicentric, and so the presence of more than one ring-enhancing lesion on CT does not exclude the possibility of a lymphoma; furthermore, 60% to 70% of patients with primary CNS lymphoma will have positive serologic tests for T. gondii. Of note, in recent investigations, PCR for Epstein-Barr virus DNA in CSF appears to be a very sensitive method for identifying patients with primary CNS lymphoma, and single-photon emission computed tomography (SPECT) with thallium 201 has been reported as a novel method for accurately distinguishing toxoplasmosis from lymphoma.
The approach to the HIV-1–infected patient with a space-occupying brain lesion varies from institution to institution; however, for the AIDS patient with multiple ring-enhancing lesions, empiric antitoxoplasmal therapy is usually given and the clinical response to treatment is monitored. Most patients with cerebral toxoplasmosis demonstrate an improvement in their systemic or neurologic symptoms within 2 weeks and a radiologic response within 3 weeks; of note, abnormalities on CT can persist for up to 6 months. The usual therapy is a combination of pyrimethamine (200 mg by mouth on the first day and then 75 to 100 mg daily), sulfadiazine (1 to 1.5 g orally every 6 hours), and folinic acid (10 to 15 mg daily) given for 4 to 6 weeks; clindamycin (600 mg by vein or by mouth every 6 hours) can be used in patients intolerant of sulfadiazine. When given with pyrimethamine and folinic acid, azithromycin, clarithromycin, and dapsone are among the other agents that have been shown to be effective in the therapy of CNS toxoplasmosis. A stereotactic or open brain biopsy is reserved for patients with single lesions that suggest lymphoma and for patients who fail to respond to antitoxoplasmal therapy within 7 to 14 days.
The outlook for patients with cerebral toxoplasmosis tends to be good, and many survive for extended periods of time. In contrast, the prognosis for patients with primary CNS lymphoma is poor; most succumb within 2 to 4 months. Finally, because the discontinuation of antitoxoplasmal therapy results in a recrudescence of the infection in up to 50% of treated patients, long-term (lifelong) suppressive therapy is indicated; pyrimethamine (25 to 50 mg daily) and folinic acid (5 to 10 mg daily) plus sulfadiazine (0.5 to 1.0 g four times daily) or clindamycin (300 mg four times daily) should be given.
Encephalopathy
Patients infected with HIV-1 can present with changes in mental status because of meningitis or cerebral mass lesions. These patients can also experience a deterioration in cognitive function caused by intercurrent conditions, including viral encephalitis (CMV, herpes simplex virus, herpes zoster virus, human herpesvirus 6) and metabolic encephalopathy (hypoxemia, drugs). Of note, PCR of the CSF for CMV DNA appears to be a rapid and sensitive technique for establishing a diagnosis of CMV encephalitis or ventriculoencephalitis, and PCR of the CSF has been employed to monitor the response of AIDS patients with CMV disease to antiviral (ganciclovir) therapy.
HIV-infected persons are also at risk for the development of progressive multifocal leukoencephalopathy (PML), which is caused by the reactivation of papovaviruses, usually Jamestown Canyon (JC) virus, and is characterized by personality changes, an altered mental status, aphasia, ataxia, and hemiparesis; occasionally, new-onset seizures are the first manifestation of PML. CT in patients with PML characteristically reveals hypodense, nonenhancing lesions confined to the white matter. Traditionally, a brain biopsy has been required for definitive diagnosis; however, PCR of the CSF for JC virus DNA appears to be a very promising assay. Unfortunately, most patients with PML die within a few months of diagnosis. The most common cause of a deterioration in cognitive function in patients infected with HIV-1, however, is the AIDS dementia complex.
Also referred to as AIDS-related dementia and AIDS encephalopathy, the AIDS dementia complex is characterized by a progressive impairment in cognitive function that is accompanied by behavioral changes and motor abnormalities. Not common in HIV-1–infected persons who are asymptomatic and constitutionally well, the prevalence of the AIDS dementia complex increases with advanced degrees of immunosuppression; the risk for the disorder also rises with age and appears to be greatest in patients with AIDS who are more than 50 years of age. Depending on the criteria used, the disorder has been detected in 25% to 90% of all patients with AIDS. Early in the course, patients with the AIDS dementia complex experience impairments in cognitive function, such as forgetfulness and an inability to concentrate, and personality changes, including apathy, withdrawal, and depression. As the condition progresses, often during a period of months, the cognitive function deteriorates, and the behavioral and motor abnormalities become more prominent; leg weakness, a loss of balance, and clumsiness of the arms and hands are common complaints. Late in the course, ataxia, psychiatric disturbances, mutism, paraplegia, incontinence, and myoclonus occur. Intercurrent illness can accentuate the neurologic findings at any stage. CT reveals cortical atrophy in about 75% of patients with the AIDS dementia complex; the CSF and electroencephalogram findings are usually abnormal, but the changes are not diagnostic of the condition. Most patients succumb within a few months following the onset of severe dementia.
The AIDS dementia complex results from infection of the CNS by HIV-1. The histo-pathology of the brains of many patients is compatible with a diffuse viral infection, suggesting a direct insult by HIV-1; however, the brains of other patients indicate that immune and other indirect mechanisms of injury contribute prominently to the neuropathology. Apoptosis, which is induced by soluble factors, including cytokines (e.g., tumor necrosis factor-a), that are produced by neighboring and uninfected cells, is one important mechanism of neuronal injury. Of note, the magnitude of cytokine production appears to be related to the extent of viral replication. Thus, it is not surprising that clinical investigations have shown that the severity of AIDS dementia complex parallels CSF levels of HIV-1 RNA. A number of other potential mechanisms of neuronal damage have been suggested; these include neurotoxicity by quinolinic acid released by HIV-infected macrophages and cellular injury by HIV-specific cytotoxic T cells. In any case, the severity of the dementia reflects the extent of the pathologic changes in the brain.
Because the CNS changes are attributable to infection with HIV-1, clinicians have been hopeful that antiretroviral therapy would prove useful in the prevention and therapy of the AIDS dementia complex, and initial reports have in general indicated a benefit of antiretroviral drugs. In particular, long-term therappy with zidovudine prevents the onset of neurocognitive defects in patients with symptomatic HIV-1 disease or AIDS, and the medication improves neurocognitive functions, such as memory and attention, in HIV-1–infected patients with AIDS dementia complex; these benefits appear to be sustained for at least months. Didanosine also appears to be effective. The impact of combination antiretroviral therapy (e.g., reverse transcriptase inhibitors plus protease inhibitors) on the incidence and clinical course of AIDS dementia complex remains to be determined. (A.L.E.)
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The author describes a patient with AIDS and concurrent cryptococcal meningitis and toxoplasmal encephalitis.
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In a prospective randomized trial that compared fluconazole (200 mg daily given orally) with amphotericin B (1 mg/kg body weight given weekly intravenously), the investigators found that the relapse rate for symptomatic cryptococcal meningitis was 2% among patients assigned to fluconazole versus 18% among patients administered amphotericin B. In addition, bacteremias and serious drug-related toxicities were more common in the amphotericin B-treated group.
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The clinical manifestations and pathophysiology of the condition are reviewed, and a detailed scheme for the clinical staging of the disorder is presented.
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Schmitt FA, et al. Neuropsychological outcome of zidovudine (AZT) treatment of patients with AIDS and AIDS-related complex. N Engl J Med 1988;319:1573.
Cognitive abnormalities attributable to the AIDS dementia complex may be decreased with the use of zidovudine.
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Didanosine (dideoxyinosine, DDI) may have a benefit in the prevention and therapy of AIDS dementia complex similar to that of zidovudine.

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