Neurologic Abnormalities in Human Immunodeficiency Virus Infection

, Department of Psychiatry and Neurology, Tulane University School of Medicine, New Orleans, La 

South Med J. 2001;94(3) 

In This Article

Opportunistic Infections and Neoplasms

Viral, fungal, parasitic, or bacterial infection may occur, reflecting either T-cell deficiency, infection reactivation (eg, toxoplasmosis), or a new opportunistic suprainfection. Central nervous system infections can be best classified according to clinical findings. Meningitic manifestations include headache, neck pain, nuchal rigidity, fever with absence of focal signs, cognitive dysfunction, and seizures; focal manifestations include brain dysfunction seizures, impaired consciousness, and focal neurologic deficit (hemiparesis, ataxia, cranial nerve paresis), usually associated with headache.

For the meningitic manifestations, lumbar puncture with CSF examination is mandatory. In immunosuppressed patients, the inflammatory response may be muted with meningeal signs, such as nuchal rigidity, and CSF pleocytosis is consequently minimal or absent (especially if the CD4 count is low). If cryptococcal meningitis is present, serum is almost always positive for cryptococcal antigen if viable organisms are present in the CSF. Diagnosis of cryptococcal meningitis is established by lymphocytic CSF pleocytosis, elevated protein and decreased glucose level, positive results on India ink study, elevated CSF cryptococcal antigen, and culture positive for fungi. Lumbar puncture is required to establish the diagnosis, but even in patients with normal results on neurologic examination and CT or MRI, post-lumbar puncture deterioration may occur.[37,38,39] Even so, lumbar puncture is mandatory to establish the diagnosis. Intracranial hypertension complicating cryptococcal meningitis is associated with poor prognosis and should be treated aggressively; corticosteroid therapy should be avoided if possible, but if necessary should be used only for a brief time.[40] Treatment with amphotericin B should be used initially, and fluconazole is the drug of choice to maintain remission after the CSF has been sterilized.

Tuberculosis and tuberculous meningitis may occur in HIV-positive patients when immunosuppression is less prominent (ie, CD4 lymphocyte counts of up to 250). The clinical features and CSF findings of tuberculous meningitis are similar to those observed in HIV-negative patients. Computed tomography or MRI may show multiple nodular, enhanced lesions contiguous with CSF spaces. Both meningitis and enhanced basal cisternal lesions resolve with treatment (isoniazid, pyrazinamide, rifamycin, ethambutol).[41]

In the HIV era, the occurrence of primary and secondary syphilis has increased,[42,43,44,45] leading to an increased incidence of neurosyphilis. The clinical manifestations of HIV-associated neurosyphilis (meningitic, meningovascular) are similar to those of HIV-negative cases, but due to the time-restricted disease course, parenchymal syndromes (general paresis, tabes dorsalis) are uncommon. Neurologic manifestations occur earlier after primary infection, and a longer course of treatment is required due to the immunocompromised status of HIV-positive patients. The following three stages of neurosyphilis may be delineated. (1) In asymptomatic neurosyphilis (CSF abnormalities without neurologic dysfunction), laboratory studies show a positive result on a serum nonspecific test for syphilis (with titer elevated at least threefold) plus CSF abnormalities (lymphocytic pleocytosis, elevated protein, normal glucose level, presence of oligoclonal bands and elevated IgG, and positive CSF VDRL test result). When patients with a negative CSF VDRL test result, reactive serum VDRL test, and abnormal CSF findings are included, the incidence of asymptomatic HIV-associated neurosyphilis is correspondingly much higher. (2) Symptoms of syphilitic meningitis (headache, nuchal rigidity, cranial nerve dysfunction) and appropriate CSF findings occur in the second stage. (3) Manifestations of meningovascular syphilis, stroke with abnormal CSF findings, occur in the last stage. Late in the course of neurosyphilis, the VDRL test result may be negative; however, the fluorescent treponemal antibody test result always remains positive. Penicillin G procaine (intramuscularly) or aqueous penicillin should be administered for 10 to 14 days. The serologic response to treatment with penicillin may be delayed in HIV-positive patients.

Toxoplasmosis is the most common mass lesion of the brain occurring in HIV-positive patients.[46] It represents reactivation of previously acquired infection and occurs in patients with CD4 counts of less than 200. Serum tests for anti-Toxoplasma antibodies are almost always positive if brain abscess due to toxoplasmosis is present. Neurologic manifestations depend on lesion location. There are usually multiple lesions, but initially the abscess may be solitary. There is no characteristic CSF finding, and if a structural lesion such as an abscess is suspected, lumbar puncture typically is contraindicated before CT or MRI. Non-contrast-enhanced CT shows single or multiple hypodense lesions. After the introduction of contrast medium, nodular or ring enhancement occurs. On MRI, contrast-enhanced lesions may be seen that are not visualized by CT. Computed tomographic and MRI findings are not specific and thus do not permit differentiation from other HIV-related focal lesions. Even so, if CT or MRI shows single or multiple enhanced lesions and serology is positive for Toxoplasma, empiric therapy with pyrimethamine and sulfadiazine (clindamycin may be substituted since hypersensitivity to sulfadiazine commonly occurs) may be initiated without initial brain biopsy.[47] If clinical and neuroimaging findings do not improve in 2 weeks, stereotactic brain biopsy should be done. If improvement occurs, maintenance therapy is required to prevent relapses.[48]

Primary CNS lymphoma is uncommon unless the CD4 count is less than 50. Neurologic manifestations may be focal (hemiparesis, ataxia, cranial nerve dysfunction) and diffuse (confusion, disorientation), especially if multifocal periventricular lesions are present.[49] Computed tomography and MRI show white matter and periventricular lesions that are densely enhanced and extend across the corpus callosum. Metabolic activity is increased within the lymphoma; results of thallium scan or single photon emission CT consequently will be positive (negative in toxoplasmosis).[50,51] Polymerase chain reaction (PCR) may detect the presence of Epstein-Barr virus in the CSF of lymphoma patients.[52,53] Primary CNS lymphoma is associated with a poor clinical prognosis, even after chemotherapy and radiotherapy. Corticosteroids should be used, since they reduce surrounding edema and even exert a direct cytotoxic effect on the tumor.

Progressive multifocal leukoencephalopathy (PML) results from infection with the JC virus. The disorder is usually detected by MRI, which shows multiple or confluent foci of abnormal density in the deep cerebral white matter.[54] Computed tomography may show multiple hypodense lesions, but MRI is more sensitive in detecting these white matter abnormalities. Because of a lack of inflammatory response, the lesions are rarely enhanced on imaging. The lesions of PML usually begin in the posterior parietal-occipital white matter and extend forward. Rarely, PML begins as a unifocal lesion and, occasionally, faint contrast enhancement is evident on CT and MRI.[55] Polymerase chain reaction amplification of JC virus RNA in the CSF may establish this diagnosis and obviate the need for brain biopsy. Because of the location of the initial lesion, typical clinical features are visual disturbances, including hallucinations, cognitive decline, hemiparesis, and gait ataxia. At autopsy, there are multiple foci of demyelination with abnormal ("ballooned" and "swollen") oligodendroglia. JC viral particles can be detected within the oligodendroglia. The disease course is one of clinical deterioration over several months, but 10% to 15% of cases stabilize or even improve spontaneously.[54,55] No antiviral therapeutic agent such as acyclovir has been shown to be effective in slowing the course of PML.


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