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Management Recommendations > CNS Disease

Ward 86 Management Recommendations

Diagnostic Approach to HIV Patients Presenting with Signs or Symptoms of Acute Central Nervous System Disease

updated September 2018

Contributors: Mark Jacobson, MD
Annie Luetkemeyer, MD
Catherine Koss, MD

Clinical presentations

HIV-infected patients may present with various signs and symptoms of central nervous system (CNS) disease, including:

  • Headache with or without meningismus
  • Altered sensorium (may be subtle in cryptococcal meningitis)
  • Fever
  • Seizure
  • Focal neurologic deficit
    • Cerebral (eg, hemiparesis, visual field cuts, sensory disturbances)
    • Spinal cord (eg, weakness [often bilateral], sensory deficit level, bowel or bladder dysfunction)
  • Any of the above may occur alone or in combination.
  • Many of the CNS diseases associated with HIV may present subacutely.
  • Cognitive decline, caused by HIV infection within the CNS, can lead to dementia. Occasionally, this decline can progress rapidly.

Causes of acute CNS disease that should be considered in HIV patients independent of their CD4 count

  1. Tuberculous meningitis
    • Most cases occur in non-U.S.-born patients with advanced HIV disease.
    • Clinical manifestations:
      • May present in 3 phases: prodromal, meningitic, and paralytic (the latter with advanced disease characterized by seizures, hemiplegia, paraplegia and/or coma).
      • Some manifestations of CNS tuberculosis may be due to mass lesions (tuberculomas and abscesses).
    • Diagnosis:
  2. Bacterial meningitis
    • The most common bacterial cause of meningitis in HIV patients is S. pneumonia. The risk of invasive pneumococcal disease is much higher in HIV-infected patients, even those suppressed on antiretroviral therapy [ART], than in non-HIV infected populations.(2)
    • Meningococcus, Haemophilus influenzae, and Listeria are rare in HIV patients. However, cases of invasive meningococcal disease due to Neisseria meningitides serogroup C were identified among men who have sex with men, many of whom were HIV infected, in New York, Los Angeles, and several European cities from 2010 to 2014.
  3. Neurosyphilis (see section on Neurosyphilis)
  4. Stroke
    • Causes of stroke in HIV-infected individuals may include coagulopathy, cardioembolism, opportunistic infections (eg, tuberculosis, syphilis, varicella-zoster virus encephalitis), bacterial endocarditis with embolism, and hemorrhage.
    • The risk of ischemic stroke is higher in HIV-infected adults than in HIV-uninfected adults after adjustment for traditional stroke risk factors.(3)
    • This association may be due, in part, to the persistent chronic inflammatory state induced by HIV.
  5. Endemic mycoses: Certain systemic fungal infections can rarely invade the CNS of people who have lived in or traveled to areas where these infections are endemic. Among HIV-infected patients, these diseases can occur at any CD4 count; however, the risk of invasive CNS disease is higher among those with lower CD4 counts. (See Table for more details.)
  6. Viruses that can cause meningitis or encephalitis in the general population (eg, herpes simplex, enterovirus, West Nile virus) also should be considered. However, the risk of these diseases does not appear to be any greater for HIV-infected persons than for the general population.

Causes of acute CNS disease that occur almost exclusively in patients with a recent absolute CD4 count of <100 cells/µL

(Conditions discussed above, which can occur at any CD4 count, also should be considered.)

  1. Cryptococcal meningitis
    • Most cases occur in patients with CD4 counts of <100 cells/µL who are not receiving ART.
    • Clinical manifestations: The tempo of symptom onset (eg, headache, fever, altered mental status) is often subacute.
    • Diagnosis:
      • The serum cryptococcal antigen assay (CrAg) is >95% sensitive for meningitis but is not specific for meningitis. CSF CrAg is 90% sensitive and 100% specific for meningitis.
      • CSF India ink stain can make the diagnosis immediately.
      • Cryptococcus can cause pneumonia with or without meningitis.
      • Patients may have isolated, symptomatic or asymptomatic cryptococcemia (ie, without meningitis or pneumonia).
    • See section on Cryptococcal Infection for additional diagnostic and management recommendations.
  2. Toxoplasmic encephalitis
    • Most cases occur in AIDS patients with CD4 counts of <100 cells/µL who are not receiving ART.
    • Clinical manifestations may include headache, focal neurologic deficits, seizure, and altered mental status.
    • Diagnosis:
      • Typically, multifocal, contrast-enhancing lesions are seen on brain computed tomography (CT) or magnetic resonance imaging (MRI).
      • The vast majority of patients with toxoplasmic encephalitis have a positive serum Toxoplasma gondii IgG antibody.(4) A recent estimate of the pooled prevalence of T gondii infection in people with HIV infection from different geographic regions of origin is 45% in sub-Saharan Africa, 30% in western and central Europe and North America, 25% in Asia and the Pacific, 61% in the Middle East and North Africa, and 49% in Latin America and the Caribbean.(5) A negative serum T gondii IgG titer makes this diagnosis unlikely, although there are case reports of IgG negative, confirmed toxoplasmic encephalitis.
      • Rarely, disseminated toxoplasmosis may manifest as pneumonitis (which can mimic Pneumocystis pneumonia) or retinitis.
      • In practice, this is a clinical diagnosis made on the basis of brain imaging findings, T gondii IgG seropositivity, and a low CD4 count.
      • The diagnosis most often is confirmed by a clinical response (improvement on neurologic exam and in imaging) to empiric anti-Toxoplasma therapy occurring within 3 weeks but rarely may require brain biopsy.
  3. Progressive multifocal leukoencephalopathy (PML)
    • Nearly all cases occur in AIDS patients who either have a CD4 of <100 cells/µL or have recently initiated ART with a CD4 count in this range.
    • PML is caused by opportunistic invasion of the brain by JC virus--a common, benign, latent polyomavirus infection in immunocompetent individuals. Latent JC infection has a high prevalence in the general population.
    • Clinical manifestations:
      • The typical presentation involves upper motor neuron deficits.
      • The presentation may be subacute over several weeks.
      • Many cases appear, or symptoms of established cases worsen, after ART is initiated (ie, unmasking or paradoxical immune reconstitution inflammation syndrome [IRIS]). This may result from an immune reconstitution inflammatory response in the brain. Edema, mass effect, and contrast enhancement often are observed in such cases--findings not seen in patients with PML who have yet to initiate ART.
    • Diagnosis:
      • Brain MRI or CT shows multifocal, asymmetric areas of white matter demyelination with periventricular and subcortical involvement being common. Mass effect and contrast enhancement are not observed unless the patient already has initiated ART (ie, PML IRIS).
      • The CSF JC virus DNA PCR assay of CSF has good specificity (>90%) for PML but relatively poor sensitivity.
    • Treatment: There are no effective antiviral drugs for PML. Only immune restoration by ART can stop progression of this disease.
  4. Other causes of encephalitis that occur primarily in patients with a CD4 count of <50 cells/µL
    1. Primary brain lymphoma (PBL)
      • The pathogenesis of this condition appears to involve immunologic loss of control of Epstein-Barr virus (EBV) replication. PBL is 1,000 times more common in HIV-infected than in HIV-uninfected individuals, although the risk has declined by 80% with the widespread availability of ART.
      • Clinical manifestations may include headache, focal neurologic deficits, seizure, and altered mental status.
      • Diagnosis:
        • In half of cases there is a single lesion seen on CT or MRI; in the other half, multiple lesions are seen. Both PBL and toxoplasmosis lesions typically enhance on brain imaging, but PBL lesions have less-restricted diffusion.
        • Though a definitive diagnosis requires brain biopsy, CSF EBV DNA positivity by PCR has a sensitivity of up to 80% and nearly 100% specificity for this diagnosis in AIDS patients with a mass lesion in the brain.(6) It should be noted, however, that the positive predictive value of this test varies with the disease prevalence in the population.
        • A positive CSF cytology consistent with lymphoma or a negative serum T gondii IgG titer also supports the diagnosis of primary brain lymphoma, as does failure to improve with empiric treatment for toxoplasmosis.
        • Of note, AIDS-associated non-Hodgkin lymphoma may cause meningitis but almost never causes brain metastases.
    2. Cytomegalovirus (CMV) encephalitis
      1. CMV encephalitis often is associated with concomitant CMV end-organ disease in the retina or gastrointestinal tract.
      2. CT or MRI brain scan typically shows periventricular enhancement.
      3. The CSF profile is variable and may be normal.
      4. The CMV DNA PCR assay of CSF has good sensitivity and specificity for this diagnosis.
      5. See section on Cytomegalovirus Disease for more information.
    3. Varicella-zoster virus (VZV)
      1. Rare cases of encephalitis and stroke have been reported due to CNS VZV infection, often in the absence of cutaneous zoster.
      2. The VZV DNA PCR assay of CSF has good sensitivity and specificity for this diagnosis.
    4. HIV-associated dementia (HAD)

      Also known as AIDS dementia complex or HIV encephalopathy, this condition is a diagnosis of exclusion, confirmed by a score of at least 2 standard deviations below the mean on at least 2 cognitive areas of standardized neuropsychological testing in the absence of delirium or other CNS disease.

      1. Most cases occur in AIDS patients with CD4 counts of <100 cells/µL who are not receiving ART.
      2. HAD generally presents as gradual cognitive deterioration occurring over months but can sometimes present subacutely with deterioration occurring over just a few weeks.
      3. The only effective treatment is ART. Clinical benefit from selecting a specific ART regimen based on the agents' ability to cross the blood-brain barrier and penetrate the CNS has NOT BEEN established by the studies published to date.
  5. Immune reconstitution inflammatory syndrome (IRIS)
    • Encephalitis rarely may be a manifestation of IRIS. This condition is generally seen only in patients who initiate ART at a very advanced stage of HIV disease.
    • Etiologic pathogens have been described in some cases and include JC virus, CMV, VZV, Mycobacterium tuberculosis, Cryptococcus, and Parvovirus. See section on Immune Reconstitution Inflammatory Syndrome for more information.

Other diagnostic considerations in the HIV patient presenting with CNS disease

  • Imaging (brain CT or MRI without contrast) should be performed before lumbar puncture. In patients with imaging results suggestive of mass effect, a lumbar puncture is contraindicated due to risk of herniation.
  • A history of any visual symptoms should be obtained, as secondary syphilis, CMV, VZV, and toxoplasmosis can present with concomitant retinitis or optic neuritis, and cryptococcal meningitis can present with visual loss. In patients who complain of floaters or vision deficits that are due to retinitis, the features observed by a dilated, indirect ophthalmologic exam often can suggest the underlying pathogen.
  • Interpreting the clinical significance of an abnormal CSF cell count can be complicated by the low-level lymphocytic pleocytosis that often occurs in patients with untreated HIV whose CD4 count is >200 cells/µL. This pleocytosis is presumed to be due to an inflammatory response to CNS HIV infection. In the era before the availability of potent ART, 15% of 424 asymptomatic HIV-infected Air Force personnel who underwent lumbar puncture had >10 WBC/µL in CSF.(7) In the modern ART era, predictors of a CSF WBC count of >5 cells/µL are a CD4 count of >200 cells/µL, detectable plasma HIV RNA, and lack of current use of ART.(8)

Table. Endemic Mycoses That Can Involve the CNS

DiseaseEndemic AreasCSF ProfileImagingDiagnostic Tests

CNS disease typically presents as meningitis and is often associated with pulmonary disease.

Southwest United States, Northwest Mexico10-10,000 WBC/µL, lymphocytic predominance. Eosinophils may be present.Hydrocephalus in 30-50% of cases. 15-20% of patients have vasculitic infarct. Abscess is rare. Serologies:

Immunodiffusion and complement fixation for IgM and IgG antibodies in serum have higher sensitivity than in CSF.

CSF cultures are positive in only 30% of patients with meningitis.


CNS disease can present as meningitis, altered mental status, or a focal neurologic deficit.

Ohio, Missouri, and Mississippi River valleys; certain areas in Latin America, Asia, and AfricaLymphocytic pleocytosisLeptomeningeal enhancement with or without single or multiple enhancing lesions (histoplasmoma)Neither Histoplasma CSF or urine antigen, serology, or CSF culture has a high sensitivity for detecting CNS histoplasmosis. All these tests should be ordered if this diagnosis is being considered, but leptomeningeal or brain biopsy make be required in some cases to confirm the diagnosis.

Often preceded by pulmonary disease.

South Central, southeastern, and midwestern United States; AfricaPleocytosis with lymphocyte or neutrophil predominanceLeptomeningeal enhancement and/or mass lesionCSF fungal culture is gold standard.

Sensitivity of Blastomyces urine and CSF antigen is 92.9% and 79.3%, respectively. Cross-reactivity of the assay with histoplasmosis and paracoccidioidomycosis is high.
Adapted from Chamie G, Marquez C, Luetkemeyer A. HIV-associated central nervous system tuberculosis. Semin Neurol. 2014 Feb;34(1):103-15.


  1. Chamie G, Marquez C, Luetkemeyer A. HIV-associated central nervous system tuberculosis. Semin Neurol. 2014 Feb;34(1):103-15.
  2. Sogaard OS, Lohse N, Gerstoft J, et al. Hospitalization for pneumonia among individuals with and without HIV infection, 1995-2007: a Danish population-based, nationwide cohort study. Clin Infect Dis. 2008 Nov 15;47(10):1345-53.
  3. Chow FC, Regan S, Feske S, et al. Comparison of ischemic stroke incidence in HIV-infected and non-HIV-infected patients in a US health care system. J Acquir Immune Defic Syndr. 2012 Aug 1;60(4):351-8.
  4. Derouin F, Leport C, Pueyo S, et al. Predictive value of Toxoplasma gondii antibody titres on the occurrence of toxoplasmic encephalitis in HIV-infected patients. ANRS 005/ACTG 154 Trial Group. AIDS. 1996 Nov;10(13):1521-7.
  5. Wang ZD, Wang SC, Liu HH, et al. Prevalence and burden of Toxoplasma gondii infection in HIV-infected people: a systematic review and meta-analysis. Lancet HIV. 2017 Apr;4(4):e177-e188.
  6. Cingolani A, De Luca A, Larocca LM, et al. Minimally invasive diagnosis of acquired immunodeficiency syndrome-related primary central nervous system lymphoma. J Natl Cancer Inst. 1998 Mar 4;90(5):364-9.
  7. Marshall DW, Brey RL, Cahill WT, et al. Spectrum of cerebrospinal fluid findings in various stages of human immunodeficiency virus infection. Arch Neurol. 1988;45:954-958.
  8. Marra CM, Maxwell CL, Collier AC, et al. Interpreting cerebrospinal fluid pleocytosis in HIV in the era of potent antiretroviral therapy. BMC Infect Dis. 2007 May 2;7:37.