10. HIV and Neurologic Deficits

Definition

Altered mental status (AMS) or focal neurologic deficits in patients with advanced HIV can be attributable to mass-occupying lesions, including toxoplasmosis and lymphoma, but there is a broad differential.

Differential Diagnosis

Causes of acute CNS disease at any CD4 count:

  • Tuberculous meningitis
  • Bacterial meningitis
  • Neurosyphilis
  • Stroke
  • Endemic mycoses
  • Viral meningitis or encephalitis
  • Malignancy: benign and malignant brain tumors, metastases

Causes of acute CNS disease with CD4 count < 100:

  • Cryptococcal meningitis
  • Toxoplasmosis encephalitis
  • Progressive multifocal leukoencephalopathy (PML)

Causes of acute CNS disease with CD4 count < 50:

  • Primary CNS lymphoma
  • Cytomegalovirus (CMV) encephalitis
  • VZV encephalitis
  • HIV associated neurocognitive disorder (HAND)

By radiologic appearance (see below for choice of imaging study):

  • CNS lesion with mass effect (signs of elevated ICP: headache, nausea/vomiting, and lethargy; typically contrast-enhancing): more commonly toxoplasmosis and CNS lymphoma; other infections include brain abscess, cryptococcus, and mycobacteria
  • CNS lesion without mass effect (typically not contrast-enhancing): PML (typically multifocal lesions in the periventricular areas and the subcortical white matter), HIV encephalopathy, and CMV

Evaluation

  • Neuroimaging: all studies should be ordered with and without contrast if possible. MRI is preferable to CT because of increased sensitivity, especially for white matter disease and posterior fossa lesions, and is the modality of choice prior to brain biopsy
  • Lumbar Puncture (LP): CT/MRI should be performed prior to LP. If there is evidence of mass effect on imaging, LP may be contraindicated due to a high risk of herniation (can ask neurology in these cases to see if LP can be performed safely). If CSF is obtained, check opening pressure and send for cell count + diff, glucose, protein, bacterial/fungal culture, CrAg, and consider additional studies based on clinical features or imaging findings (HSV PCR, VZV PCR, AFB stain/culture, VDRL, cytology, universal PCR, next generation metagenomic sequencing, etc.). A tube can be placed on hold, thus not every study need be ordered on the first pass
  • Brain biopsy: the gold standard for diagnosing CNS lesions in HIV/AIDS patients. Location of the lesions is the primary factor determining the risk of biopsy
  • Serum studies: consider testing for Vitamin B12, TSH, HCV Ab, CMP, T gondii IgG, serum CrAg, RPR, CD4 count and viral load depending on the presentation
  • Screen for major depression, anxiety, and substance use disorders
  • Additional workup depends on suspected diagnosis:
    • Bacterial abscess: physical exam looking for source (oropharyngeal/sinus infection, endocarditis, intra-abdominal infection), additional imaging including echocardiogram, blood cultures
    • Neurosyphilis: diagnosis with reactive CSF VDRL as well as increased CSF leukocytes and protein
    • TB meningitis: CSF lymphocytosis with low glucose and high protein, AFB smear/culture, NAATs.
    • Toxoplasmosis encephalitis: diagnosed clinically on imaging findings (multifocal, contrast enhancing lesions on CT/MRI), T gondii IgG seropositivity, and CD4 count < 200; often confirmed by clinical response to treatment; brain biopsy is rarely required
    • Cryptococcal meningitis: CSF CrAg or culture positive. Note that in HIV patients, a negative serum CrAg is sufficient to rule out CNS disease as the sensitivity of the serum and CSF CrAg are similar in this patient population (>95%). Immunocompetent patients require an LP

Management

  • Toxoplasma encephalitis: often treated empirically
    • Pyrimethamine plus sulfadiazine plus leucovorin
    • Clinical and radiographic response to therapy is supportive of diagnosis; if no improvement seen in 1-2 weeks, pursue brain biopsy to further evaluate
    • Primary CNS lymphoma: consult Oncology for initiation of chemotherapy and consult ID/HIV for initiation of ART
  • If evidence of cerebral edema/mass effect with depressed mental status or focal neurologic deficit: dexamethasone 10mg IV x 1 then 4 mg IV q6 hours
    • Avoid giving dexamethasone if diagnosis of lymphoma is still in question and low concern for herniation, as it can lead to false negative results on brain biopsy
  • PML or HIV-associated neurocognitive disorder (HAND): ART is the treatment of choice
  • Cryptococcal meningitis (positive CSF CrAg or CSF culture) treatment (HIV/AIDS patients):
    • Induction (minimum 2 weeks): liposomal amphotericin B + flucytosine
    • Consolidation (minimum 8 weeks): fluconazole 400mg PO daily
    • Maintenance (minimum 1 year): fluconazole 200mg PO daily
    • Amphotericin precautions:
      • Ensure adequate hydration to prevent nephrotoxicity (usually 500cc NS bolus before and after dose as tolerated)
      • Watch for K+, Mg++, and Ca++ wasting
    • Serial LPs: for patients with obtundation or severe HA and elevated ICP (opening pressure greater than 250 mm H20) – at least daily lumbar puncture to decrease the opening pressure to <200 mm H20. If daily LPs are not logistically feasible, then a lumbar drain can be placed
    • Increased ICP accounts for >90% of deaths in the first two weeks of treatment and failure to manage elevated ICP is the most common and dangerous mistake in management
    • Maintenance therapy can be safely discontinued for patients on ART with CD4 count > 100 and undetectable VL for > 3 months and at least one year of maintenance therapy
    • Refer to IDSA guidelines for management of cryptococcal meningitis for further details: https://doi.org/10.1086/649858

Key Points 

  • Altered mental status in a patient with HIV, particularly with a CD4 count less than 200, requires further work-up
  • Make sure additional tubes are held after LP for the additional studies that will inevitably be needed
  • Timing of initiation of ART differs between the different clincial syndromes. See section Initiation of Antiretrovirals in Acute OI

Tan, Ik Lin, et al. "HIV-associated opportunistic infections of the CNS." The Lancet Neurology 11.7 (2012): 605-617.

Perfect JR, Dismukes WE, Dromer F, et al. Clinical practice guidelines for the management of cryptococcal disease: 2010 update by the Infectious Diseases Society of America. Clinical Infectious Diseases 2010; 50: 291-322.

Kaplan JE, Benson C, Holmes KK, et al.  Guidelines for prevention and treatment of opportunistic infections in HIV-infected adults and adolescents. MMWR 2009 58(RR04):1-198.

John R. Perfect, William E. Dismukes, Francoise Dromer, et al. Clinical Practice Guidelines for the Management of Cryptococcal Disease: 2010 Update by the Infectious Diseases Society of America, Clinical Infectious Diseases, Volume 50, Issue 3, 1 February 2010, Pages 291–322, https://doi.org/10.1086/649858

Thwaites GE, Chau TT, Farrar JJ. Improving the bacteriological diagnosis of tuberculous meningitis. J Clin Microbiol. 2004;42(1):378‐379. doi:10.1128/jcm.42.1.378-379.2004

Jacobson MA Diagnostic Approach to HIV Patients Presenting with Signs or Symptoms of Acute Central Nervous System Disease. HIVInSite, 2018