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Neurologic Manifestations of HIV Disease 

Neurologic Manifestations of HIV Disease
Chapter:
Neurologic Manifestations of HIV Disease
Author(s):

Emily Shuman

DOI:
10.1093/med/9780190862800.003.0058
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date: 18 September 2020

  1. A. Introduction. HIV-infected patients frequently develop neurologic disorders, which can be divided into five clinical categories: meningitis, space-occupying lesions, encephalopathy, myelopathy, and peripheral neuropathy.

  2. B. Meningitis

    1. a. Causes of meningitis. The following are common causes of meningitis in HIV-positive patients.

      1. i. Bacteria (see Chapter 87).

      2. ii. Viruses. Herpes simplex virus (HSV) and cytomegalovirus (CMV) may cause aseptic meningitis and encephalitis. HIV itself may cause a slight cerebrospinal fluid (CSF) pleocytosis and elevated CSF protein without clinical symptoms of meningitis.

      3. iii. Fungi. Cryptococcal meningitis is common, especially if the CD4 count is below 50 cells/µL. It often presents as fever and headache without neck stiffness or photophobia. Remember, a lumbar puncture with no pleocytosis does not rule out cryptococcal meningitis. When this infection is in the differential diagnosis, an opening pressure should always be obtained and cryptococcal antigen (CrAg) tests should be performed on CSF.

      4. iv. Spirochetes. The incidence of central nervous system (CNS) syphilis is greater in HIV-infected patients than non–HIV-infected patients.

      5. v. Mycobacteria. Tuberculosis is the most common mycobacterial cause of CNS disease in HIV-positive patients.

      6. vi. Malignancy. Lymphomatous meningitis is the most common malignant etiology.

    2. b. Approach to the patient. In general, the approach to an HIV-positive patient with suspected meningitis is the same as that for other, immune-competent patients (see Chapter 87). However, the increased likelihood of certain etiologies leads to a few specific considerations for HIV-infected patients presenting with possible meningitis.

      1. i. Serum and CSF CrAg titers should be obtained in HIV-infected patients who are being evaluated for possible meningitis. The sensitivity of these tests exceeds 95%.

      2. ii. Serum rapid plasma reagin (RPR) and CSF Venereal Disease Research Laboratory (VDRL) tests are often performed to evaluate the possibility of neurosyphilis.

      3. iii. The presence of an unexplained CSF lymphocytic pleocytosis or evidence of a basilar meningitis (e.g., meningitis with cranial nerve findings) usually raises suspicion of meningitis related to tuberculosis, other endemic fungal infections, or lymphoma.

        1. 1. CSF analysis. Multiple CSF samples should be sent for cytology, fungal, and acid-fast bacillus (AFB) staining and culture. Always obtain and keep an extra sample of CSF in case additional tests are needed. Remember, lumbar punctures are rarely useful for evaluating space-occupying lesions in HIV-infected patients and are contraindicated in patients with mass effect or posterior fossa lesions.

        2. 2. A tuberculin purified protein derivative (PPD) skin test or serum interferon-Υ‎ release assay (IGRA) may be performed to evaluate exposure to tuberculosis; however, a negative test does not exclude the diagnosis.

        3. 3. Magnetic resonance imaging (MRI) is often useful to look for basilar meningitis; a biopsy of the brain or meninges is sometimes necessary for definitive diagnosis.

    3. c. Treatment depends on the cause.

      1. i. Bacteria. Treatment of routine bacterial meningitis is no different from that in an immunocompetent patient.

      2. ii. Viruses. HSV and CMV are treated with acyclovir and ganciclovir as first-line agents, respectively. See D. b., later in the chapter, for details on therapy of disease caused by JC virus.

      3. iii. Fungi. Combination therapy with amphotericin B (0.7 mg/kg/day) and 5-flucytosine (25 mg/kg given orally every 6 hours) is recommended for initial treatment of cryptococcal meningitis. After 14 days, these drugs are discontinued, and fluconazole (400 mg/day) is initiated orally. After 8 weeks (or when the CSF is sterile as demonstrated by a repeat lumbar puncture), the dose may be reduced for maintenance therapy to 200 mg/day. The duration of this therapy depends on the patient’s CD4 count and HIV viral load over time but may be lifelong.

      4. iv. Spirochetes. Intravenous penicillin G for 14 days is recommended for patients with CNS syphilis. Treatment may need to be prolonged in patients with severe immune compromise.

      5. v. Mycobacteria. Standard regimens for tuberculosis are used for CNS tuberculosis, but the duration of therapy is extended, and corticosteroids may be beneficial.

      6. vi. Malignancy. HIV infection is not a contraindication to chemotherapy or radiation therapy, and the appropriate treatment of the underlying malignancy should be pursued.

  3. C. Space-Occupying Lesions. Space-occupying lesions may present as headaches, seizures, focal sensory or motor deficits, visual field defects, or altered mental status.

    1. a. Causes of space-occupying lesions. Although all the following causes should be considered in a patient who presents with signs and symptoms of a space-occupying lesion, the first two are the most common in HIV-positive patients.

      1. i. Toxoplasmosis

      2. ii. Primary CNS lymphoma

      3. iii. Bacterial abscess

      4. iv. Cryptococcoma

      5. v. Histoplasmoma

      6. vi. Tuberculoma

      7. vii. Nocardiosis

    2. b. Approach to the patient with a space-occupying lesion

      1. i. Imaging studies. A computed tomography (CT) or MRI scan is useful for evaluating suspected CNS disease in HIV-infected patients.

        1. 1. CT scan. Many space-occupying lesions are better seen with contrast enhancement, which should be used in the absence of contraindications.

        2. 2. MRI is generally a more sensitive test and may reveal multiple lesions when only a single lesion is seen on CT scan.

      2. ii. Laboratory studies

        1. 1. A serum CrAg titer is frequently ordered.

        2. 2. Blood cultures and a PPD test or IGRA may also be obtained, depending on the clinical situation.

        3. 3. Toxoplasmosis immunoglobulin G (IgG) titers. A Toxoplasma gondii IgM titer has limited utility because nearly all cases of toxoplasmosis in HIV-infected patients are due to reactivated disease. However, determining whether a patient has been exposed to T. gondii in the past (e.g., a positive toxoplasmosis IgG serology) can help determine whether the patient is at risk for reactivation. Individuals receiving prophylaxis for toxoplasmosis are at decreased risk for developing CNS disease. Daily trimethoprim-sulfamethoxazole is the first-line prophylaxis regimen for patients with CD4 counts <100 cells/µL.

        4. 4. CD4 counts. Like all infections in HIV, the patient’s risk for a specific disease depends on the degree of immunosuppression. Bacterial abscess, tuberculoma, and lymphoma can be seen at relatively high CD4 counts, whereas cryptococcomas and toxoplasmosis more commonly occur in patients with CD4 counts <100 cells/µL.

          Hot Key

          Lumbar punctures are rarely useful for evaluating space-occupying lesions in HIV-infected patients and are contraindicated in patients with mass effect or posterior fossa lesions.

      3. iii. Stereotactic brain biopsy. This procedure should be performed early in the diagnostic workup if the patient does not have a high likelihood of CNS toxoplasmosis, including:

        1. 1. Patients with negative toxoplasma IgG serologies

        2. 2. Patients with an increased risk for processes other than toxoplasmosis (e.g., injection drug users, who have an increased risk for brain abscess)

        3. 3. Patients with single lesions on MRI (because finding a single lesion makes toxoplasmosis less likely)

        4. 4. Patients with progressive neurologic deficits or mass effect on imaging (because appropriate treatment is needed immediately)

        5. 5. Patients who do not have regression of the space-occupying lesion or lesions after 2 weeks of empiric toxoplasmosis therapy

    3. c. Treatment depends on the cause. Among individuals believed to be at high risk for toxoplasmosis, empiric therapy is often given for 2 weeks, followed by repeat imaging to evaluate for response. Standard therapy is sulfadiazine (or high-dose clindamycin) combined with pyrimethamine.

  4. D. Encephalopathy

    1. a. In patients with HIV, any alteration in mental status requires a thorough evaluation to rule out reversible causes (see Chapter 81). An imaging study (preferably an MRI) and spinal fluid analysis are necessary to rule out infectious or malignant processes. Neuropsychiatric testing may be necessary to help rule out depression, which can often occur in patients with HIV.

    2. b. Progressive multifocal leukoencephalopathy (PML) due to JC virus is a common cause of cognitive impairment and focal neurologic deficits in patients with late-stage HIV infection. Imaging studies reveal patchy periventricular and/or subcortical white matter lesions best seen on MRI. Polymerase chain reaction (PCR) testing for JC virus may be positive even in the absence of a CSF pleocytosis. No definitive therapy exists. Antiretroviral therapy (ART) may improve symptoms.

    3. c. Some patients are ultimately diagnosed as having HIV-associated dementia, an illness that occurs late in the course of HIV infection and is often characterized by memory deficits, gait difficulty, behavioral changes including depression, and psychomotor slowing. CT scan may reveal brain atrophy at a rate greater than expected for age. MRI findings include symmetric subcortical white matter lesions with high intensity on T2-weighted images. ART has reduced the incidence of HIV-associated dementia but has not has not been shown to reverse dementia after it has begun.

  5. E. Myelopathy. Myelopathy usually presents with progressive lower extremity weakness that may be accompanied by bladder or bowel incontinence. Evidence of upper motor neuron disease with spastic paraparesis and hyperreflexia are usually noted unless peripheral neuropathy is also present.

    1. a. Causes of myelopathy. Spinal cord disease often results from infection, external compression injury (i.e., cord compression), or miscellaneous insults.

      1. i. Infection. Viruses (CMV, HSV, varicella-zoster virus [VZV], and HIV), fungi (Cryptococcus), spirochetes (Treponema pallidum), and parasites (Toxoplasma) can infect the spinal cord, leading to myelopathy.

      2. ii. Cord compression may result from epidural abscesses (e.g., from bacterial infection or tuberculosis) or from malignancy (e.g., CNS lymphoma).

      3. iii. Miscellaneous causes

        1. 1. Vascular insults (e.g., vasculitis)

        2. 2. Vitamin B12deficiency

        3. 3. HIV-related vacuolar myelopathy is a diagnosis of exclusion and usually occurs late in the course of HIV infection. Motor weakness and decreased proprioception often reflect preferential loss of myelin from the lateral and dorsal columns, respectively. Examination reveals a spastic paraparesis with lower extremity hyperreflexia. There is no proven therapy.

    2. b. Approach to the patient

      1. i. Imaging studies. MRI of the involved area of spinal cord helps to rule out spinal cord compression.

      2. ii. Laboratory studies

        1. 1. Spinal fluid analysis with PCR for CMV, HSV, and VZV, CrAg titers (serum and CSF), and RPR and VDRL titers (serum and CSF) should be obtained.

        2. 2. Serology for CMV may be useful to evaluate the possibility of CMV polyradiculopathy.

        3. 3. A vitamin B12 level should be obtained.

  6. F. Peripheral Neuropathy. Peripheral neuropathy is common in patients with AIDS.

    1. a. Causes of peripheral neuropathy. Routine causes of peripheral neuropathy should be considered (see Chapter 82); however, some common causes and patterns of peripheral neuropathy in patients with HIV are listed here.

      1. i. Polyneuropathy

        1. 1. Distal symmetric peripheral neuropathies are the most commonly seen peripheral neuropathies in HIV-infected patients. Typically, patients present with painful dysesthesias. The etiologies are many, but common causes include antiretroviral medications (most commonly didanosine and stavudine) or HIV itself, particularly in late-stage disease. In cases in which medication is the suspected cause, therapy should be changed (when possible) to agents not associated with neuropathy. Symptomatic therapy with tricyclic antidepressants or gabapentin may be helpful.

        2. 2. Predominantly motor neuropathies

          • a. CMV polyradiculopathy may cause progressive lower extremity weakness associated with a CSF neutrophilic pleocytosis (in the absence of bacterial infection). Therapy with ganciclovir may result in clinical improvement.

          • b. An inflammatory demyelinating polyneuropathy may result in severe motor weakness and significantly depressed nerve conduction velocities. The clinical scenario resembles that of the more acute Guillain-Barré syndrome. Plasmapheresis is often used as treatment.

      2. ii. Mononeuritis multiplex is much less common than polyneuropathy. Although HIV itself is an etiology, other infections (e.g., CMV, VZV) and malignancies (e.g., lymphoma) should be ruled out.

    2. b. Approach to the patient. Other potentially reversible causes of peripheral neuropathy should be considered (see Chapter 82).

Suggested Further Readings

Bhatia NS, Chow FC. Neurologic complications in treated HIV-1 infection. Curr Neurol Neurosci Rep 2016;16:62.Find this resource:

Kaku M, Simpson DM. HIV neuropathy. Curr Opin HIV AIDS 2014;9.Find this resource:

Tan IL, Smith BR, von Geldern G, Mateen FJ, McArthur JC. HIV-associated opportunistic infections of the CNS. Lancet Neurol 2012;11:605–17.Find this resource: