Herbert B. Newton, MD, FAAN
DESCRIPTION
Neurological complications are common in patients with HIV infection and AIDS, affecting all levels of the central and peripheral nervous system. The etiology of these disorders is variable and may result from direct effects of HIV infection, damage from inflammatory processes and cytokine production, neoplasms, opportunistic infections, metabolic abnormalities, vascular damage, and toxic effects of HIV therapy.
EPIDEMIOLOGY
Incidence
- Before highly active antiretroviral therapy (HAART), it was estimated that approximately 10% of AIDS patients presented with a neurological complaint, while 30–50% developed neurological complications during their disease. In addition, HIV dementia was estimated to have an incidence of 7.5–20% in retrospective studies. The incidence of neurological complications appears to be decreasing, most likely due to widespread use of HAART.
- All races affected; most common in Caucasians and blacks. Any age can be affected; most common between 20 and 40 years of age. Both sexes can be affected; most often diagnosed in males.
RISK FACTORS
No specific risk factors have been identified other than diagnosis of HIV infection, low CD4 counts (i.e., less than 100/µL), and lack of antiretroviral therapy.
Genetics
Genetic factors have not been identified.
GENERAL PREVENTION
Other than the use of HAART therapy, no other preventive measures are known.
PATHOPHYSIOLOGY/ETIOLOGY
- The etiology is variable and depends on the specific process involving the nervous system. In severely immunocompromised patients, opportunistic infections and neoplasms can involve the central or peripheral nervous system, including toxoplasmosis, cryptococcal and tuberculous meningitis, neurosyphilis, progressive multifocal leukoencephalopathy (PML; papovavirus), cytomegalovirus (CMV), herpes simplex virus (HSV), and primary CNS lymphoma (PCNSL).
- HIV is neurotropic and can be cultured early from the nervous system. However, productive infection within neural tissues does not appear to be the major cause of HIV dementia, vacuolar myelopathy, myopathy, or peripheral neuropathy. Although HIV does shed toxic substances such as gp120, viral initiation of inflammation and secretion of toxic cytokines (e.g., tumor necrosis factor α, interleukins 1β and 6) may be more critical in mediating neural tissue injury.
- Neurological complications can also develop as a result of treatment with antiretroviral therapy (e.g., zidovudine myopathy).
HISTORY
- HIV dementia (i.e., AIDS dementia complex) usually manifests with progressive impairment of short-term memory, cognition, concentration, and motivation. Associated motor abnormalities include unsteady gait, leg weakness, tremor, and incoordination. Late-stage patients have global dementia with severe psychomotor slowing, confusion, reduced verbal output, weakness, and spasticity.
- Space-occupying lesions include cerebral toxoplasmosis, PCNSL, PML, tuberculous or fungal abscess, focal viral encephalitis, and metastatic tumors (i.e., lymphoma or Kaposi's sarcoma). Symptoms consist of progressive headache, confusion, lethargy, personality changes, memory loss, seizures, nausea/emesis, and focal deficits (e.g., hemiparesis, dysphasia).
- Encephalitis typically develops from toxoplasmosis, CMV, and HSV while meningitis is most frequently caused by Cryptococcus and other fungi, tuberculosis, and leptomeningeal lymphoma. HIV can cause an aseptic meningitis syndrome. Encephalitic patients present with acute confusion, lethargy, seizures, fever, headache, and meningismus. Patients with meningitis develop subacute headache, fever, meningismus, lethargy, and nausea.
- Vacuolar myelopathy usually develops as part of HIV dementia, but can occur in isolation. It presents as a progressive myelopathy with spastic paraparesis, hyperactive reflexes, Babinski's signs, gait ataxia, tremor, and urinary incontinence. In some patients, a sensory level may be appreciated.
- For neuromuscular complications of HIV see AIDS: Neuromuscular Complications on that topic.
PHYSICAL EXAM
The neurological exam will vary depending on the specific syndrome involved, as noted above.
DIAGNOSTIC TESTS AND INTERPRETATION
Lab
Initial Lab Tests
In general, the most important tests will consist of blood counts (including CD4 counts, to determine stage of HIV infection), infectious cultures of appropriate tissues, and serum antibody titers of various infectious agents. Other specific tests may be helpful in certain cases, such as Venereal Disease Research Laboratory test (VDRL) or vitamin B12 levels.
Imaging
Initial Approach
MRI, with and without administration of gadolinium, is the most sensitive technique to evaluate HIV patients with cranial or spinal neurological complaints. HIV dementia may demonstrate atrophy or scattered, nonenhancing white-matter lesions. Similarly, PML presents with patchy, nonenhancing, periventricular white-matter lesions that slowly enlarge and coalesce. Cerebral toxoplasmosis usually demonstrates multiple ring-enhancing lesions with surrounding edema. PCNSL presents as a solitary or multifocal lesion within the deep periventricular white matter that typically enhances with contrast. Mild edema and/or mass effect may be noted. Tuberculous or fungal abscesses cause ring-enhancing lesions with surrounding edema. Focal viral encephalitis (e.g., CMV, varicella-zoster virus, HSV) may produce mass lesions with minimal enhancement. Other potential enhancing mass lesions include metastatic systemic lymphoma and Kaposi's sarcoma.
Diagnostic Procedures/Other
Lumbar puncture is often helpful to differentiate the etiology of brain or spinal processes, and should at least include routine CSF studies, bacterial/fungal antigens, cytology, CSF bacterial/viral/fungal cultures, smear and culture for acid-fast bacilli, and VDRL. Other tests that may be helpful in selected patients include electroencephalography (i.e., seizure activity), electromyography and nerve conduction studies (i.e., neuropathy and myopathy), and neuropsychological testing (i.e., HIV dementia).
Pathological Findings
The pathological features will vary depending on the primary process and region of the nervous system, as noted above.
DIFFERENTIAL DIAGNOSIS
The differential diagnosis is extensive and includes any non-HIV-related disease with a similar presentation affecting the central or peripheral nervous system.
MEDICATION
First Line
All patients should be evaluated for HAART, since this may prevent or abrogate the direct effects of HIV on the central and peripheral nervous system. In addition, HAART may prevent or reduce the risk of opportunistic infectious and neoplastic complications. All other drug decisions have to be individualized to the specific neurological complication of each patient.
ADDITIONAL TREATMENT
General Measures
Antiretroviral therapy should be maximized, if possible (i.e., HAART). HAART consists of a combination of two nucleoside reverse transcriptase inhibitors (e.g., zidovudine, didanosine, abacavir) and at least one protease inhibitor (e.g., saquinavir, indinavir) and/or one non-nucleoside reverse transcriptase inhibitor (e.g., nevirapine, delavirdine). Nutritional and metabolic deficiencies should be corrected, especially those that might impact neurological function (e.g., hyponatremia). All systemic infections should be diagnosed and treated. Medications should be reviewed for potential central or peripheral neurotoxicity.
Additional Therapies
Patients with HIV dementia may stabilize or improve slightly on antiretroviral therapy (zidovudine or HAART). Cerebral toxoplasmosis usually responds to combination therapy with pyrimethamine (50–75 mg/day), sulfadiazine (6–8 g/day), and leucovorin (10 mg/day). Patients with PCNSL should receive whole brain irradiation (4,000–5,000 cGy), although chemotherapy can be beneficial in selected patients with good performance status. Infectious neurological complications require therapy specific to the agent involved.
SURGERY/OTHER PROCEDURES
Biopsy may be required to differentiate focal intracranial lesions. Less often, biopsy may be helpful to diagnose the cause of neuropathy or myopathy.
IN-PATIENT CONSIDERATIONS
Initial Stabilization
Will be variable according to the specific neurological complication.
Admission Criteria
Patients are generally admitted for acute neurological changes such as altered level of consciousness, confusion, focal or generalized weakness, seizure activity, headache, and focal neurological deficits (e.g., dysphasia, hemianopsia).
Discharge Criteria
Patients with persistent neurological deficits should be considered for rehabilitation, after stabilization.
FOLLOW-UP RECOMMENDATIONS
Will be variable according to the specific neurological complication.
Patient Monitoring
Follow-up of neurological status will be required. This is particularly true for some of the infectious complications that need long-term therapy (e.g., toxoplasmosis, CMV).
PATIENT EDUCATION
PROGNOSIS
The course and prognosis for many of the neurological complications mentioned above is quite poor, since most occur in patients with low CD4 counts and advanced disease. The 6-month cumulative mortality rate for stage 2–4 HIV dementia is 67%. Similar 6-month cumulative mortality rates are noted for PML (85%), PCNSL (70%), and cerebral toxoplasmosis (51%). Some infectious complications caused by specific agents may respond to appropriate therapy, such as CMV encephalitis and neurosyphilis.
COMPLICATIONS
Will be variable according to the specific neurological complication.
