Central Nervous System Complications in HIV
- Author: Prityi Rani, MD; Chief Editor: Niranjan N Singh, MD, DM more...
Neurologic complications occur in more than 40% of patients with HIV infection. They are the presenting feature of AIDS in 10-20% of cases. At autopsy, the prevalence of neuropathologic abnormalities is 80%.[1, 2, 3, 4] Although an ongoing decline in HIV-associated CNS disease has been observed in very recent years, the mortality from these diseases remains high.
Types of CNS complications
Several different types of CNS complications accompany HIV infection. Conditions that may be caused, directly or indirectly, by HIV itself include the following:
HIV-associated neurocognitive disorder (HAND syndrome) 
Certain peripheral neuropathies
Conditions caused by infectious, autoimmune, or neoplastic processes secondary to immunodeficiency include the following:
Cerebrovascular diseases [8, 9]
Certain neuropathies and myopathies
Cytomegalovirus (CMV) encephalitis
Some neurologic conditions are caused by antiretroviral drugs. In addition, AIDS patients are susceptible to the same neurologic diseases as patients who do not have HIV infection.
In AIDS, a clinical presentation often cannot be explained with a single diagnosis. New-onset neurologic complications often are superimposed on an ongoing process with a different etiology. Clinical features reflect the sum of deficits at several anatomic sites.
CNS complications in children
The manifestations of AIDS and its neurologic complications differ in children, whose immune and nervous systems are infected at an immature stage, whether in utero, during delivery, or postpartum. CNS complications tend to progress more rapidly in children, probably because of the inability of their immune systems to mount an appropriate T-cell, B-cell, or cytokine response to the infection.
Neurologic involvement in HIV infection is more frequent in children than in adults. It may take the form of a loss of previously acquired intellectual and motor milestones or of developmental delay. Opportunistic infections due to reactivation of dormant organisms are unusual, as children may not have been exposed yet to the responsible organisms. Distinguishing features include blood vessel calcification in the basal ganglia, large necrotizing cortical and subcortical lesions, microcephaly, and infection of astrocytes.
Neurologic immune reconstitution inflammatory syndrome
Neurologic immune reconstitution inflammatory syndrome (NeuroIRIS) is a newly recognized complication of combination antiretroviral therapy. In a recent retrospective study of 461 patients started on combination antiretroviral therapy, 7 patients (0.7%) developed NeuroIRIS. In general, the risk of IRIS appears to be high in patients whose CD4+ lymphocyte count is below 50 cells/mL at the start of antiretroviral therapy.
Associated cerebrovascular diseases
Specific types of cerebrovascular disease are associated with HIV infection. In addition, with improved treatment and prolonged survival, more HIV-infected patients reach an older age and are at risk for cerebrovascular diseases unrelated to HIV infection. HIV-positive patients may suffer transient ischemic attacks (TIAs) or hemorrhagic, thrombotic, or embolic strokes.
A Danish population study showed that HIV-infected individuals have an increased risk of stroke with and without proven risk factors. Low CD4 cell count at the start of antiretroviral therapy and exposure to abacavir, but not with HAART, were important risk factors seen in this population.
HIV-positive patients are at risk for strokes at much younger ages than typically are associated with stroke. As in the HIV-seronegative population, age itself is a risk factor for stroke in HIV-infected individuals.
Patient education information
When immune defenses are impaired, opportunistic infections and neoplasms arise, often from reactivation of previously acquired organisms. This mechanism applies to agents such as Toxoplasma gondii and Epstein-Barr virus (EBV); the latter is strongly associated with CNS lymphoma. Other organisms, such as the JC or SV40 viruses that cause progressive multifocal leukoencephalopathy, may be activated directly by HIV gene products.
The likelihood of a particular neurologic syndrome correlates with the clinical stage of HIV infection as reflected by viral load, immune response, and CD4+ lymphocyte counts. This, in turn, is related to the severity of immunodeficiency and autoimmunity and to serum and tissue cytokine levels.
Manifestations of acute HIV infection are often subclinical but may include meningitis, acute encephalopathy with seizures, confusion, and delirium. HIV enters the CNS soon after initial infection. Early peripheral nerve manifestations include isolated acute cranial nerve palsies and Guillain-Barré syndrome.
Neurologic complications seen in AIDS include AIDS dementia complex, vacuolar myelopathy, opportunistic infections and neoplasms, and chronic neuropathies (usually several years after HIV infection).
Neurologic immune reconstitution inflammatory syndrome
NeuroIRIS manifests several weeks after the start of highly active antiretroviral therapy. There is a paradoxical clinical deterioration despite improving CD4 cell counts and viral load. Antiretroviral-naive patients are at particular risk independent of baseline CD4+ counts. NeuroIRIS is an uncommon complication of combination antiretroviral therapy but has a very poor outcome.
AIDS seems to confer additional risk for ischemic and hemorrhagic stroke independent of other stroke-related risk factors. Some mechanisms responsible for strokes, both nonspecific and specific to HIV, include hypertension, hypotension, cardiac disease, illicit drug use, coagulopathy, vasculitis (infectious, autoimmune), and hemorrhage (including hemorrhage into neoplasms and abscesses), but other mechanisms may be operative that are less well understood.
Premature atherosclerotic cerebral arteriopathy associated with highly active antiretroviral therapy (HAART)–induced metabolic disorders has become an additional risk factor in patients with AIDS.
Several studies have documented subclinical cervical artery atherosclerosis, as assessed by intima-media thickness, ultrasound detection of carotid artery plaques, and intracerebral small-vessel disease, all being associated with the induced metabolic changes.
Carotid intima-media thickness (c-IMT) and coronary artery calcium (CAC) progression are increasingly being used to predict vascular risk. A 3-year follow-up study of 255 HIV-infected adults found that although c-IMT and CAC progression rates were higher than expected for their respective age and risk groups, traditional cardiovascular risk factors are the strongest predictors of carotid and coronary atherosclerotic disease progression in this population. Aggressive cardiovascular risk reduction slows progression of atherosclerosis in patients with preexisting disease.
The differential diagnosis of CNS complications in HIV-infected patients includes herpes simplex encephalitis, cerebrovascular complications, meningitis, CNS cryptococcosis, CNS toxoplasmosis, cytomegalovirus encephalitis, progressive multifocal leukoencephalopathy, CNS lymphoma, vacuolar myelopathy, and HIV-1 encephalopathy and AIDS dementia complex.
Other problems to be considered include immune reconstitution inflammatory syndrome (IRIS), brainstem syndromes, and efavirenz-related side effects. Efavirenz has been implicated in relation to various short- and long-term neuropsychiatric side effects, including mood lability, concentration difficulties, nightmares, and anxiety.
A consultant often faces the challenge of differentiating slow progression of HIV-associated dementia, myelopathy, or neuropathy from an acute, new-onset process such as infection with cytomegalovirus or toxoplasmosis. Such intervening conditions must be diagnosed rapidly and appropriate treatment initiated expeditiously.
Failure to recognize a potentially reversible condition that is fatal if not treated would constitute deviation from the standard of care. Multiple ancillary tests need to be performed, even when the level of suspicion is relatively low.
Imaging studies often make diagnoses rather than just confirming them. The most sensitive study is often MRI with and without gadolinium (or other contrast agents). If MRI is not available or if patient motion is expected to compromise the image, head CT scan without and with intravenous contrast is the next best solution.
Algorithmic Approach for Evaluation and Treatment
Several algorithms have been developed for the evaluation and treatment of adult HIV-seropositive patients with neurologic symptoms and signs. These algorithms proceed through several branch points, depending on the results of previous tests.
CT and MRI
A brain CT scan or MRI with and without contrast is indicated for all patients presenting with altered mental status, headaches, seizures, or focal neurologic signs. MRI is clearly the superior technique but is not available universally.
If this initial imaging study is normal, or shows atrophy or focal signal abnormalities but no mass lesion, diagnostic consideration should be given to meningitides, AIDS dementia complex (ADC), or progressive multifocal leukoencephalopathy.
Open biopsy with decompression
If imaging shows one or more focal mass lesions with impending herniation, an open biopsy with decompression is indicated. The rarity of toxoplasmosis in children may warrant a brain biopsy without any preceding studies. Treatment for lymphoma, toxoplasmosis, or other opportunistic infections and neoplasms is initiated depending on results.
T SPECT or
If imaging shows one or more focal mass lesions without impending herniation, additional studies are warranted. When available, thallium-201 single-photon emission computed tomography (201 T SPECT) or 18-fluorodeoxyglucose positron emission tomography (18 FDG-PET) scan in conjunction with polymerase chain reaction (PCR) studies of the cerebrospinal fluid (CSF) for Epstein-Barr virus can provide strong evidence that a mass lesion represents a lymphoma. This may reduce the need for a stereotactic biopsy.
When these studies cannot be conducted, toxoplasmosis serology in conjunction with imaging results will determine how to proceed.
In cases of a single mass lesion and negative serology, a stereotactic brain biopsy is indicated.
In cases of multiple lesions with negative or positive serology, therapy for toxoplasmosis should be initiated.
In cases of multiple or single lesions with positive serology, therapy for toxoplasmosis should be initiated.
Immune reconstitution inflammatory syndrome
Immune reconstitution inflammatory syndrome (IRIS) must be considered in patients who deteriorate clinically or radiologically after starting highly active antiretroviral therapy (HAART) despite improving viral load and CD4 count. Treatment remains empirical; some patients respond to steroids.
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