Central Nervous System Complications in HIV

Based on current World Health Organization (WHO) statistics, there are more than 36 million people living with human immunodeficiency virus (HIV) today. More than 19 million of them receive antiretroviral therapy (ART). ^[18]  Despite the increased life longevity of patients infected with HIV, neurologic complications remain common. Infection with HIV can affect both the peripheral and central nervous systems (CNS) in their entirety as well as muscles. With the advancement and greater availability of ART, CNS complications due to opportunistic infections as a result of severe immunocompromise have decreased. However, manifestations of neurologic dysfunction not caused by opportunistic infections (primary manifestations) are still prevalent. ^{[19, 20]}  

Complications of the nervous system can occur in more than 40% of patients with HIV. Aseptic meningitis and acute demyelinating polyneuropathy (AIDP) can be the presenting symptoms of acute HIV infection. Aseptic meningitis can be seen in as many as 25% of patients and can occur within 10–20 days of systemic infection. In 10–20% of cases, neurologic manifestations are the presenting signs/symptoms of AIDS. At autopsy, the prevalence of neuropathologic abnormalities is 80%. ^{[1, 2, 3, 4, 21]}

Types of Neurologic Complications

As mentioned above, neurologic complications that are associated with HIV infection include those caused directly by the virus and others caused through indirect mechanisms.

CNS manifestations include the following:

• HIV-associated neurocognitive disorder (HAND) ^[6]

• Vacuolar myelopathy

• Cerebrovascular disease ^{[8, 19]}

• Aseptic Meningitis

Peripheral nervous system/muscle manifestations include the following:

• Peripheral neuropathies

• Myopathies

Conditions caused by infectious, autoimmune, neoplastic processes secondary to immunodeficiency or those related to treatment include:

• CNS lymphoma

• Immune Reconstitution Inflammatory Syndrome of the CNS (CNS-IRIS) ^{[19, 20]}

• Kaposi sarcoma

• Progressive multifocal leukoencephalopathy (PML)

• Fungal infections (eg, cryptococcal meningitis, Penicillium marneffei encephalitis) ^[7]

• Tuberculous meningitis

• Cytomegalovirus (CMV) encephalitis

In addition, HIV-infected patients are susceptible to the same neurologic diseases as patients without 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.

Patient Education Information

For patient education information, see the Dementia Center, Immune System Center, and Sexually Transmitted Diseases Center, as well as Dementia Due to HIV Infection and HIV/AIDS.

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 PML, 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.

Entrance of HIV into the CNS occurs early in the course of infection, likely within days to weeks. In contrast to the periphery where HIV infects the CD4+ T cells, in the brain, HIV targets astrocytes and perivascular macrophages/microglial cells. Several mechanisms of entry have been proposed and likely relates to transendothelial migration of infected CD4 lymphocytes and/or migration of infected monocytes. ^{[20, 23]}

Replication of HIV in the CNS results in the stimulation of proinflammatory cytokines and neurotoxins, leading to oxidative stress. Macrophages infected with the virus can form multinucleated giant cells, a classic feature seen on pathology of HIV infection in the brain. Astrocytes act as a reservoir for the virus, which typically is dormant there unless the host cells make contact with lymphocytes or become activated by cytokines. Due to the slow turnover rate of astrocytes, this site allows the virus to reside in the brain indefinitely, thereby rendering its eradication unsuccessful thus far. ^{[19, 20, 23]}

Neurons are not directly infected with the virus and damage ensues through indirect processes such as neurotoxic proteins Tat and GP120 or through the release of proinflammatory cytokines from infected macrophages. Areas of the brain most vulnerable to damage include but are not limited to the basal ganglia, subcortical white matter, and frontal cortex. ^[24]

HIV-associated neurocognitive disorder (HAND)

HAND is a group of neurocognitive disorders consisting of HIV-associated dementia (HAD), previously referred to as "AIDS dementia complex," and mild neurocognitive disorder (MND). HAD, the more severe form of HAND encompasses changes in personality, memory deficits, and motor dysfunction. Before ART, 20% of infected patients died with HAD. ^{[19, 26]}  At autopsy, most persons with AIDS had findings consistent with HIV encephalitis. After the introduction of ART, fewer than 5% of patients have HAD, and almost none have HIV encephalitis at autopsy. However, based on the CHARTER study, MND, a milder form of neurocognitive disorder, occurs in as many as 45% of infected individuals. ^[25]

The continued presence of HAND despite aggressive treatment with ART and decrease in viral load suggests that there is a continued immune response, oxidative dress and inflammation within the brain. To date, the lowest CD4+ count at any point during infection, or the CD4+ nadir, is the best marker for the risk of HAND, although other potential biomarkers are being investigated. ^[19]

The diagnosis of HAND is a clinical one. The Frascati criteria, developed in 2007, allowed for uniformity in the diagnosis of HAND. It involves neuropsychological testing across various cognitive domains. Activities of daily living and ruling out other potential factors/causes for cognitive decline are also part of the diagnostic criteria. ^[27]

Currently, there is no specific treatment for HAND and management is geared toward preventing HIV replication in the CNS. Choosing an antiretroviral then becomes paramount in patients with HAND or those at a high risk. CNS penetration of the drug is of utmost importance for the reduction of CNS viral replication. A CNS penetration effectiveness index (CPE) can aid clinicians in choosing the correct medication. ^[20]  Maraviroc was found to lead to cognitive improvement over a 12-month period. ^[28]  While higher CPE index ART regimens result in a lower CNS viral load, some regimens have resulted in worsening neuropsychological performance suggesting drug neurotoxicity. Efavirenz is one such medication. ^[20]

Cerebrovascular disease

HIV infection seems to confer a 20–80% increased risk for ischemic and hemorrhagic stroke independent of other stroke-related risk factors. ^[26] Additionally, with improved treatment and survival, more HIV-infected patients reach an older age and are at risk for cerebrovascular diseases unrelated to HIV.

The increased risk of stroke in HIV infection is likely multifactorial. Established risk factors such as hyperlipidemia, hypertension, diabetes, and smoking seem to be more prevalent in HIV infection. Low levels of CD4+ and a high viral load, indicating worse immunodeficiency, are additional stroke risk factors. Protease inhibitors have been linked to metabolic syndrome and may increase the risk of small vessel disease and stroke. ^{[20, 26]}

In addition, as patients continue to live longer with HIV, they acquire the risk factors of stroke that are associated with advanced age. The presenece of these metabolic changes have been associated with subclinical cervical artery atherosclerosis, carotid artery plaques, and intracerebral small-vessel disease. ^[9]

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. ^[14]

In addition, cerebral aneurysms have been described in patients with HIV infection who are not on ART. At this time, no clear cause has been established but possible mechanisms include varicella-zoster virus infection or a consequence of HIV affecting blood vessels. ^[20]

CNS Immune Reconstitution Inflammatory Syndrome (CNS-IRIS)

CNS-IRIS manifests after the start of highly active antiretroviral therapy, most commonly within 1–6 months of ART initiation. ^[19] There is a paradoxical clinical deterioration despite improving CD4 cell counts and viral load. Patients with lower CD4+ counts and higher viral load are particularly at risk. In general, the risk of IRIS appears to be high in patients whose CD4+ lymphocyte count is below 50 cells/µL at the start of antiretroviral therapy. ^[12]

Diagnosis of CNS-IRIS is made using magnetic resonance imaging (MRI) with intravenous gadolinium to assess for enhancement indicating a breach in the blood-brain barrier consistent with inflammation. Treatment of CNS-IRIS is supportive with some studies suggesting that steroids may be beneficial. ^[19]  The Cryptococcal Optimum ART Timing (COAT) study suggested that postponing initiation of ART until after diagnosis and treatment of cryptococcal meningitis reduced mortality. Current guidelines recommend initiating ART at least 2 weeks after completion of antifungal therapy. ^{[19, 29, 31]}

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 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 option.

Several algorithms have been developed for the evaluation and treatment of adult HIV-seropositive patients with neurologic symptoms and signs. ^[16] These algorithms proceed through several branch points, depending on the results of previous tests.

CT and MRI

A brain CT or MRI with and without contrast is indicated for all patients presenting with altered mental status, headaches, seizures, or focal neurologic signs. MRI is 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, HAND, or PML.

Open biopsy with decompression

If imaging shows one or more focal mass lesions with impending herniation, an open biopsy with decompression is indicated. Treatment for lymphoma, toxoplasmosis, or other opportunistic infections and neoplasms is initiated depending on results.

T SPECT or FDG-PET

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.

Further testing/treatment

In cases of a single mass lesion and negative serology, a stereotactic brain biopsy is indicated. ^[17]

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.