Neurological Manifestations of HIV and AIDS

This chapter includes an accompanying lecture presentation that has been prepared by the authors: .

Key Concepts

Human immunodeficiency virus (HIV) can affect the nervous system directly as well as indirectly via increased risk of nervous system infections, malignancies, and immune-mediated syndromes.
HIV-associated neurocognitive disorder is a dementing illness due to direct central nervous system (CNS) injury from HIV.
CD8 ⁺ encephalitis and tumefactive demyelination are two immune-mediated HIV-associated CNS complications.
HIV can affect the peripheral nervous system, causing neuropathy and myopathy.
Incidence of CNS infection by the parasite Toxoplasma gondii, most often manifesting radiographically as enhancing lesions in the brain, is increased in patients with HIV infection.
Risk of developing meningitis due to the fungus Cryptococcus neoformans is elevated in patients with HIV infection.
Patients with HIV infection are at greater risk for developing other viral infections of the CNS, including those caused by JC virus and cytomegalovirus.
HIV infection increases the risk of developing CNS malignancies including primary CNS lymphoma; this is often associated with Epstein-Barr virus in this patient population.
Treatment of HIV infection with antiretroviral therapy may be associated with an immune reconstitution inflammatory syndrome that can affect the CNS.

Since the introduction of antiretroviral therapies in 1990s, the incidence of acquired immunodeficiency syndrome (AIDS) caused by the human immunodeficiency virus (HIV) has decreased remarkably, changing the landscape of neurological HIV manifestations from those of opportunistic infections and lymphomas to various degrees of neurocognitive involvement, CD8 ⁺ -mediated HIV encephalitis that at times can mimic tumors, and rare cases of tumefactive demyelination. ^,

AIDS is defined by the Centers for Disease Control and Prevention as occurring in any HIV-infected individual with a helper T-cell (CD4 ⁺ ) count of less than 200/μL in blood or with specific opportunistic infections or rare malignancies classified as AIDS-defining illnesses. AIDS-defining illnesses are often found coincident with CD4 ⁺ T-cell counts of less than 200/μL in blood.

HIV is a retrovirus that infects cells by often nonspecific docking and binding of the viral envelope to the CD4 receptor. This is followed by coreceptor binding at one of two chemokine receptors—CCR5 or CXCR4—on the host cell, which leads to viral entry. Although the primary cell of focus in HIV infection is the T lymphocyte, other cell types, including resident cells of the brain such as microglia and astrocytes, are also susceptible. Once an individual is infected, CD4 ⁺ T lymphocytes are gradually depleted until cell-mediated immunity finally deteriorates and AIDS develops. The latency period between HIV infection and the development of AIDS may be many years or even decades. The symptoms and signs of HIV infection are protean and may go unrecognized as being related to HIV. HIV enters the central nervous system (CNS) early in the course of the disease. Within 3 months of infection, patients with HIV have detectable brain atrophy. HIV treatment in the form of antiretroviral therapy (ART) is effective, and as a result, AIDS has become a chronic illness in some communities. ^, Neurological manifestations of well-controlled HIV infection today largely consist of a number of chronic neurocognitive syndromes, increased risk of stroke, and rare cases of CD8 ⁺ -mediated HIV encephalitis and tumefactive demyelination. In patients who are compliant with ART, the incidence of opportunistic infections and lymphomas has significantly decreased over the past decade.

Surgeons are frequently consulted regarding patients with HIV infection who present with mass-like lesions of the brain and spinal cord. Biopsy or resection of intracranial lesions that might be performed in otherwise healthy individuals is often delayed in patients with AIDS pending response to trials of medical therapy for conditions commonly encountered. However, cases must be approached individually and must be based on an understanding of risk-benefit ratios in this population.

In this chapter we focus on the neurological manifestations of HIV/AIDS and the role of the neurosurgeon in their diagnosis and management. Because neurosurgeons are often called on to consult about patients with HIV/AIDS, an understanding of HIV infection and its consequences in the nervous system will help guide practice.

The neurological complications of HIV/AIDS can be divided into five areas: (1) consequences of HIV infection itself, (2) opportunistic (and other) infections, (3) immune-mediated syndromes secondary to HIV, (4) AIDS-related malignancies (primary and metastatic), and (5) complications of HIV treatment. These categories often coexist in a given patient and complicate diagnosis and treatment. Some HIV-associated neurological complications are associated with more than one of these categories. For example, peripheral neuropathy may be caused by the virus itself, by opportunistic infections, or by antiretroviral therapies. In these cases, the reader may be referred to different sections, as appropriate. We consider each in turn in the following discussions.

HIV Infection of the Nervous System

Both the CNS and the peripheral nervous system can be directly affected by HIV. Although controversy still exists regarding the extent to which CNS cells (except for microglia and astrocytes) can harbor HIV, immunologic responses to HIV-infected cells and viral proteins in the CNS probably account for many of the neurological complications associated with HIV/AIDS. These complications include many of the disorders whose diagnosis and treatment are more elusive, as outlined in Table 58.1 .

TABLE 58.1

Common Neurological Conditions Associated With HIV Infection (Independent of Subsequent Opportunistic Infection, AIDS-Associated Malignancies, and Treatment-Related Toxic Effects) ^a

Neurological Consequences of Primary HIV Infection	Clinical Manifestations	Imaging Findings	CSF Findings	Ancillary Tests	Treatment
Acute retroviral syndrome	Aseptic meningitis Cranial neuropathy Polyradiculopathy AIDP	Usually normal Meningeal enhancement may occur	Lymphocytic pleocytosis Cytoalbumic dissociation in AIDP	Electrical studies consistent with neuropathic process	Symptomatic medications for neuropathy Immune modulation for AIDP
HIV-associated neurocognitive disorder	Gradual decline in cognition (adults); developmental delay, often progressive (children)	Progressive atrophy with periventricular white matter changes	Mild elevation of protein levels Lymphocytic pleocytosis	Diffuse slowing on EEG	ART (but CNS resistance occurs)
Tumefactive demyelination in HIV	Focal presentation, may mimic multiple sclerosis	White matter single or multiple lesions, which may appear tumor-like	Normal or with a mild pleocytosis		Corticosteroids
CD8 ⁺ HIV-associated encephalitis	Acute encephalitis with focal findings	White and gray matter lesions with subtle enhancement ^b	CSF pleocytosis		Corticosteroids
Myelopathy	Spasticity Weakness Sensory ataxia Incontinence	Cord atrophy High–signal intensity lesions on T2-weighted images	Often normal Elevated protein levels Pleocytosis (rare)	Abnormal SEPs	ART (but CNS resistance occurs)
Stroke	Acute neurological change consistent with stroke	Findings consistent with stroke (no distinguishing features)	Normal	None	Risk reduction Rehabilitation
Neuropathy	Distal Symmetrical Sensory > motor Often painful	None	Normal	Reduced nerve conduction velocity and amplitude	Symptomatic (WHO analgesic ladder) Correction of nutritional deficiencies
Myopathy	Proximal weakness > distal weakness	None	Normal	Elevated serum creatine kinase level Myopathic changes on EMG	Immune modulation Discontinuation of offending medications, steroids

AIDP, Acute inflammatory polyradiculopathy; AIDS, acquired immunodeficiency syndrome; ART, antiretroviral therapy; CNS, central nervous system; CSF, cerebrospinal fluid; EEG, electroencephalogram; EMG, electromyogram; HIV, human immunodeficiency virus; SEPs, somatosensory evoked potentials; WHO, World Health Organization.

a See text for details.

b Can mimic a tumor.

Acute Retroviral Syndrome

In the majority of patients with acute HIV infection, the infection results in an acute retroviral syndrome. However, these symptoms are often vague and escape detection. The onset of new neurological symptoms can raise suspicion for acute HIV infection. Aseptic meningitis occurs in almost 25% of infected individuals. Other neurological manifestations of acute HIV infection include facial nerve palsies, radiculopathy, and acute demyelinating polyneuropathy. These symptoms usually manifest within 2 to 6 weeks of infection and may be the primary reason that an individual seeks medical attention after HIV infection.

The neurological signs and symptoms of acute retroviral syndrome are probably distinct from the infection of CNS tissue itself. Nevertheless, HIV infection of the CNS is an early event that is thought to occur through trafficking of infected monocytes/macrophages and CD4 ⁺ T lymphocytes into the brain. Microglia, or resident CNS macrophages, are early reservoirs of HIV infection. Furthermore, astrocytes can also be infected by HIV. Astrocyte infection is CD4 ⁺ lymphocyte independent and results in nonproductive virus. However, the presence of HIV proteins within astrocytes may account for many of the chronic effects of CNS infection by HIV, especially in the pediatric population.

HIV-Associated Neurocognitive Disorders

HIV infection of the brain is associated with a spectrum of clinical findings often referred to as HIV-associated neurocognitive disorder, HIV-associated dementia, or more rarely HIV-associated encephalopathy (HAE). Approximately half of HIV-seropositive patients are thought to have cognitive impairment. In the era of widespread use of ART, severe forms such as HIV-associated dementia have become rarer while prevalence of the milder forms such as asymptomatic neurocognitive involvement or mild neurocognitive disorder has remained unchanged. ^, HIV-associated neurocognitive changes manifest differently in children and adults. Like other forms of dementia, HIV infection is associated with a spectrum of clinical severity from mild cognitive impairment that does not interfere with activities of daily living (asymptomatic neurocognitive impairment), to impairment that affects activities of daily living (mild neurocognitive impairment), to impairment that severely affects activities of daily living (HIV-associated dementia). HIV-associated neurocognitive disorder in adult patients is characterized by a gradual decline in cognitive functioning, often occurring long after the initial infection. Motor slowing is usually evident, sometimes coincident with, but often after, the onset of cognitive decline. Both are progressive, and behavioral changes may also become apparent. Neuroimaging reveals diffuse atrophy. Nonenhancing periventricular white matter changes may also be present ( Fig. 58.1 ), and the electroencephalogram usually shows diffuse slowing. Cerebrospinal fluid (CSF) evaluation often reveals mild lymphocytic pleocytosis and elevation in protein levels. Focal lesions on imaging or more extreme findings on CSF evaluation should prompt evaluation for other or coexisting illnesses. Some of these radiographic findings may be manifestations of reversible causes, such as metabolic derangements ( Fig. 58.2 ).

Figure 58.1, Human immunodeficiency virus (HIV)–associated encephalopathy (HAE).

HIV-associated neurocognitive disorder in children is similar to that in adults in many ways, but because the infection occurs during brain development, some differences may be observed. Specifically, evidence for more widespread infection of astrocytes and even of neurons may be found. ^, Developmental delay may be the first sign of HIV infection and can manifest as either motor or language delay. Behavioral consequences may also be present. Frequently these manifestations exist together.

CD8 ⁺ Encephalitis in HIV

CD8 ⁺ encephalitis in HIV patients treated with ART is a novel entity that was added to the spectrum of HIV CNS complications in 2013. It presents with features of acute encephalitis and responds to corticosteroid therapy. Magnetic resonance imaging shows diffuse white matter abnormalities affecting both white and gray matter, with subtle punctate or linear areas of enhancement ( Fig. 58.3 ); however, cases of CD8 ⁺ encephalitis lesions mimicking tumors have been described. The syndrome occurs in virologically controlled individuals on ART who nevertheless have evidence of HIV viral escape into the CNS. Some cases may be precipitated by a recent viral infection such as an upper respiratory infection, but differ from the acute disseminated encephalomyelitis (ADEM) histopathologically. Biopsy is frequently required for the diagnosis. The main differential diagnosis includes glial tumors, lymphoma, and tumefactive demyelination. Histologic analysis shows CD8 ⁺ lymphocyte perivascular infiltration, diffuse microglial activation, and reactive astrocytosis.

Tumefactive Demyelination in HIV

When patients with primary HIV present with focal neurological findings and MRI reveals tumor-like single or multiple lesions, tumefactive demyelination should be strongly considered in the differential diagnosis of infections, gliomas, lymphomas, and other tumors. ^, ^, Some of these lesions have an open ring configuration (C-shaped enhancement) on postcontrast imaging, which is frequently seen in tumefactive demyelinating lesions ( Fig. 58.4 ). At times, this clinical presentation may precipitate the diagnosis of HIV.

Proton magnetic resonance spectroscopy can be helpful in differentiating tumefactive demyelination from high-grade gliomas, but in many cases a biopsy is nevertheless required for a definitive diagnosis for focal demyelination. Tumefactive demyelination responds well to corticosteroid therapy. ART would need to be initiated at the same time if the diagnosis of HIV is concurrently discovered. Although tumefactive demyelination is a distinct entity that occurs in patients with HIV and is generally monophasic, rarely this can be the very first presentation of what may later manifest as multiple sclerosis.

Myelopathy

The spinal cord is commonly involved in HIV infection. The characteristic lesion in adults consists of vacuolar changes, predominantly in the lateral and posterior columns of the thoracic cord, although any level may be affected. Even though myelopathy is present in up to 50% of autopsy cases, clinical manifestations are much less frequently described, either because they are less pronounced than other neurological symptoms (i.e., those of dementia and neuropathy) or because they are attributed to some other cause. Common symptoms include spasticity, weakness, sensory ataxia, urinary incontinence, and erectile dysfunction. The disorder is usually a late manifestation of AIDS. Although it is also common in children, the nature of the myelopathic changes differs from that commonly observed in adults.

The cause of vacuolar myelopathy remains poorly understood, but HIV-infected macrophages are often present. There is no compelling evidence for overt HIV infection of spinal cord tissue itself. Two hypotheses, not mutually exclusive, might explain the pathologic features: (1) toxicity that is associated with proinflammatory cytokine production by infected macrophages, and (2) impairment of intraspinal methylation essential for myelination and neurotransmitter metabolism. Pathologic examination reveals a symmetrical axon-sparing process initially, which in advanced cases may disrupt axons and appear more asymmetrical.

The diagnosis is usually clinical, but findings at MRI include atrophic changes of the thoracic cord with occasional increased signal on T2-weighted and fluid-attenuated inversion recovery (FLAIR) sequences. CSF is often normal. On occasion, mild lymphocytic pleocytosis and protein elevation are observed. Somatosensory evoked potentials are frequently abnormal even before clinical symptoms develop.

HIV-associated vacuolar myelopathy tends to be insidious in onset. There is no effective treatment. Therefore, in any patient with a rapidly progressive myelopathic disorder, especially one associated with focal back pain or marked CSF abnormalities, alternative diagnoses should be sought because treatments may be available. Such alternative diagnoses include disorders caused by other retroviruses (human T-cell lymphotropic virus types I and II), cytomegalovirus (CMV), herpes simplex virus type 2, and herpes zoster. Less common causes include those associated with malignancies, especially lymphoma and myeloma. Ischemic myelopathies are rarely reported.

HIV-Associated Stroke

HIV infection is associated with an increased risk for stroke and has been associated with an increased incidence of traditional vascular risk factors such as hypertension and hyperlipidemia. It is also associated with an increased risk of hypercoagulability, manifested by the presence of antiphospholipid antibodies, elevated levels of tissue-type plasminogen activator antigen, elevated levels of plasminogen activator inhibitor 1, and protein S deficiency in HIV-positive patients with stroke. It is not completely understood whether each of these factors increases the stroke risk in this patient population. ^, HIV has also been associated with vasculitis and endocarditis. ^, Although rare in children, stroke should be considered in those with HIV infection and an acute onset of neurological symptoms because cerebrovascular disease is well documented. In addition, dyslipidemia, a common side effect of ART, carries an increased risk for stroke. To date, however, no compelling evidence of a strong association between ART and an increased incidence of stroke has been documented. In conclusion, stroke must be considered in the differential diagnosis of any HIV-positive individual with an abrupt onset of neurological symptoms.

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