Anthony S. Fauci H. Clifford Lane
Clinical disease of the nervous system accounts for a significant degree of morbidity in a high percentage of patients with HIV infection. Neurologic problems occur throughout the course of infection and may be inflammatory, demyelinating, or degenerative in nature. These problems fall into four basic categories: neurologic disease caused by HIV itself, HIV-related neoplasms, opportunistic infections of the nervous system, and adverse effects of medical therapy (Table 42-1).
NEUROLOGIC DISEASES IN PATIENTS WITH HIV INFECTION
The current CDC classification system for HIV-infected adolescents and adults categorizes persons on the basis of clinical conditions associated with HIV infection and CD4+ T lymphocyte counts. The system is based on three ranges of CD4+ T lymphocyte counts and three clinical categories and is represented by a matrix of nine mutually exclusive categories (Tables 42-2 and 42-3). Using this system, any HIV-infected individual with a CD4+ T cell count of <200/μL has AIDS by definition, regardless of the presence of symptoms or opportunistic diseases (Table 42-2). Once individuals have had a clinical condition in category B, their disease classification cannot be reverted back to category A, even if the condition resolves; the same holds true for category C in relation to category B.
1993 REVISED CLASSIFICATION SYSTEM FOR HIV INFECTION AND EXPANDED AIDS SURVEILLANCE CASE DEFINITION FOR ADOLESCENTS AND ADULTS
CLINICAL CATEGORIES OF HIV INFECTION
The definition of AIDS is indeed complex and comprehensive and was established not for the practical care of patients, but for surveillance purposes. Thus, the clinician should not focus on whether or not the patient fulfills the strict definition of AIDS, but should view HIV disease as a spectrum ranging from primary infection, with or without the acute syndrome, to the asymptomatic stage, to advanced disease.
HIV is the etiologic agent of AIDS; it belongs to the family of human retroviruses (Retroviridae) and the subfamily of lentiviruses. Nononcogenic lentiviruses cause disease in other animal species, including sheep, horses, goats, cattle, cats, and monkeys. The four recognized human retroviruses belong to two distinct groups: the human T lymphotropic viruses (HTLV)-I and HTLV-II, which are transforming retroviruses; and the human immunodeficiency viruses, HIV-1 and HIV-2, which cause cytopathic effects either directly or indirectly. The most common cause of HIV disease throughout the world, and certainly in the United States, is HIV-1, which comprises several subtypes with different geographic distributions. HIV-2 was first identified in 1986 in West African patients and was originally confined to West Africa. However, a number of cases that can be traced to West Africa or to sexual contacts with West Africans have been identified throughout the world.
MORPHOLOGY OF HIV
Electron microscopy shows that the HIV virion is an icosahedral structure (Fig. 42-1A) containing numerous external spikes formed by the two major envelope proteins, the external gp120 and the transmembrane gp41. The virion buds from the surface of the infected cell and incorporates a variety of host proteins, including major histocompatibility complex (MHC) class I and II antigens, into its lipid bilayer. The structure of HIV-1 is schematically diagrammed in Fig. 42-1B.
A. Electron micrograph of HIV. Figure illustrates a typical virion following budding from the surface of a CD4+ T lymphocyte, together with two additional incomplete virions in the process of budding from the cell membrane. B.Structure of HIV-1, including the gp120 outer membrane, gp41 transmembrane components of the envelope, genomic RNA, enzyme reverse transcriptase, p18(17) inner membrane (matrix), and p24 core protein (capsid). (Copyright by George V. Kelvin. Adapted from RC Gallo: Sci Am 256:46, 1987.)
REPLICATION CYCLE OF HIV
HIV is an RNA virus whose hallmark is the reverse transcription of its genomic RNA to DNA by the enzyme reverse transcriptase. The replication cycle of HIV begins with the high-affinity binding of the gp120 protein via a portion of its V1 region near the N terminus to its receptor on the host cell surface, the CD4 molecule (Fig. 42-2). The CD4 molecule is a 55-kDa protein found predominantly on a subset of T lymphocytes that are responsible for helper function in the immune system. It is also expressed on the surface of monocytes/macrophages and dendritic/Langerhans cells. Once gp120 binds to CD4, the gp120 undergoes a conformational change that facilitates binding to one of a group of co-receptors. The two major co-receptors for HIV-1 are CCR5 and CXCR4. Both receptors belong to the family of seven-transmembrane-domain G protein–coupled cellular receptors, and the use of one or the other or both receptors by the virus for entry into the cell is an important determinant of the cellular tropism of the virus. Certain dendritic cells express a diversity of C-type lectin receptors on their surface, one of which is called DC-SIGN, that also bind with high affinity to the HIV gp120 envelope protein, allowing the dendritic cell to facilitate the binding of virus to the CD4+ T cell upon engagement of dendritic cells with CD4+ T cells. Following binding of the envelope protein to the CD4 molecule associated with the previously-mentioned conformational change in the viral envelope gp120, fusion with the host cell membrane occurs via the newly exposed gp41 molecule penetrating the plasma membrane of the target cell and then coiling upon itself to bring the virion and target cell together. Following fusion, the preintegration complex, composed of viral RNA and viral enzymes and surrounded by a capsid protein coat, is released into the cytoplasm of the target cell. As the preintegration complex traverses the cytoplasm to reach the nucleus, the viral reverse transcriptase enzyme catalyzes the reverse transcription of the genomic RNA into DNA, and the protein coat opens to release the resulting double-stranded HIV-DNA. At this point in the replication cycle, the viral genome is vulnerable to cellular factors that can block the progression of infection. In particular, the cytoplasmic TRIM5-α protein in rhesus macaque cells blocks SIV replication at a point shortly after the virus fuses with the host cell. Although the exact mechanisms of action of TRIM5-α remain unclear, the human form is inhibited by cyclophilin A and is not effective in restricting HIV replication in human cells. The recently described APOBEC family of cellular proteins also inhibits progression of virus infection after virus has entered the cell. APOBEC proteins bind to nascent reverse transcripts and deaminate viral cytidine, causing hypermutation of HIV genomes. It is still not clear whether (1) viral replication is inhibited by the binding of APOBEC to the virus genome with subsequent accumulation of reverse transcripts, or (2) by the hypermutations caused by the enzymatic deaminase activity of APOBEC proteins. HIV has evolved a powerful strategy to protect itself from APOBEC.
The replication cycle of HIV. See text for description. (Adapted from AS Fauci: Nature 384:529, 1996.) The viral protein Vif targets APOBEC for proteasomal degradation.
With activation of the cell, the viral DNA accesses the nuclear pore and is exported from the cytoplasm to the nucleus, where it is integrated into the host cell chromosomes through the action of another virally encoded enzyme, integrase. HIV provirus (DNA) selectively integrates into the nuclear DNA preferentially within introns of active genes and regional hotspots. This provirus may remain transcriptionally inactive (latent) or it may manifest varying levels of gene expression, up to active production of virus.
Cellular activation plays an important role in the replication cycle of HIV and is critical to the pathogenesis of HIV disease. Following initial binding and internalization of virions into the target cell, incompletely reverse-transcribed DNA intermediates are labile in quiescent cells and do not integrate efficiently into the host cell genome unless cellular activation occurs shortly after infection. Furthermore, some degree of activation of the host cell is required for the initiation of transcription of the integrated proviral DNA into either genomic RNA or mRNA. This latter process may not necessarily be associated with the detectable expression of the classic cell surface markers of activation. In this regard, activation of HIV expression from the latent state depends on the interaction of a number of cellular and viral factors. Following transcription, HIV mRNA is translated into proteins that undergo modification through glycosylation, myristylation, phosphorylation, and cleavage. The viral particle is formed by the assembly of HIV proteins, enzymes, and genomic RNA at the plasma membrane of the cells. Budding of the progeny virion occurs through specialized regions in the lipid bilayer of the host cell membrane known as lipid rafts, where the core acquires its external envelope. The virally encoded protease then catalyzes the cleavage of the gag-pol precursor to yield the mature virion. Progression through the virus replication cycle is profoundly influenced by a variety of viral regulatory gene products. Likewise, each point in the replication cycle of HIV is a real or potential target for therapeutic intervention. Thus far, the reverse transcriptase, protease, and integrase enzymes as well as the process of virus–target cell binding and fusion have proven clinically to be susceptible to pharmacologic disruption.
PATHOPHYSIOLOGY AND PATHOGENESIS
The hallmark of HIV disease is a profound immunodeficiency resulting primarily from a progressive quantitative and qualitative deficiency of the subset of T lymphocytes referred to as helper T cellsoccurring in a setting of polyclonal immune activation. The helper subset of T cells is defined phenotypically by the presence on its surface of the CD4 molecule, which serves as the primary cellular receptor for HIV. When the number of CD4+ T cells declines below a certain level, the patient is at high risk for developing a variety of opportunistic diseases, particularly the infections and neoplasms that are AIDS-defining illnesses. Some features of AIDS, such as Kaposi sarcoma and certain neurologic abnormalities, cannot be explained completely by the immunosuppressive effects of HIV, since these complications may occur prior to the development of severe immunologic impairment.
While there has been a remarkable decrease in the incidence of HIV encephalopathy among those with access to treatment in the era of effective ARV therapy, HIV-infected individuals can still experience a variety of neurologic abnormalities due either to opportunistic infections and neoplasms or to direct effects of HIV or its products. With regard to the latter, HIV has been demonstrated in the brain and CSF of infected individuals with and without neuropsychiatric abnormalities. The main cell types that are infected in the brain in vivo are the perivascular macrophages and the microglial cells; monocytes that have already been infected in the blood can migrate into the brain, where they then reside as macrophages, or macrophages can be directly infected within the brain. The precise mechanisms whereby HIV enters the brain are unclear; however, they are thought to relate, at least in part, to the ability of virus-infected and immune-activated macrophages to induce adhesion molecules such as E-selectin and vascular cell adhesion molecule-1 (VCAM-1) on brain endothelium. Other studies have demonstrated that HIV gp120 enhances the expression of intercellular adhesion molecule-1 (ICAM-1) in glial cells; this effect may facilitate entry of HIV-infected cells into the CNS and may promote syncytia formation. Virus isolates from the brain are preferentially R5 strains as opposed to X4 strains; in this regard, HIV-infected individuals who are heterozygous for CCR5-Δ32 appear to be relatively protected against the development of HIV encephalopathy compared to wild-type individuals. Distinct HIV envelope sequences are associated with the clinical expression of the AIDS dementia complex. There is no convincing evidence that brain cells other than those of monocyte/macrophage lineage can be productively infected in vivo.
HIV-infected individuals may manifest white matter lesions as well as neuronal loss. Given the absence of evidence of HIV infection of neurons either in vivo or in vitro, it is highly unlikely that direct infection of these cells accounts for their loss. Rather, the HIV-mediated effects on neurons and oligodendrocytes are thought to involve indirect pathways whereby viral proteins, particularly gp120 and Tat, trigger the release of endogenous neurotoxins from macrophages and to a lesser extent from astrocytes. In addition, it has been demonstrated that both HIV-1 Nef and Tat can induce chemotaxis of leukocytes, including monocytes, into the CNS. Neurotoxins can be released from monocytes as a consequence of infection and/or immune activation. Monocyte-derived neurotoxic factors have been reported to kill neurons via the N-methyl-D-aspartate (NMDA) receptor. In addition, HIV gp120 shed by virus-infected monocytes could cause neurotoxicity by antagonizing the function of vasoactive intestinal peptide (VIP), by elevating intracellular calcium levels, and by decreasing nerve growth factor levels in the cerebral cortex. A variety of monocyte-derived cytokines can contribute directly or indirectly to the neurotoxic effects in HIV infection; these include TNF-α, IL-1, IL-6, TGF-β, IFN-γ, platelet-activating factor, and endothelin. Furthermore, among the CC-chemokines, elevated levels of monocyte chemotactic protein (MCP) 1 in the brain and CSF have been shown to correlate best with the presence and degree of HIV encephalopathy. In addition, infection and/or activation of monocyte-lineage cells can result in increased production of eicosanoids, quinolinic acid, nitric oxide, excitatory amino acids such as L-cysteine and glutamate, arachidonic acid, platelet activating factor, free radicals, TNF-α, and TGF-β, which may contribute to neurotoxicity. Astrocytes may play diverse roles in HIV neuropathogenesis. Reactive gliosis or astrocytosis has been demonstrated in the brains of HIV-infected individuals, and TNF-α and IL-6 have been shown to induce astrocyte proliferation. In addition, astrocyte-derived IL-6 can induce HIV expression in infected cells in vitro. Furthermore, it has been suggested that astrocytes may downregulate macrophage-produced neurotoxins. It has been reported that HIV-infected individuals with the E4 allele for apolipoprotein E (apo E) are at increased risk for AIDS encephalopathy and peripheral neuropathy. The likelihood that HIV or its products are involved in neuropathogenesis is supported by the observation that neuropsychiatric abnormalities may undergo remarkable and rapid improvement upon the initiation of combination antiretroviral therapy (cART).
It has also been suggested that the CNS may serve as a relatively sequestered site for a reservoir of latently infected cells that might be a barrier for the eradication of the virus by cART.
Clinical disease of the nervous systems accounts for a significant degree of morbidity in a high percentage of patients with HIV infection (Table 42-1). The neurologic problems that occur in HIV-infected individuals may be either primary to the pathogenic processes of HIV infection or secondary to opportunistic infections or neoplasms. Among the more frequent opportunistic diseases that involve the CNS are toxoplasmosis, cryptococcosis, progressive multifocal leukoencephalopathy, and primary CNS lymphoma. Other less common problems include mycobacterial infections; syphilis; and infection with CMV, HTLV-I, T. cruzi, or Acanthamoeba. Overall, secondary diseases of the CNS occur in approximately one-third of patients with AIDS. These data antedate the widespread use of cART, and this frequency is considerably less in patients receiving effective antiretroviral drugs. Primary processes related to HIV infection of the nervous system are reminiscent of those seen with other lentiviruses, such as the Visna-Maedi virus of sheep.
NEUROLOGIC DISEASES CAUSED BY HIV
HIV-associated cognitive impairment
The term HIV-associated neurocognitive disorders (HAND) is used to describe a spectrum of disorders that range from asymptomatic neurocognitive impairment (ANI) to minor neurocognitive disorder (MND) to clinically severe dementia. The most severe form, HIV-associated dementia (HAD), also referred to as the AIDS dementia complex, or HIV encephalopathy, is considered an AIDS-defining illness. Most HIV-infected patients have some neurologic problem during the course of their disease. Even in the setting of suppressive cART, approximately 50% of HIV-infected individuals can be shown to have mild to moderate neurocognitive impairment using sensitive neuropsychiatric testing. Virtually all patients with HIV infection have some degree of nervous system involvement with the virus. This is evidenced by the fact that CSF findings are abnormal in ~90% of patients, even during the asymptomatic phase of HIV infection. CSF abnormalities include pleocytosis (50–65% of patients), detection of viral RNA (~75%), elevated CSF protein (35%), and evidence of intrathecal synthesis of anti-HIV antibodies (90%). It is important to point out that evidence of infection of the CNS with HIV does not imply impairment of cognitive function. The neurologic function of an HIV-infected individual should be considered normal unless clinical signs and symptoms suggest otherwise.
HIV-associated dementia (also known as HIV encephalopathy) consists of a constellation of signs and symptoms of CNS disease. While this is generally a late complication of HIV infection that progresses slowly over months, it can be seen in patients with CD4+ T cell counts >350 cells/μL. A major feature of this entity is the development of dementia, defined as a decline in cognitive ability from a previous level. It may present as impaired ability to concentrate, increased forgetfulness, difficulty reading, or increased difficulty performing complex tasks. Initially these symptoms may be indistinguishable from findings of situational depression or fatigue. In contrast to “cortical” dementia (such as Alzheimer’s disease), aphasia, apraxia, and agnosia are uncommon, leading some investigators to classify HIV-associated dementia as a “subcortical dementia” characterized by defects in short-term memory and executive function. In addition to dementia, patients with HIV-associated dementia may also have motor and behavioral abnormalities. Among the motor problems are unsteady gait, poor balance, tremor, and difficulty with rapid alternating movements. Increased tone and deep tendon reflexes may be found in patients with spinal cord involvement. Late stages may be complicated by bowel and/or bladder incontinence. Behavioral problems include apathy and lack of initiative, with progression to a vegetative state in some instances. Some patients develop a state of agitation or mild mania. These changes usually occur without significant changes in level of alertness. This is in contrast to the finding of somnolence in patients with dementia due to toxic/metabolic encephalopathies.
HIV-associated dementia is the initial AIDS-defining illness in ~3% of patients with HIV infection and thus only rarely precedes clinical evidence of immunodeficiency. Clinically significant encephalopathy eventually develops in ~25% of untreated patients with AIDS. As immunologic function declines, the risk and severity of HIV encephalopathy increase. Autopsy series suggest that 80–90% of patients with HIV infection have histologic evidence of CNS involvement. Several classification schemes have been developed for grading HIV-associated dementia; a commonly used clinical staging system is outlined in Table 42-4.
CLINICAL STAGING OF HIV ENCEPHALOPATHY (AIDS DEMENTIA COMPLEX)
The precise cause of HIV-associated dementia remains unclear, although the condition is thought to be a result of a combination of direct effects of HIV on the CNS and associated immune activation. HIV has been found in the brains of patients with HIV-associated dementia by Southern blot, in situ hybridization, PCR, and electron microscopy. Multinucleated giant cells, macrophages, and microglial cells appear to be the main cell types harboring virus in the CNS. Histologically, the major changes are seen in the subcortical areas of the brain and include pallor and gliosis, multinucleated giant cell encephalitis, and vacuolar myelopathy. Less commonly, diffuse or focal spongiform changes occur in the white matter. Areas of the brain involved in motor, language, and judgment are most severely affected.
There are no specific criteria for a diagnosis of HIV-associated dementia, and this syndrome must be differentiated from a number of other diseases that affect the CNS of HIV-infected patients. The diagnosis of dementia depends upon demonstrating a decline in cognitive function. This can be accomplished objectively with the use of a Mini-Mental Status Examination (MMSE) in patients for whom prior scores are available. For this reason, it is advisable for all patients with a diagnosis of HIV infection to have a baseline MMSE. However, changes in MMSE scores may be absent in patients with mild HIV-associated dementia. Imaging studies of the CNS, by either MRI or CT, often demonstrate evidence of cerebral atrophy (Fig. 42-3). MRI may also reveal small areas of increased density on T2-weighted images. Lumbar puncture is an important element of the evaluation of patients with HIV infection and neurologic abnormalities. It is generally most helpful in ruling out or making a diagnosis of opportunistic infections. In HIV-associated dementia, patients may have the nonspecific findings of an increase in CSF cells and protein level. While HIV RNA can often be detected in the spinal fluid and HIV can be cultured from the CSF, this finding is not specific for HIV-associated dementia. There appears to be no correlation between the presence of HIV in the CSF and the presence of HIV-associated dementia. Elevated levels of macrophage chemoattractant protein (MCP-1), β2-microglobulin, neopterin, and quinolinic acid (a metabolite of tryptophan reported to cause CNS injury) have been noted in the CSF of patients with HIV-associated dementia. These findings suggest that these factors as well as inflammatory cytokines may be involved in the pathogenesis of this syndrome.
AIDS dementia complex. Postcontrast CT scan through the lateral ventricles of a 47-year-old man with AIDS, altered mental status, and dementia. The lateral and third ventricles and the cerebral sulci are abnormally prominent. Mild white matter hypodensity is also seen adjacent to the frontal horns of the lateral ventricles.
Combination antiretroviral therapy is of benefit in patients with HIV-associated dementia. Improvement in neuropsychiatric test scores has been noted for both adult and pediatric patients treated with antiretrovirals. The rapid improvement in cognitive function noted with the initiation of cART suggests that at least some component of this problem is quickly reversible, again supporting at least a partial role of soluble mediators in the pathogenesis. It should also be noted that these patients have an increased sensitivity to the side effects of neuroleptic drugs. The use of these drugs for symptomatic treatment is associated with an increased risk of extrapyramidal side effects; therefore, patients with HIV-associated dementia who receive these agents must be monitored carefully. It is felt by many physicians that the decrease in the prevalence of severe cases of HIV-associated dementia brought about by cART has resulted in an increase in the prevalence of milder forms of this disorder.
Aseptic meningitis may be seen in any but the very late stages of HIV infection. In the setting of acute primary infection patients may experience a syndrome of headache, photophobia, and meningismus. Rarely, an acute encephalopathy due to encephalitis may occur. Cranial nerve involvement may be seen, predominantly cranial nerve VII but occasionally V and/or VIII. CSF findings include a lymphocytic pleocytosis, elevated protein level, and normal glucose level. This syndrome, which cannot be clinically differentiated from other viral meningitides (Chap. 41), usually resolves spontaneously within 2–4 weeks; however, in some patients, signs and symptoms may become chronic. Aseptic meningitis may occur any time in the course of HIV infection; however, it is rare following the development of AIDS. This fact suggests that clinical aseptic meningitis in the context of HIV infection is an immune-mediated disease.
Spinal cord disease, or myelopathy, is present in ~20% of patients with AIDS, often as part of HIV-associated neurocognitive disorder. In fact, 90% of the patients with HIV-associated myelopathy have some evidence of dementia, suggesting that similar pathologic processes may be responsible for both conditions. Three main types of spinal cord disease are seen in patients with AIDS. The first of these is a vacuolar myelopathy. This condition is pathologically similar to subacute combined degeneration of the cord such as occurs with pernicious anemia. Although vitamin B12 deficiency can be seen in patients with AIDS as a primary complication of HIV infection, it does not appear to be responsible for the myelopathy seen in the majority of patients. Vacuolar myelopathy is characterized by a subacute onset and often presents with gait disturbances, predominantly ataxia and spasticity; it may progress to include bladder and bowel dysfunction. Physical findings include evidence of increased deep tendon reflexes and extensor plantar responses. The second form of spinal cord disease involves the dorsal columns and presents as a pure sensory ataxia. The third form is also sensory in nature and presents with paresthesias and dysesthesias of the lower extremities. In contrast to the cognitive problems, these spinal cord syndromes do not respond well to antiretroviral drugs, and therapy is mainly supportive.
One important disease of the spinal cord that also involves the peripheral nerves is a myelopathy and polyradiculopathy seen in association with CMV infection. This entity is generally seen late in the course of HIV infection and is fulminant in onset, with lower extremity and sacral paresthesias, difficulty in walking, areflexia, ascending sensory loss, and urinary retention. The clinical course is rapidly progressive over a period of weeks. CSF examination reveals a predominantly neutrophilic pleocytosis, and CMV DNA can be detected by CSF PCR. Therapy with ganciclovir or foscarnet can lead to rapid improvement, and prompt initiation of foscarnet or ganciclovir therapy is important in minimizing the degree of permanent neurologic damage. Combination therapy with both drugs should be considered in patients who have been previously treated for CMV disease. Other diseases involving the spinal cord in patients with HIV infection include HTLV-I-associated myelopathy (HAM), neurosyphilis, infection with herpes simplex or varicella-zoster, TB, and lymphoma.
Peripheral neuropathies are common in patients with HIV infection. They occur at all stages of illness and take a variety of forms. Early in the course of HIV infection, an acute inflammatory demyelinating polyneuropathy resembling Guillain-Barré syndrome may occur (Chap. 46). In other patients, a progressive or relapsing-remitting inflammatory neuropathy resembling chronic inflammatory demyelinating polyneuropathy (CIDP) has been noted. Patients commonly present with progressive weakness, areflexia, and minimal sensory changes. CSF examination often reveals a mononuclear pleocytosis, and peripheral nerve biopsy demonstrates a perivascular infiltrate suggesting an autoimmune etiology. Plasma exchange or IVIg has been tried with variable success. Because of the immunosuppressive effects of glucocorticoids, they should be reserved for severe cases of CIDP refractory to other measures. Another autoimmune peripheral neuropathy seen in patients with AIDS is mononeuritis multiplex (due to a necrotizing arteritis of peripheral nerves). The most common peripheral neuropathy in patients with HIV infection is a distal sensory polyneuropathy, also referred to as painful sensory neuropathy, predominantly sensory neuropathy, or distal symmetric peripheral neuropathy. This condition may be a direct consequence of HIV infection or a side effect of dideoxynucleoside therapy. It is more common in taller individuals, older individuals, and those with lower CD4 counts. Two-thirds of patients with AIDS may be shown by electrophysiologic studies to have some evidence of peripheral nerve disease. Presenting symptoms are usually painful burning sensations in the feet and lower extremities. Findings on examination include a stocking-type sensory loss to pinprick, temperature, and touch sensation and a loss of ankle reflexes. Motor changes are mild and are usually limited to weakness of the intrinsic foot muscles. Response of this condition to antiretrovirals has been variable, perhaps because antiretrovirals are responsible for the problem in some instances. When due to dideoxynucleoside therapy, patients with lower extremity peripheral neuropathy may complain of a sensation that they are walking on ice. Other entities in the differential diagnosis of peripheral neuropathy include diabetes mellitus, vitamin B12 deficiency, and side effects from metronidazole or dapsone. For distal symmetric polyneuropathy that fails to resolve following the discontinuation of dideoxynucleosides, therapy is symptomatic; gabapentin, carbamazepine, tricyclics, or analgesics may be effective for dysesthesias. Treatment-naive patients may respond to cART.
Myopathy may complicate the course of HIV infection; causes include HIV infection itself, zidovudine, and the generalized wasting syndrome. HIV-associated myopathy may range in severity from an asymptomatic elevation in creatine kinase levels to a subacute syndrome characterized by proximal muscle weakness and myalgias. Quite pronounced elevations in creatine kinase may occur in asymptomatic patients, particularly after exercise. The clinical significance of this as an isolated laboratory finding is unclear. A variety of both inflammatory and noninflammatory pathologic processes have been noted in patients with more severe myopathy, including myofiber necrosis with inflammatory cells, nemaline rod bodies, cytoplasmic bodies, and mitochondrial abnormalities. Profound muscle wasting, often with muscle pain, may be seen after prolonged zidovudine therapy. This toxic side effect of the drug is dose-dependent and is related to its ability to interfere with the function of mitochondrial polymerases. It is reversible following discontinuation of the drug. Red ragged fibers are a histologic hallmark of zidovudine-induced myopathy.
Lymphomas occur with an increased frequency in patients with congenital or acquired T cell immunodeficiencies. AIDS is no exception; at least 6% of all patients with AIDS develop lymphoma at some time during the course of their illness. This is a 120-fold increase in incidence compared to the general population. In contrast to the situation with Kaposi’s sarcoma, primary CNS lymphoma, and most opportunistic infections, the incidence of AIDS-associated systemic lymphomas has not experienced as dramatic a decrease as a consequence of the widespread use of effective cART. Lymphoma occurs in all risk groups, with the highest incidence in patients with hemophilia and the lowest incidence in patients from the Caribbean or Africa with heterosexually acquired infection. Lymphoma is a late manifestation of HIV infection, generally occurring in patients with CD4+ T cell counts <200/μL. As HIV disease progresses, the risk of lymphoma increases. The attack rate for lymphoma increases exponentially with increasing duration of HIV infection and decreasing level of immuno-logic function. At 3 years following a diagnosis of HIV infection, the risk of lymphoma is 0.8% per year; by 8 years after infection, it is 2.6% per year. As individuals with HIV infection live longer as a consequence of improved cART and better treatment and prophylaxis of opportunistic infections, it is anticipated that the incidence of lymphomas may increase.
The clinical presentation of lymphoma in patients with HIV infection is quite varied, ranging from focal seizures to rapidly growing mass lesions in the oral mucosa to persistent unexplained fever. At least 80% of patients present with extranodal disease, and a similar percentage have B-type symptoms of fever, night sweats, or weight loss. Virtually any site in the body may be involved. The most common extranodal site is the CNS, which is involved in approximately one-third of all patients with lymphoma. Approximately 60% of these cases are primary CNS lymphoma.
Primary CNS lymphoma accounts for ~20% of the cases of lymphoma in patients with HIV infection. In contrast to HIV-associated Burkitt’s lymphoma, primary CNS lymphomas are usually positive for EBV. In one study, the incidence of Epstein-Barr positivity was 100%. This malignancy does not have a predilection for any particular age group. The median CD4+ T cell count at the time of diagnosis is ~50/μL. Thus, CNS lymphoma generally presents at a later stage of HIV infection than systemic lymphoma. This fact may at least in part explain the poorer prognosis for this subset of patients.
Primary CNS lymphoma generally presents with focal neurologic deficits, including cranial nerve findings, headaches, and/or seizures. MRI or CT generally reveals a limited number (one to three) of 3- to 5-cm lesions (Fig. 42-4). The lesions often show ring enhancement on contrast administration and may occur in any location. Locations that are most commonly involved with CNS lymphoma are deep in the white matter. Contrast enhancement is usually less pronounced than that seen with toxoplasmosis. The main diseases in the differential diagnosis are cerebral toxoplasmosis and cerebral Chagas’ disease. In addition to the 20% of lymphomas in HIV-infected individuals that are primary CNS lymphomas, CNS disease is also seen in HIV-infected patients with systemic lymphoma. Approximately 20% of patients with systemic lymphoma have CNS disease in the form of leptomeningeal involvement. This fact underscores the importance of lumbar puncture in the staging evaluation of patients with systemic lymphoma.
Central nervous system lymphoma. Postcontrast T1-weighted MR scan in a patient with AIDS, an altered mental status, and hemiparesis. Multiple enhancing lesions, some ring-enhancing, are present. The left Sylvian lesion shows gyral and subcortical enhancement, and the lesions in the caudate and splenium (arrowheads) show enhancement of adjacent ependymal surfaces.
Both conventional and unconventional approaches have been employed in an attempt to treat HIV-related lymphomas. Systemic lymphoma is generally treated by the oncologist with combination chemotherapy. Earlier disappointing figures are being replaced with more optimistic results for the treatment of systemic lymphoma following the availability of more effective cART and the use of rituximab in CD20+ tumors. While there is controversy regarding the use of antiretrovirals during chemotherapy, there is no question that their use overall in patients with HIV lymphoma has improved survival. As in most situations in patients with HIV disease, those with the higher CD4+ T cell counts tend to do better. Response rates as high as 72% with a median survival of 33 months and disease-free intervals up to 9 years have been reported. Treatment of primary CNS lymphoma remains a significant challenge. Treatment is complicated by the fact that this illness usually occurs in patients with advanced HIV disease. Palliative measures such as radiation therapy provide some relief. The prognosis remains poor in this group, with a 2-year survival of 29%.
HIV-related opportunistic infections
The most common HIV-related neurologic opportunistic infections are toxoplasmosis, cryptococcal infections, and progressive multifocal leukoencephalopathy. The risk of many such infections correlates well with the CD4+ T cell count (Fig. 42-5). A selected group of common and important opportunistic infections of the nervous system in patients with HIV is discussed next.
Relationship between CD4+ T cell counts and the development of opportunistic diseases. Boxplot of the median (line inside the box), first quartile (bottom of the box), third quartile (top of the box), and mean (asterisk) CD4+ lymphocyte count at the time of the development of opportunistic disease. Can, candidal esophagitis; CMV, cytomegalovirus infection; Crp, cryptosporidiosis; Cry, cryptococcal meningitis; DEM, AIDS dementia complex; HSV, herpes simplex virus infection; HZos, herpes zoster; KS, Kaposi’s sarcoma; MAC, Mycobacterium avium complex bacteremia; NHL, nonHodgkin’s lymphoma; PCP, primary Pneumocystis jiroveci pneumonia; PCP2, secondary P. jiroveci pneumonia; PML, progressive multifocal leukoencephalopathy; Tox, Toxo-plasma gondii encephalitis; WS, wasting syndrome. (From RD Moore, RE Chaisson: Ann Intern Med 124:633, 1996.)
C. neoformans is the leading infectious cause of meningitis in patients with AIDS. It is the initial AIDS-defining illness in ~2% of patients and generally occurs in patients with CD4+ T cell counts <100/μL. Cryptococcal meningitis is particularly common in patients with AIDS in Africa, occurring in ~5% of patients. Most patients present with a picture of subacute meningoencephalitis with fever, nausea, vomiting, altered mental status, headache, and meningeal signs. The incidence of seizures and focal neurologic deficits is low. The CSF profile may be normal or may show only modest elevations in WBC or protein levels and decreases in glucose. In addition to meningitis, patients may develop cryptococcomas and cranial nerve involvement. Approximately one-third of patients also have pulmonary disease. Uncommon manifestations of cryptococcal infection include skin lesions that resemble molluscum contagiosum, lymphadenopathy, palatal and glossal ulcers, arthritis, gastroenteritis, myocarditis, and prostatitis. The prostate gland may serve as a reservoir for smoldering cryptococcal infection. The diagnosis of cryptococcal meningitis is made by identification of organisms in spinal fluid with India ink examination or by the detection of cryptococcal antigen. A biopsy may be needed to make a diagnosis of CNS cryptococcoma. Treatment is with IV amphotericin B, at a dose of 0.7 mg/kg daily, or liposomal amphotericin 4-6 mg/kg daily, with flucytosine, 25 mg/kg qid for at least 2 weeks, and, if possible, until the CSF culture turns negative. This is followed by fluconazole, 400 mg/d PO for 8 weeks, and then fluconazole, 200 mg/d until the CD4+ T cell count has increased to >200 cells/μL for 6 months in response to cART. Repeated lumbar puncture may be required to manage increased intracranial pressure. Symptoms may recur with initiation of cART as an immune reconstitution syndrome. Other fungi that may cause meningitis in patients with HIV infection are C. immitis and H. capsulatum. Meningoencephalitis has also been reported due to Acanthamoeba or Naegleria.
Toxoplasmosis has been one of the most common causes of secondary CNS infections in patients with AIDS, but its incidence is decreasing in the era of cART. It is most common in patients from the Caribbean and from France, where the seroprevalence of T. gondii is around 50%. Toxoplasmosis is generally a late complication of HIV infection and usually occurs in patients with CD4+ T cell counts <200/μL. Cerebral toxoplasmosis is thought to represent a reactivation of latent tissue cysts. It is 10 times more common in patients with antibodies to the organism than in patients who are seronegative. Patients diagnosed with HIV infection should be screened for IgG antibodies to T. gondii during the time of their initial workup. Those who are seronegative should be counseled about ways to minimize the risk of primary infection including avoiding the consumption of undercooked meat and careful hand washing after contact with soil or changing the cat litter box. The most common clinical presentation of cerebral toxoplasmosis in patients with HIV infection is fever, headache, and focal neurologic deficits. Patients may present with seizure, hemiparesis, or aphasia as a manifestation of these focal deficits or with a picture more influenced by the accompanying cerebral edema and characterized by confusion, dementia, and lethargy, which can progress to coma. The diagnosis is usually suspected on the basis of MRI findings of multiple lesions in multiple locations, although in some cases only a single lesion is seen. Pathologically, these lesions generally exhibit inflammation and central necrosis and, as a result, demonstrate ring enhancement on contrast MRI (Fig. 42-6) or, if MRI is unavailable or contraindicated, on double-dose contrast CT. There is usually evidence of surrounding edema. In addition to toxoplasmosis, the differential diagnosis of single or multiple enhancing mass lesions in the HIV-infected patient includes primary CNS lymphoma and, less commonly, TB or fungal or bacterial abscesses. The definitive diagnostic procedure is brain biopsy. However, given the morbidity than can accompany this procedure, it is usually reserved for the patient who has failed 2–4 weeks of empiric therapy. If the patient is seronegative for T. gondii, the likelihood that a mass lesion is due to toxoplasmosis is <10%. In that setting, one may choose to be more aggressive and perform a brain biopsy sooner. Standard treatment is sulfadiazine and pyrimethamine with leucovorin as needed for a minimum of 4–6 weeks. Alternative therapeutic regimens include clindamycin in combination with pyrimethamine; atovaquone plus pyrimethamine; and azithromycin plus pyrimethamine plus rifabutin. Relapses are common, and it is recommended that patients with a history of prior toxoplasmic encephalitis receive maintenance therapy with sulfadiazine, pyrimethamine, and leucovorin as long as their CD4+ T cell counts remain <200 cells/μL. Patients with CD4+ T cell counts <100/μL and IgG antibody to Toxoplasma should receive primary prophylaxis for toxoplasmosis. Fortunately, the same daily regimen of a single double-strength tablet of TMP/SMX used for P. jiroveciprophylaxis provides adequate primary protection against toxoplasmosis. Secondary prophylaxis/maintenance therapy for toxoplasmosis may be discontinued in the setting of effective cART and increases in CD4+ T cell counts to >200/μL for 6 months.
Central nervous system toxoplasmosis. A coronal post-contrast T1-weighted MR scan demonstrates a peripheral enhancing lesion in the left frontal lobe, associated with an eccentric nodular area of enhancement (arrow); this so-called eccentric target sign is typical of toxoplasmosis.
Progressive multifocal leukoencephalopathy (PML)
JC virus, a human polyomavirus that is the etiologic agent of progressive multifocal leukoencephalopathy (PML), is an important opportunistic pathogen in patients with AIDS. While ~80% of the general adult population have antibodies to JC virus, indicative of prior infection, <10% of healthy adults show any evidence of ongoing viral replication. PML is the only known clinical manifestation of JC virus infection. It is a late manifestation of AIDS and is seen in ~4% of patients with AIDS. The lesions of PML begin as small foci of demyelination in subcortical white matter that eventually coalesce. The cerebral hemispheres, cerebellum, and brainstem may all be involved. Patients typically have a protracted course with multifocal neurologic deficits, with or without changes in mental status. Approximately 20% of patients experience seizures. Ataxia, hemiparesis, visual field defects, aphasia, and sensory defects may occur. MRI typically reveals multiple, non-enhancing white matter lesions that may coalesce and have a predilection for the occipital and parietal lobes. The lesions show signal hyperintensity on T2-weighted images and diminished signal on T1-weighted images. The measurement of JC virus DNA levels in CSF has a diagnostic sensitivity of 76% and a specificity of close to 100%. Prior to the availability of cART, the majority of patients with PML died within 3–6 months of the onset of symptoms. Paradoxical worsening of PML has been seen with initiation of cART as an immune reconstitution syndrome. There is no specific treatment for PML; however, a minimal median survival of 2 years and survival of >15 years have been reported in patients with PML treated with cART for their HIV disease. Unfortunately only ~50% of patients with HIV infection and PML show neurologic improvement with cART. Studies with other antiviral agents such as cidofovir have failed to show clear benefit. Factors influencing a favorable prognosis for PML in the setting of HIV infection include a CD4+ T cell count >100/μL at baseline and the ability to maintain an HIV viral load of <500 copies per milliliter. Baseline HIV-1 viral load does not have independent predictive value of survival. PML is one of the few opportunistic infections that continues to occur with some frequency despite the widespread use of cART.
Reactivation American trypanosomiasis may present as acute meningoencephalitis with focal neurologic signs, fever, headache, vomiting, and seizures. Accompanying cardiac disease in the form of arrhythmias or heart failure should increase the index of suspicion. The presence of antibodies to Trypanosoma cruzi supports the diagnosis. In South America, reactivation of Chagas’ disease is considered to be an AIDS-defining condition and may be the initial AIDS-defining condition. The majority of cases occur in patients with CD4+ T cell counts <200 cells/μL. Lesions appear radiographically as single or multiple hypodense areas, typically with ring enhancement and edema. They are found predominantly in the subcortical areas, a feature that differentiates them from the deeper lesions of toxoplasmosis. T. cruzi amastigotes, or trypanosomes, can be identified from biopsy specimens or CSF. Other CSF findings include elevated protein and a mild (<100 cells/μL) lymphocytic pleocytosis. Organisms can also be identified by direct examination of the blood. Treatment consists of benzimidazole (2.5 mg/kg bid) or nifurtimox (2 mg/kg qid) for at least 60 days, followed by maintenance therapy for the duration of immunodeficiency with either drug at a dose of 5 mg/kg three times a week. As is the case with cerebral toxoplasmosis, successful therapy with antiretrovirals may allow discontinuation of therapy for Chagas’ disease.
Specific neurologic presentations
Stroke may occur in patients with HIV infection. In contrast to the other causes of focal neurologic deficits in patients with HIV infection, the symptoms of a stroke are sudden in onset. Patients with HIV infection have an increased prevalence of many classic risk factors associated with stroke, including smoking and diabetes. It also appears that HIV infection itself can lead to an increase in carotid artery stiffness. Among the secondary infectious diseases in patients with HIV infection that may be associated with stroke are vasculitis due to cerebral varicella zoster or neurosyphilis and septic embolism in association with fungal infection. Other elements of the differential diagnosis of stroke in the patient with HIV infection include atherosclerotic cerebral vascular disease, thrombotic thrombocytopenic purpura, and cocaine or amphetamine use.
Seizures may be a consequence of opportunistic infections, neoplasms, or HIV-associated dementia. The seizure threshold is often lower than normal in patients with advanced HIV infection due to the frequent presence of electrolyte abnormalities. Seizures are seen in 15–40% of patients with cerebral toxoplasmosis, 15–35% of patients with primary CNS lymphoma, 8% of patients with cryptococcal meningitis, and 7–50% of patients with HIV-associated dementia. Seizures may also be seen in patients with CNS tuberculosis, aseptic meningitis, and progressive multifocal leukoencephalopathy. Seizures may be the presenting clinical symptom of HIV disease. In one study of 100 patients with HIV infection presenting with a first seizure, cerebral mass lesions were the most common cause, responsible for 32 of the 100 new-onset seizures. Of these 32 cases, 28 were due to toxoplasmosis and 4 to lymphoma. HIV-associated dementia accounted for an additional 24 new-onset seizures. Cryptococcal meningitis was the third most common diagnosis, responsible for 13 of the 100 seizures. In 23 cases, no cause could be found, and it is possible that these cases represent a sub-category of HIV-associated dementia. Of these 23 cases, 16 (70%) had two or more seizures, suggesting that anti-convulsant therapy is indicated in all patients with HIV infection and seizures unless a rapidly correctable cause is found. While phenytoin remains the initial treatment of choice, hypersensitivity reactions to this drug have been reported in >10% of patients with AIDS, and therefore the use of phenobarbital, valproic acid, or levetiracetam must be considered as an alternative. Due to a variety of drug-drug interactions between antiseizure medications and antiretrovirals, drug levels need to be monitored carefully.