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 cells occurring 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. A co-receptor must also be present together with CD4 for efficient binding, fusion, and entry of HIV-1 into its target cells (Figs. 48-3 and 48-4). HIV uses two major co-receptors, CCR5 and CXCR4, for fusion and entry; these co-receptors are also the primary receptors for certain chemoattractive cytokines termed chemokines and belong to the seven-transmembrane-domain G protein–coupled family of receptors. A number of mechanisms responsible for cellular depletion and/or immune dysfunction of CD4+ T cells have been demonstrated in vitro; these include direct infection and destruction of these cells by HIV, as well as indirect effects such as immune clearance of infected cells, cell death associated with aberrant immune activation, and immune exhaustion due to aberrant cellular activation with resulting cellular dysfunction. Patients with CD4+ T cell levels below certain thresholds are at high risk of developing a variety of opportunistic diseases, particularly the infections and neoplasms that are AIDS-defining illnesses. Some features of AIDS, such as Kaposi’s sarcoma and certain neurologic abnormalities, cannot be explained completely by the immunodeficiency caused by HIV infection, since these complications may occur prior to the development of severe immunologic impairment.
The combination of viral pathogenic and immunopathogenic events that occurs during the course of HIV disease from the moment of initial (primary) infection through the development of advanced-stage disease is complex and varied. It is important to appreciate that the pathogenic mechanisms of HIV disease are multifactorial and multiphasic and are different at different stages of the disease. Therefore, it is essential to consider the typical clinical course of an untreated HIV-infected individual in order to more fully appreciate these pathogenic events (Fig. 48-6).
Typical course of an untreated HIV-infected individual. See text for detailed description. (From G Pantaleo et al: N Engl J Med 328:327, 1993. Copyright 1993 Massachusetts Medical Society. All rights reserved.)
NEUROPATHOGENESIS IN HIV DISEASE
While there has been a remarkable decrease in the incidence in the severe forms of HIV encephalopathy among those with access to treatment in the era of effective cART, HIV-infected individuals can still experience milder forms of neurocognitive impairment despite adequate cART. A variety of factors may contribute to the neurocognitive decline, which includes lack of complete control of HIV replication in the brain, production of HIV proteins that may be neurotoxic, low CD4+ T cell nadir, chronic immune activation, comorbidities such as drug abuse, and the potential for neurotoxicity of certain of the antiretroviral drugs. HIV has been demonstrated in the brain and CSF of infected individuals with and without neuropsychiatric abnormalities. As opposed to lymphoid tissues, there are no resident lymphocytes in the brain. The main cell types that are infected in the brain in vivo are the perivascular macrophages and the microglial cells; low-level viral replication is also seen in perivascular astrocytes. 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. 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. Once HIV enters the brain due to pressures of the local environment, it evolves to develop distinct sequences in the env, tat, and LTR genes. These unique sequences have been associated with neurocognitive dysfunction; however, it is unclear if they are causal (see below).
HIV-infected individuals may manifest white matter lesions as well as neuronal loss. The white matter lesions are due to axonal injury and a disruption of the blood-brain barrier and not due to demyelination. 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 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-1 (MCP-1 or CCL-2) 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. Treatment with cART leads to improvement in neuropsychiatric manifestations and a decrease in these cytokine levels in CSF, suggesting that they are driven by the virus or by its products. However, even in patients on long-term cART, there may be evidence of persistently activated lymphocytes in the CSF. It is unclear if these lymphocytes may contribute to neuronal injury in the brain or are critical for controlling the CNS viral reservoir. The contribution of host genetic factors to development of neuropsychiatric manifestations of HIV infection has not been well studied. However, evidence supports the role of the E4 allele for apoE in an increased risk of HIV-associated neurocognitive disorders and peripheral neuropathy.
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 virus by cART.
Neurologic problems directly attributable to HIV occur throughout the course of infection and may be inflammatory, demyelinating, or degenerative in nature. 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. As noted in the section on pathogenesis, damage to the CNS may be a direct result of viral infection of the CNS macrophages or glial cells or may be secondary to the release of neurotoxins and potentially toxic cytokines such as IL-1β, TNF-α, IL-6, and TGF-β. It has been reported that HIV-infected individuals with the E4 allele for apoE are at increased risk for AIDS encephalopathy and peripheral neuropathy. 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.
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. 47), 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 suggests that clinical aseptic meningitis in the context of HIV infection is an immune-mediated disease.
Cryptococcus is the leading infectious cause of meningitis in patients with AIDS. While the vast majority of these are due to C. neoformans, up to 12% may be due to C. gattii. Cryptococcal meningitis 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 untreated 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. The opening pressure in the CSF is usually elevated. 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. Blood cultures for fungus are often positive. A biopsy may be needed to make a diagnosis of CNS cryptococcoma. Treatment is with IV amphotericin B 0.7 mg/kg daily, or liposomal amphotericin 4–6 mg/kg daily, with flucytosine 25 mg/kg qid for at least 2 weeks if possible, continuing with amphotericin alone ideally until the CSF culture turns negative. Decreases in renal function in association with amphotericin can lead to increases in flucytosine levels and subsequent bone marrow suppression. Amphotericin 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 (see above). 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.
HIV-associated dementia 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 encephalopathy as a “subcortical dementia” characterized by defects in short-term memory and executive function (see below). In addition to dementia, patients with HIV encephalopathy 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, irritability, 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-associated dementia increases. 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 encephalopathy; a commonly used clinical staging system is outlined in Table 48-4.
TABLE 48-4CLINICAL STAGING OF HAND ACCORDING TO FRASCATI CRITERIA ||Download (.pdf) TABLE 48-4CLINICAL STAGING OF HAND ACCORDING TO FRASCATI CRITERIA
|STAGE ||NEUROCOGNITIVE STATUSa ||FUNCTIONAL STATUSb |
|Asymptomatic ||1 SD below mean in 2 cognitive domains ||No impairments in activities of daily living |
|Mild neurocognitive disorder ||1 SD below mean in 2 cognitive domains ||Impairments in activities of daily living |
|HIV-associated dementia ||2 SD below mean in 2 cognitive domains ||Notable impairments in activities of daily living |
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 encephalopathy 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 function, 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 (Table 48-1). The diagnosis of dementia depends on 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 encephalopathy. Imaging studies of the CNS, by either MRI or CT, often demonstrate evidence of cerebral atrophy (Fig. 48-7). 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 encephalopathy, 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 encephalopathy. There appears to be no correlation between the presence of HIV in the CSF and the presence of HIV encephalopathy. 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 encephalopathy. 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 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 encephalopathy who receive these agents must be monitored carefully. It is felt by many physicians that the decrease in the prevalence of severe cases of HAND brought about by cART has resulted in an increase in the prevalence of milder forms of this disorder.
Seizures may be a consequence of opportunistic infections, neoplasms, or HIV encephalopathy (Table 48-5). The seizure threshold is often lower than normal in patients with advanced HIV infection due in part 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 encephalopathy. 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 encephalopathy 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 subcategory of HIV encephalopathy. Of these 23 cases, 16 (70%) had 2 or more seizures, suggesting that anticonvulsant 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 or valproic acid should be considered as alternatives. Due to a variety of drug-drug interactions between antiseizure medications and antiretrovirals, drug levels need to be monitored carefully.
TABLE 48-5CAUSES OF SEIZURES IN PATIENTS WITH HIV INFECTION ||Download (.pdf) TABLE 48-5CAUSES OF SEIZURES IN PATIENTS WITH HIV INFECTION
|DISEASE ||OVERALL CONTRIBUTION TO FIRST SEIZURE, % ||FRACTION OF PATIENTS WHO HAVE SEIZURES, % |
|HIV encephalopathy ||24–47 ||7–50 |
|Cerebral toxoplasmosis ||28 ||15–40 |
|Cryptococcal meningitis ||13 ||8 |
|Primary central nervous system lymphoma ||4 ||15–30 |
|Progressive multifocal leukoencephalopathy ||1 ||20 |
Patients with HIV infection may present with focal neurologic deficits from a variety of causes. The most common causes are toxoplasmosis, progressive multifocal leukoencephalopathy, and CNS lymphoma. Other causes include cryptococcal infections (discussed above), stroke, and reactivation of Chagas’ disease.
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%. This figure is closer to 15% in the United States. 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. 48-8) 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 rate that can accompany this procedure, it is usually reserved for the patient who has failed 2–4 weeks of empiric therapy for toxoplasmosis. 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. jiroveci prophylaxis 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 postcontrast T1-weighted MRI 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.
JC virus, a human polyomavirus that is the etiologic agent of progressive multifocal leukoencephalopathy (PML), is an important opportunistic pathogen in patients with AIDS (Chap. 46). While ~80% of the general adult population has 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 ~1–4% 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. Headache, fever, nausea, and vomiting are rarely seen. Their presence should suggest another diagnosis. MRI typically reveals multiple, nonenhancing 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 median survival of 2 years and survival of >15 years have been reported in patients with PML treated with cART for their HIV disease. Despite having a significant impact on survival, 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/mL. 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 T. 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.
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 has been reported that HIV infection itself can lead to an increase in carotid artery stiffness. The relative increase in risk for stroke as a consequence of HIV infection is more pronounced in women and in individuals between the ages of 18 and 29. 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.
Primary CNS lymphoma is discussed below in the section on neoplastic diseases.
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, as mentioned above. This condition is pathologically similar to subacute combined degeneration of the cord, such as that occurring 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 seen in patients with HIV encephalopathy, 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-1-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. 54). 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 (Chap. 54) due to a necrotizing arteritis of peripheral nerves. The most common peripheral neuropathy in patients with HIV infection is a distal sensory polyneuropathy (DSPN) also referred to as painful sensory neuropathy (HIV-SN), 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-naïve 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.