I. GENERAL CONSIDERATIONS
The nervous system is involved early in the course of HIV infection and may produce the presenting clinical manifestations. Early natural history studies found neurologic symptoms and signs in 40% to 70% of patients during the course of the disease, whereas autopsy series demonstrated neuropathologic changes in 90% to 100% of persons with AIDS, affecting all levels of the neuraxis. These neurologic manifestations can result from effects of HIV itself or from opportunistic processes. Acute meningitis, meningoencephalitis, or polyneuritis can mark HIV seroconversion. Subsequently, neuropathy, encephalopathy, myelopathy, and myopathy can occur. Opportunistic illnesses (OI) of the CNS occur in conjunction with marked immune suppression.
Current therapeutic advances with combinations of antiretroviral agents known as highly active or combination antiretroviral therapy (HAART/cART) have had a profound effect on the frequency of both HIV-induced and opportunistic CNS disease. Neurologic complications continue to occur, however; as presentations in persons not known to have HIV infection, and among those who fail cART because of nonadherence or the emergence of resistant HIV strains. Recently, it has become apparent that subtle neurologic manifestations of HIV infection occur in patients on cART, including individuals who appear to be responding to treatment with suppression of systemic disease markers and symptoms. More common conditions causing neurologic complications in AIDS are listed in Table 44.1, although numerous case reports identify a wider spectrum of possible complicating infections.
Some general considerations helpful in approaching HIV+ patients with neurologic disease are listed below:
A. The imaging modality of choice in HIV-related CNS disease is MRI; however, particular imaging patterns may be nonspecific.
B. Multiple pathologic conditions in the CNS may occur concurrently in patients with profound immune suppression.
C. Most OIs appear with significant immune suppression as reflected by CD4+ lymphocyte counts of 200 per mm3 or less.
D. Neurologic manifestations of OIs in patients with AIDS can be subtle and lack classic disease features seen in other settings.
E. Specific diagnosis of OIs requires confirmation by culture, or demonstration of genetic material in CSF or biopsied tissue. Empiric therapy based on a presumptive diagnosis is appropriate in some circumstances; however, the absence of a typical treatment response should be prompt early further evaluation.
F. HIV-associated cognitive deficits are becoming more subtle in the era of successful cART and may occur in patients who appear to have successful control of systemic disease.
G. Not all neurologic symptoms occurring in HIV+ patients result from HIV or associated opportunistic processes, particularly when the HIV infection appears to be well-controlled. Such patients are subject to all of the common neurologic conditions that affect other populations.
H. Treatment strategies in AIDS are continuously evolving, particularly cART regimens.
II. CONDITIONS ATTRIBUTED TO HIV INFECTION
A. HIV-asssociated neurocognitive disorders (HAND). HIV-associated dementia (HAD; HIV dementia, AIDS dementia complex, and HIV encephalopathy) occurred in up to 20% of patients in the pre-cART era, usually after marked immune suppression developed, with progressive and disabling impairments in cognition, motor function, and behavior. Since the widespread use of cART, these forms of severe dementia are seen much less frequently. However, subtle forms of measurable cognitive impairment persist and may be increasing in prevalence as a consequence of longer survival and independent evolution of HIV in the relatively sequestered CNS. Three categories have been proposed to describe the current spectrum of HAND (Table 44.2):
1. Asymptomatic neurocognitive impairment (ANI). Individuals with acquired subclinical impairments in at least two cognitive domains on neurocognitive testing, without delirium, symptomatic complaints, or impaired daily activities.
2. Mild neurocognitive disorder. Individuals with clear sensorium and with acquired impairments in at least two cognitive domains causing at least mild interference with daily activities.
3. HAD. Individuals with clear sensorium and with more severe acquired impairments in at least two cognitive domains sufficient to produce marked interference with daily activities.
A recent study employing neurocognitive testing found that 69% of patients with HIV infection taking cART and without detectable virus in the blood or cognitive complaints had subtle cognitive impairments. Of 27% with cognitive complaints, 84% had HAND. Another recent study found HAND in 22% of a large cohort taking cART. Studies have demonstrated discordant presence of HIV in CSF despite absence of virus in blood, and specific HIV viral strains found in CSF, which vary from those found in plasma, and which may have different antiretroviral resistance patterns.
TABLE 44.1 Entities Causing Neurologic Complications in AIDS
Encephalopathy
Diffuse
HIV
PML
CMV
VZV
Syphilis
Toxoplasmosis
Aspergillosis
Toxic (medications)
Metabolic (e.g., hypoxia and sepsis)
Focal
Toxoplasmosis
PML
Lymphoma
Cryptococci
CMV
HSV
VZV
Syphilis
Tuberculosis
Fungal abscess
Nocardia asteroids
Pyogenic abscess
Myelopathy
HIV
CMV
HSV
VZV
Syphilis
Lymphoma
Tuberculosis
Toxoplasmosis
Vitamin B12 deficiency
Nocardia asteroides
Pyogenic abscess
Meningitis
HIV
Cryptococci
Syphilis
Tuberculosis
Lymphoma
CMV
HSV
VZV
Other fungi
Neuropathy
HIV
Toxic (e.g., dideoxynucleosides)
CMV
Lymphoma
Syphilis
Vitamin B12 deficiency
Myopathy
HIV
Toxic (zidovudine)
Toxoplasmosis
Pyogenic
CMV
Abbreviation: HSV, herpes simplex virus.
TABLE 44.2 Criteria for HAND
A. HIV-associated ANI
Acquired impairment in cognitive functioning involving at least two ability domains
Cognitive impairment does not interfere with daily functioning
Criteria for dementia or delirium are not present
No evidence for an alternative etiology for the ANI
B. HIV-associated MND
Acquired impairment in cognitive functioning involving at least two ability domains
Cognitive impairment produces at least mild interference in function at work, home or in social activities
Criteria for dementia or delirium are not present
No evidence for an alternative etiology for the MND
C. HAD
Acquired impairment in cognitive functioning involving at least two ability domains
Marked interference in function (e.g., inability to work, manage affairs, etc.)
Criteria for delirium not present (clear sensorium)
No evidence of another cause for the dementia
Abbreviation:
MND, mild neurocognitive disorder. Adapted from Antinori A, Arendt G, Becker JT, et al. Updated research nosology for HIV-associated neurocognitive disorders. Neurology. 2007;69:1789–1799.
Comorbid conditions may contribute to cognitive impairment in HIV-infected patients including concurrent hepatitis C virus infection, CNS active medications, substance use, and age-related cognitive changes. cART may alter lipid metabolism with accelerated atherosclerosis increasing the risk of cerebrovascular disease with related cognitive deficits.
The pathogenesis of HAD is not well-understood. Pre-cART autopsy studies demonstrated multinucleated giant cells containing HIV, myelin pallor, microglial nodules, and loss of neurons and synaptic density. cART era studies have found less significant correlations between the first three elements and clinical impairments. Neurons are not infected by HIV and die in locations remote from the perivascular macrophages and microglia that harbor the virus. Indirect neurotoxicity resulting from soluble factors released by infected cells causing activation of inflammatory mechanisms and disruption of critical trophic influences which culminate in neuronal apoptosis and neurite damage are pathogenic hypotheses that are currently favored.
1. Clinical features. A clinical triad of cognitive impairment, behavioral changes, and motor impairment characteristic of HAD was described early in the AIDS pandemic. Cognitive features include slowness of thought processing, perseveration, impairments of complex attention, and impaired recall of acquired memories. Behavioral features include apathy, withdrawal from social interaction, and depression. Uncommonly, mania or atypical psychoses occur. Motor features include hyper-reflexia, hypertonia, ataxia, and tremors, typically affecting the legs initially but also involving fine motor coordination of the upper extremities. Extrapyramidal features including bradykinesia, facial masking, rigidity, and postural instability may be seen.
In cART treated patients, these features are attenuated and the temporal course is prolonged. Psychomotor slowing, lassitude, and mild extrapyramidal or fine motor impairments are most commonly seen. The impact can be significant nonetheless, both on the more demanding aspects of daily activities and by altering adherence to cART regimens resulting in loss of viral suppression. Individuals may have mild cognitive abnormalities on testing but no apparent changes in daily functioning. Performance fluctuation on cognitive tests is seen in more mildly affected individuals with some improving and others evolving to more severe impairments.
2. Diagnosis. A clear sensorium is a requisite for the diagnosis. Evidence of functional impairment often comes to attention from impaired work performance or reports from a companion who assumes responsibility for handling funds and documents. Withdrawal from social activities is common, and depression may be a comorbid feature. A cognitive screening protocol employing the trailmaking and digit symbol tests has been used with reasonable sensitivity in large clinical trials and can be done quickly as part of a routine examination. OIs (see the following sections) must be excluded with MRI and CSF analysis, and comorbid metabolic conditions, medications with CNS effects, and influences of recreational drugs or alcohol should be excluded.
MRI in HAND may be normal, demonstrate atrophic changes, or reveal a confluent symmetric leukoencephalopathy. CSF is normal or shows mild-to-moderate protein elevation. In the cART era, many patients with asymptomatic or mild impairments are not severely immune suppressed. Neurocognitive measures are sensitive but must be compared with appropriate normative populations with similar age, educational level, ethnicity, and gender. Depression can be evaluated with instruments such as the Beck depression screening test.
3. Therapy.
a. Antiviral agents. Zidovudine, in high doses, which inhibits HIV reverse transcriptase and penetrates into CSF reasonably well, was the first antiretroviral agent shown in a controlled prospective trial to have efficacy in HAD, as measured by serial cognitive testing. Currently, cART therapy with combinations of anti-nucleosides, non-nucleoside reverse transtriptase inhibitors, protease inhibiting agents, and integrase inhibitors has been associated with a marked reduction in the frequency of HAD. Optimal suppression of HIV viral load should be sought as measured by highly sensitive plasma assays. CSF viral load should also be assessed including individuals with HAND despite undetectable HIV in plasma.
There is no established optimal cART regimen for HAND; however, antiretroviral resistance testing of recovered virus from blood and CSF can aid in the selection of a cART regimen. Although conflicting reports exist regarding the value of selecting agents with higher CSF penetration, such as stavudine, zidovudine, abacavir, efavirenz, nevirapine, and indinavir for combination regimens, or the use of CSF HIV viral load suppression as a marker of treatment efficacy, these measures are often employed, particularly in patients with worsening cognition. New strategies targeting mediators of neurotoxicity are being explored and a search for reliable and timely surrogate markers of CNS disease is an area of current active research. Individuals who qualify should be offered the option of such clinical trials when available.
b. Supportive therapy.
Apathy and withdrawal can be managed with modafenil 200 to 400 mg daily (not an FDA approved indication) or methylphenidate at 5 to 10 mg two or three times a day.
Depression is usually managed with selective serotonin reuptake inhibitors such as fluoxetine or others. Tricyclic antidepressants such as nortriptyline at initial dosages of 25 mg at bedtime, increasing in 25-mg increments every 1 to 2 weeks (or similar agents at comparable doses) are alternatives; however, anticholinergic effects of these drugs can precipitate delirium.
Seizures occur with increased frequency in HIV-infected patients. Because of potential interactions with antiretroviral agents, nonenzyme-inducing anticonvulsants, which are not metabolized by the cytorchrome P-450 system, such as leviracetam, lamotrigine, gabapentin, or pregabalin are preferred.
Supervision. Progression of HIV-associated cognitive change results in loss of ability to manage personal business and financial affairs. Provisions for assistance and ultimately legal transfer of decision-making powers for both financial and health care decisions, and advance health care directives, should be arranged. Assistance in the home may be needed for the provision of meals and facilitation of personal care. Residence in a sheltered facility can be considered when the need for assistance precludes independent living.
4. Outcome. cART has reduced the severity and mortality of HAND; however, by prolonging survival of patients with HIV infection, it may also lead to an increase in prevalence of cognitive impairment. The natural history of HAND in the era of successful cART is currently evolving.
B. HIV myelopathy. Neuropathologic evidence of myelopathy has been found at autopsy in up to half of patients with AIDS, although it affects fewer patients clinically. In the cART era, the frequency appears to be decreasing. Vacuolar changes with foamy macrophages are found predominantly in the myelin of the dorsal and lateral columns of the thoracic spinal cord, resembling changes seen in subacute combined degeneration (see Chapter 45). Signs of active HIV infection such as microglial nodules and infected macrophages are not associated. The specific cause is unknown; however, a deficiency of transmethylation pathways has been hypothesized.
Rarely, an acute self-limited meningomyelitis has been reported as a seroconversion reaction to HIV.
1. Clinical features. Insidiously progressive spastic paraparesis and sensory ataxia with neurogenic bladder dysfunction are typical of vacuolar myelopathy.
2. Diagnosis is made on the clinical features once other causes of chronic myelopathy have been excluded, particularly vitamin B12 (cobalamin) deficiency, syphilis, human T-cell lymphotropic virus type I infection, and indolent OIs. Myelopathy resulting from recreational inhalation of nitrous oxide or toluene can mimic vacuolar myelopathy. MRI of the spinal cord can be normal or reveal atrophy or nonspecific intramedullary T2 signal abnormalities. CSF should be obtained to exclude other conditions.
3. Therapy. No specific therapy has been shown to prevent the progression of myelopathy. Although optimizing cART is recommended, no favorable effect on the neurologic deficits has been demonstrated.
Supportive therapy is beneficial. Spasticity can be managed with baclofen in divided doses up to 80 mg daily, and/or tizanidine which is more sedating and may be limited to evening use starting at 2 to 4 mg. Anticholinergic agents such as oxybutynin at 2.5 to 5.0 mg three or four times a day may relieve urinary frequency, urgency, and incontinence.
External supports enhance safer mobility in patients with sufficient leg strength. Motorized scooters or wheelchairs can maintain mobility in weaker patients who are otherwise capable of independent activity.
4. Outcome. Most patients with HIV myelopathy follow a slowly progressive course that may stabilize for long periods of time. A long survival time with cART has resulted in a need to manage chronic disability with periodic neurologic evaluation to adjust supportive therapy. Abrupt neurologic changes should prompt evaluation for a superimposed opportunistic process.
C. HIV (DSP). DSP may be the most common neurologic disorder associated with HIV infection producing symptoms in up to 50% of those with advanced infecton. Despite a diminished incidence in some cohort studies since the widespread availability of cART, and the reduced use of neurotoxic antiretroviral agents, a strong association with age and the longer survival of HIV-infected patients may result in continued significant morbidity from this condition.
1. Pathology. DSP is a dying back axonal neuropathy predominantly affecting distal small unmyelinated fibers with involvement of myelinated fibers in more severe cases. Direct infection of the nerve fibers has not been shown, and the pathogenesis is currently thought to result from toxic cytokines released by activated immune cells.
2. Clinical features. The most prominent symptom of DSP is pain, characterized by symmetric burning, stabbing, or shooting discomfort, which can be disabling in severity. Initial symptoms often include paresthesias and numbness, beginning in the feet and gradually ascending, which may involve the distal upper extremities. With involvement of larger fibers, balance is affected. Examination reveals distal impairment of vibration, pin and temperature perception, and absent or diminished ankle reflexes. Sensory ataxia and weakness of small muscles in the feet, such as extensor hallucis, are not uncommon.
3. Diagnosis. The diagnosis is clinical and follows exclusion of other causes of small fiber neuropathy, particularly a toxic neuropathy associated with dideoxynucleoside antiretroviral agents (didanosine and stavudine), which is clinically identical, and differentiated by the onset of symptoms within months of initiating these agents. Other causes of neuropathy in this population such as glucose intolerance, vitamin B12 deficiency, and hepatitis C infection may mimic or influence the neuropathic features. Electrophysiologic changes may be modest due to the predominantly small fiber involvement; however, reduced distal sensory nerve action potentials and slowing of nerve conduction velocities may be seen. Quantitative sensory testing may be more sensitive.
4. Therapy.
a. There is no established therapy for DSP, and treatment is directed at symptom relief.
b. Pain relief is important to optimize function and improve quality of life. There are no agents currently approved by the FDA for the treatment of HIV painful neuropathy, and regimens for treating other neuropathic pain syndromes are employed including anticonvulsants, antidepressants, and nonspecific analgesics including opioids.
c. Antiretroviral therapy has not been convincingly shown to modify the course of the neuropathy; however, higher plasma viral load has been associated with pain severity in some studies and should be addressed.
d. Neurotoxic agents should be discontinued whenever possible, particularly dideoxynucleosides. Toxic neuropathy may persist for 6 to 8 weeks after discontinuation of these agents, and occasionally may temporarily worsen.
e. Any metabolic deficiencies should be corrected.
f. Topical lidocaine or capsaicin formulations may be effective adjuvants.
g. Nonpharmacologic approaches such as acupuncture, transcutaneous electrical nerve stimulation, biofeedback, and relaxation therapies can be tried.
5. Outcome. Symptomatic management can be helpful in alleviating discomfort, but reversal of DSP is unlikely. Acute worsening of DSP sometimes occurs when concurrent pathologies are superimposed.
D. Inflammatory demyelinating polyneuropathy (IDP). Acute IDP usually occurs early in the course of HIV infection and may represent a response to seroconversion. The natural history is similar to that of Guillain–Barré’s syndrome (GBS) in non-HIV infected persons and is presumed to result from an immune reaction to the virus that also targets peripheral myelin. Chronic IDP also results from immune-mediated demyelination and may be relapsing or progressive.
1. Clinical features. Acute IDP manifests as progressive motor weakness, areflexia, and variable sensory and autonomic symptoms that evolve over days, usually beginning in the distal lower extremities and ascending.
Some cases progress to respiratory insufficiency necessitating mechanical ventilatory support. Chronic IDP may follow a progressive or relapsing course over months with similar motor weakness and areflexia but with more prominent sensory impairment.
2. Diagnosis. Typical clinical features are suggestive of IDP. Electrophysiologic studies reveal prominent slowing and motor nerve conduction blocks, prolonged or absent F-wave responses, and variable degrees of axonal damage and denervation. CSF shows prominent protein elevation and in contrast to typical GBS, may be associated with moderate lymphocytic pleocytosis.
3. Therapy.
a. Plasma exchange with a total course of 200 to 250 ml per kg divided into five exchanges over a 2-week period with 5% albumin replacement is effective. An alternative therapeutic option is the use of pooled human immune globulin in dosages of 0.4 g/kg daily for 5 days given as an intravenous (IV) infusion at 0.05 to 4.0 ml/kg/hour as tolerated. IgA deficiency should be excluded before initiating immune globulin transfusions. Patients with chronic IDP need maintenance therapy with one treatment every 2 to 4 weeks. Intervals can be gradually extended as response occurs.
b. Patients with impending respiratory failure (vital capacity <1,000 ml) need elective intubation until adequate respiratory function returns.
c. Adjunctive therapy is important to prevent complications of immobility and maintain function in anticipation of neuromuscular recovery. Prophylaxis for venous thrombosis should be maintained until patients are ambulatory. Physical therapy should be initiated at the bedside with passive range of motion to prevent contracture formation advancing to more vigorous therapy with improvement in strength. Neuralgic pain can be treated as in DSP (see II.C.). As strength improves, mobilization may require support devices and orthotics.
4. Outcome. Acute IDP resolves with recovery in most patients. Chronic IDP has a more variable outcome, and residual neurologic impairment often persists.
E. HIV myopathy. Myopathy may develop in patients with HIV infection as a result of zidovudine toxicity, HIV-related polymyositis, or, rarely, infection with opportunistic pathogens. Zidovudine myopathy usually appears after at least 6 months of treatment and is thought to result from mitochondrial toxicity. The pathogenesis of HIV myopathy is thought to be an autoimmune myositis. Uncommonly, opportunistic myositis due to toxoplasmosis or other agents can occur in immunocompromised patients.
1. Clinical features. Symmetric progressive proximal weakness with elevation of serum creatine kinase levels is typical of HIV and zidovudine myopathy. Myalgia is variable.
2. Diagnosis. Clinical features are suggestive. Electromyography demonstrates small myopathic motor unit potentials with increased recruitment, fibrillation, and complex discharges. Concurrent neuropathy is not uncommon. Muscle biopsy may reveal scattered muscle fiber degeneration and inflammatory infiltrates of CD8+ T lymphocytes and macrophages. Mitochondrial abnormalities and inclusions such as nemaline rod bodies may be present.
3. Therapy. Patients taking myotoxic agents should discontinue them. For worsening patients and those with acute severe myalgia and immune compromise, biopsy should be considered to exclude opportunistic or inflammatory myositis. Corticosteroids may be started for immune myositis at 40 to 60 mg per day and tapered as response allows. An increased risk of opportunistic infections is associated with steroid therapy in more immune suppressed patients.
4. Outcome. Most patients respond to either withdrawal of toxic agents or institution of steroid therapy. Lack of response to empiric measures should prompt muscle biopsy.
F. Aseptic meningitis or meningoencephalitis may appear acutely with HIV seroconversion. Typical symptoms of headache, fever, neck stiffness, and occasionally cranial neuropathy and confusion or lethargy are seen. This condition is often self-limited. A chronic subclinical, aseptic meningitis occurs in many patients with HIV infection. Moderate protein elevation, a modest lymphocytic pleocytosis, elevated gamma globulin index, and occasionally oligoclonal bands are seen. The importance of this condition lies primarily in its potential for causing diagnostic confusion during evaluation for possible neurosyphilis or OI.
III. OPPORTUNISTIC ILLNESSES
OI of the nervous system are currently seen less frequently in patients with HIV infection as a result of cART; however, they continue to occur as presenting manifestations of AIDS, and in patients who have poor responses or lack access to current therapeutic regimens. Due to limitations of space, only the most common OIs are reviewed here. More extensive discussions can be found in the references.
A. Cryptococcus. Cryptococcus neoformans is the most common opportunistic pathogen causing meningitis in patients with AIDS. In addition to meningitis, it can cause localized cryptococcomas in brain parenchyma. Extra-neurologic cryptococcal infection can be found in lung, bone marrow, liver, urinary tract (prostate), and skin. The fungus is acquired through inhalation and spreads to the CNS hematogenously.
1. Clinical features. The most common presentation is meningitis with symptoms of headache, malaise, and fever. Nausea is associated in approximately one-half and meningismus occurs in one-fourth to one-third of HIV-associated cases. Cranial neuropathy is the most common focal impairment. Papilledema and altered mentation may be seen, and elevated intracranial pressure (ICP) is common. Seizures and focal CNS signs may be observed with parenchymal involvement, and cerebral infarctions due to cryptococcal meningitis have been reported.
2. Diagnosis. Imaging studies may be normal or show meningeal enhancement in patients with meningitis. Parenchymal cryptococcoma has variable enhancement patterns. Cystic lesions caused by the extension of organisms into Virchow–Robin’s spaces are most often seen in the basal ganglia and do not enhance. Lumbar puncture usually yields CSF under increased pressure. CSF pleocytosis is often modest and may be absent in patients with advanced immune suppression. Depressed glucose and elevated protein levels vary. CSF cryptococcal antigen titers are usually positive, and CSF cultures yield cryptococci in patients with meningitis; however, results of both tests may be negative when isolated crypotcoccomas occur. Definitive diagnosis of isolated parenchymal lesions requires biopsy. Serum cryptococcal antigen is highly sensitive and is positive in 99% of cases, but is not specific for meningitis. Blood cultures may reveal the organism.
3. Therapy.
a. Mortality in cryptococcal meningitis most often occurs in the first 2 weeks. Acute therapy with amphotericin B 0.7 to 1.0 mg per kg a day plus flucytosine 100 mg per day for 2 weeks is recommended for patients with normal renal function. Liposomal amphotericin B at 4 mg/kg/day, or amphotericin B lipid complex at 5 mg/kg/day can be substituted in patients with renal insufficiency. For patients unable to tolerate amphotericin B, high dose fluconazole (800 to 1200 mg per day) has been used with higher doses being more effective. Flucytosine can be used with fluconazole for acute therapy with some increased risk of toxicity. In patients responding to acute treatment, consolidation therapy with fluconazole 400 mg twice a day is given for 8 weeks or until sterile CSF cultures are obtained.
b. Adjunctive therapy. Aggressive management of increased ICP is required with serial lumbar punctures and, if necessary, lumbar drains or ventriculoperitoneal shunts. The goal of treatment is to maintain ICP in the normal range. Acetazolamide therapy is not recommended as it has been associated with increased adverse events.
HAART should be initiated but may be associated with an immune reconstitution inflammatory syndrome (IRIS) in up to 30% of cases, which may mimic persistent or recurrent meningitis (see III.J.).
c. Maintenance therapy. Successful sterilization of CSF with induction therapy is followed by maintenance therapy with fluconazole at doses of 200 mg per day until successful restoration of immune function with cART.
4. Outcome. The acute mortality for cryptococcal meningitis in retrospective series of patients with AIDS ranges from 11% to 45%, with the majority of deaths during the first 2 weeks. The most important prognostic factor is the degree of obtundation at presentation and the presence and response to treatment of increased ICP. Other factors reported to negatively affect prognosis are CSF cryptococcal antigen titers greater than 1:1,024, extra-neurologic cryptococcal infection, and hyponatremia. CSF should be sampled after completion of acute induction therapy. Persistently positive cryptococcal cultures should be managed with continued higher doses of antibiotics. Serum cryptococcal antigen cannot be used to monitor CSF response.
B. CNS toxoplasmosis. Toxoplasma gondii is an intracellular parasite acquired by ingestion which typically remains dormant in the absence of immune suppression. CNS toxoplasmosis remains the most common opportunistic encephalitis and cause of CNS mass lesions in patients with AIDS.
1. Clinical features. The most common presentation is a subacute multifocal encephalitis beginning with headache and fever followed by progressive focal and diffuse neurologic deficits appearing over days to weeks. Impaired mentation, hemiparesis, and ataxia are commonly seen. Involvement of the basal ganglia can result in movement disorders. Acute presentation with seizures can occur, and rare instances of chronic diffuse encephalitis mimicking dementia and isolated myelitis have been reported.
2. Diagnosis. MRI reveals multiple enhancing lesions in most patients; however, isolated mass lesions can occur in up to 14% of patients and nonenhancing infarction-like patterns, meningoencephalitis, and myelitis have been reported. The appearance of the mass lesions is nonspecific, although a signet ring sign has been suggested to be highly suggestive when present. IgG antibodies to Toxoplasma organisms are present in the blood in almost all cases; however, IgM antibodies and convalescent increases in IgG titers are not seen, and rare cases of seronegative pathologically proven toxoplasmosis have been described. Specific antibodies to T. gondii, and ToxoplasmaDNA, can be detected in CSF. Definitive diagnosis requires pathologic demonstration of organisms or their DNA. Radionuclide imaging with thallium single photon emission computed tomography (SPECT) may be helpful in differentiating abscesses from primary CNS lymphomas (PCNSL), but does not distinguish TE from other abscesses. Diagnostic brain biopsy is indicated in patients with negative serology for T. gondii and single lesions, or for lesions worsening or failing to respond to antibiotic therapy directed at the organism.
3. Therapy.
a. Because of the typically rapid response to therapy, empiric treatment of patients with AIDS and cerebral lesions suggesting TE, and positive serology for T. gondii is warranted. A clinical response is expected within 2 weeks. Optimal therapy combines oral sulfadiazine at 1.5 to 2 g every 6 hours and pyrimethamine in an initial dose of 100 to 200 mg followed by 50 mg per day. Folinic acid at 10 to 15 mg per day is added to counteract myelosuppression from the pyrimethamine. Patients unable to take sulfa can substitute clindamycin at 600 mg every 6 hours with similar efficacy for acute infection, although subsequent relapse rates may be higher. Atovaquone and azithromycin have also been used in the place of sulfa. Severely ill patients unable to take oral medication have been treated with IV clindamycin or trimethoprim-sulfamethoxazole. Corticosteroids should be avoided in patients treated empirically for TE to prevent diagnostic confusion with CNS lymphoma.
b. Successful initial therapy is continued for 6 weeks or until stable regression of all lesions. Maintenance therapy with sulfadiazine at 500 mg four times a day or clindamycin at 300 mg four times a day, combined with pyrimethamine at 50 mg per day and folinic acid 10 mg per day is continued until stable immune restoration is achieved with cART.
4. Outcome. Therapeutic monitoring is particularly important for patients treated empirically for CNS toxoplasmosis. Imaging should be repeated 2 to 3 weeks after the initiation of antibiotic therapy. Failure of lesions to respond should prompt brain biopsy. Biopsy should be considered for any lesion that enlarges despite therapy to exclude an alternate or concurrent process.
C. CNS lymphoma: PCNSL has become less frequent with the widespread use of cART. Almost all are B cell lymphomas containing Epstein–Barr’s virus (EBV) DNA. Patients with AIDS may also have leptomeningeal lymphoma, usually due to seeding from a cerebral tumor or to metastasis of a systemic lymphoma.
1. Clinical features. Symptoms usually evolve over weeks, and diagnosis may be delayed by empiric therapy for presumed toxoplasmosis. Subacutely progressive headache, lethargy, cognitive impairment, and focal neurologic deficits related to tumor location, such as hemiparesis, aphasia, ataxia, or visual field deficits, are common manifestations. Seizures may cause acute presentations. Meningitis, meningoencephalitis, or meningoradiculitis with cranial nerve abnormalities are commonly seen in patients with leptomeningeal lymphoma.
2. Diagnosis. PCNSL is usually, but not invariably, contrast enhancing. Single or multiple lesions with diffuse or ring enhancement may be seen. Lesions may be difficult to differentiate from CNS toxoplasmosis or other cerebral abscesses by MRI. SPECT may show increased uptake in PCNSL, in contrast to decreased activity in an abscess, although sensitivity and specificity varies across studies. Brain biopsy is usually required for the diagnosis of PCNSL. MRI may be normal or reveal meningeal enhancement with leptomeningeal lymphoma and diagnosis is usually made on CSF cytologic analysis. Detection of EBV DNA in CSF suggests lymphoma that is confirmed by malignant cells.
3. Therapy. Effective cART has had a favorable influence on survival in PCNSL patients and should be aggressively pursued. Cranial irradiation is independently associated with prolonged survival. Limited data are available on chemotherapy which is poorly tolerated in immune suppressed patients. Regimens with antiviral effects directed at EBV might plausibly offer benefit but are yet to be shown effective.
4. Outcome. Prognosis of CNS lymphoma in AIDS remains poor with mean survivals measured in months; however, effective cART has had some benefit on prognosis and longer survivals are occasionally seen.
D. Progressive multifocal leukoencephalopathy (PML). Prior to the cART era, PML was estimated to affect 4% of AIDS patients and was a presenting illness in up to 20% of these. The incidence has since declined although not to the extent of other OIs. PML results from reactivation of a polyoma virus, JC virus (JCV). The majority of adults have antibodies to JCV indicating prior exposure to the virus and latency. In the setting of immune suppression, possibly linked to the loss of specific CD8+ cytotoxic T-lymphocytes, symptoms of PML may appear.
1. Clinical features. Subacute cognitive impairment, visual field defects, hemiparesis, ataxia, and speech or language disturbances evolving over weeks are typical presentations. Some patients come to medical attention with seizures or acute stroke-like presentations while others may evolve over several months.
2. Diagnosis. MRI typically demonstrates asymmetric lesions in cerebral white matter on T2-weighted sequences. A scalloped appearance reflecting involvement of the subcortical arcuate fibers is suggestive when present. Frontal, parietal, temporal, basal ganglia, cerebellar and brainstem lesions may be seen. In contrast to other settings in which the disease occurs, PML lesions in AIDS enhance following contrast infusion in a minority of cases, usually in relatively less immune suppressed patients. Single lesions are sometimes seen. Definitive diagnosis requires confirmation of JCV infection, either in CNS tissue obtained at biopsy, or by demonstration of JCV DNA in CSF in a patient with compatible clinical and imaging features. High-sensitivity JCV polymerase chain reaction (PCR) assays which can detect 50 copies per ml or less should be used to analyze CSF.
3. Therapy. Currently, only effective cART has been shown to benefit AIDS-associated PML. CNS IRIS is a potential complication following effective cART therapy and may be difficult to distinguish from worsening PML (see discussion of IRIS in III.J.). Controlled trials with cytosine arabinoside and cidofovir have failed to show additional benefit in HIV-infected cohorts. Case reports suggest possible benefit with mirtazapine but no controlled study has been done. A recent trial of mefloquine was discontinued following an interim analysis.
4. Outcome. In the pre-cART era, median survivals were about 6 months, although some patients with less severe immune suppression survived longer. Effective cART therapy has extended survival to years, usually with residual neurologic impairments. Higher JCV load in CSF may be associated with poorer prognosis. Return of specific JCV cytotoxic CD8+ immune cells has been associated with better prognosis. IRIS may occur with institution of cART.
E. Cytomegalovirus (CMV). CMV is ubiquitously acquired, and serologic evidence of exposure is present in most adults. Although a transient systemic illness may occur on acquisition, normal immune function prevents further manifestations. The most common symptomatic CMV infections in patients with AIDS occur in the retina and gastrointestinal tract.
1. Clinical features.
a. CMV encephalitis (CMVE) is characterized by subacute confusion, delirium, impaired attention, memory, and cognitive processing with varying focal signs, including cranial neuropathy, nystagmus, weakness, spasticity, and ataxia. Clinical symptoms evolve over weeks in severely immune suppressed patients. Focal encephalitis with mass lesions or aseptic meningitis can also occur.
b. CMV polyradiculomyelitis (CMVRM) presents as a subacute motor weakness with areflexia and sphincter dysfunction (usually urinary retention) evolving over days to weeks (see Chapter 46). Painful paresthesias in the perineum and lower-extremities, and features of myelopathy such as a sensory level and Babinski’s signs, may be found on examination. Symptoms in the lower extremities may ascend resembling GBS.
c. CMV multifocal neuropathy is characterized by motor weakness, depressed reflexes, and sensory deficits involving nerves of both upper and lower extremities in an asymmetric pattern evolving over weeks to months. Motor features overshadow the sensory findings.
d. Less commonly, CMV can cause meningomyelitis or myositis.
2. Diagnosis. The clinical syndromes are suggestive, but are not pathognomonic for CMV OI in severely immune suppressed AIDS patients. MRI with gadolinium contrast may reveal enhancement of ventricular ependyma with CMVE, of meninges in some patients with meningoencephalitis or meningomyelitis, and of lumbar nerve roots and conus medullaris in some patients with CMVRM. Normal findings or nonspecific atrophic changes may also be seen. CSF studies in CMVRM characteristically reveal a mixed pleocytosis with a prominent polymorphonuclear component, hypoglycorrhachia, elevated protein. In CMVE, pleocytosis is less common. CSF is normal or reveals nonspecific protein elevation in patients with CMV multifocal mononeuropathy.
Demonstration of CMV DNA in CSF using PCR amplification techniques is both a sensitive and a specific indicator of active CMV infection. Patients with AIDS and CMV infection of the nervous system typically have systemic infection as well.
3. Therapy. No controlled treatment studies of opportunistic CMV infections of the nervous system have been carried out. Three virustatic agents are available for the management of active CMV infection in AIDS, and some authors recommend combination therapy for the treatment of patients with CNS CMV disease, although this may be associated with more toxicity.
a. Ganciclovir is given in an induction dosage of 5 mg per kg IV twice a day for 14 to 21 days followed by a maintenance dosage of 5 mg per kg a day.
b. Foscarnet has better CSF penetration than does ganciclovir. An induction dosage of 90 mg per kg IV twice a day for patients with normal renal function is given for 14 to 21 days and followed by reduction to a maintenance dosage of 90 to 120 mg per day. Doses must be reduced for patients with renal insufficiency.
c. Cidofovir in the setting of normal renal function is given as an IV infusion at 5 mg per kg in 1 L of fluid once a week for 2 successive weeks and then every 2 weeks. The dose must be decreased for impaired renal function, and additional hydration with a second liter of fluid is recommended if tolerable. Probenecid 2 g orally is given 3 hours before the infusion and then 1 g is given 2 and 8 hours after completion of the infusion. Ocular monitoring for hypotony and renal function monitoring are required.
d. Viral resistance may develop to any of these agents during prolonged therapy, and CMV neurologic disease emerging during maintenance therapy for CMV retinitis or enteritis should be managed with induction dosages of alternate agents. Even when drugs have failed individually, patients may respond to combined therapy.
4. Outcome. No prospective studies are available to guide therapy for CMV neurologic disease in AIDS. Responses to therapy for CMVE, CMVRM, and multifocal neuropathy are reported anecdotally. Immune suppressed patients should continue maintenance therapy, although the optimal regimen is unknown. CSF studies may be the best markers of neurologic disease activity and should be performed on the completion of induction therapy and for neurologic worsening.
F. Varicella–zoster virus (VZV). VZV commonly occurs in patients with HIV infection at multiple stages of the disease and may produce encephalitis, myelitis, and mono or polyradiculitis. The virus, which causes chickenpox, is acquired early in life and resides latently in sensory ganglia, where it can intermittently produce recurrent radiculitis. Retrograde extension to the CNS along contiguous sensory roots and fiber tracts has been shown to occur. Patients with radiculitis often have self-limited dermatologic eruptions, which may be accompanied by prolonged neuralgia. CNS extension may be marked by vasculitis resulting in cerebral infarction, particularly after ophthalmic zoster, and can result in necrotizing myelitis and brainstem, focal or diffuse cerebral encephalitis.
1. Clinical features.
a. VZV radiculitis is characterized by painful paresthesias in a restricted dermatomal distribution of a spinal or trigeminal nerve root. A vesicular rash usually follows, but VZV can occur without the rash. The skin eruption typically heals over weeks; however, pain may persist.
b. VZV myelitis may be limited or progressive resulting in spastic weakness, sensory impairment, and sphincter dysfunction. Myoclonus is sometimes associated as is meningitis. Dermatomal VZV may or may not be associated.
c. Meningitis with lymphocytic pleocytosis, increased protein level, and depressed or normal glucose level may also be seen.
d. Polyradiculitis, which is clinically indistinguishable from CMVRM, can be caused by VZV.
e. VZV encephalitis can be focal or diffuse in patients with AIDS, manifesting as seizures, confusion, progressive language and cognitive impairment, and sensory or motor abnormalities. Progression can be gradual and the level of immune suppression more modest than with other OIs. Meningitis may be associated.
f. VZV vasculitis can cause acute focal features resulting from cerebral or spinal infarction, or diffuse leukoencephalitis due to small vessel involvement.
2. Diagnosis. When the characteristic dermatologic eruption occurs, diagnosis of radiculitis is not difficult. In patients with CNS disease, MRI may reveal focal or diffuse areas of high-signal intensity on T2-weighted images of brain or spinal cord. Enhancing focal lesions and meningeal enhancement may be seen. Confirmed diagnosis is based on the demonstration of viral DNA in CSF or tissue or an elevated specific VZV antibody index in CSF.
3. Therapy. Patients with HIV infection and VZV radiculitis should be treated with valacyclovir or famciclovir for 7 to 10 days. Neuralgia can be managed with pregabalin 75 to 150 mg twice a day, or gabapentin 300 to 600 mg three or four times a day. Amitriptyline 25 mg at bedtime may be added and increased by 25 mg per day at weekly intervals to 100 mg at bedtime. Some patients may benefit from topical application of capsaicin to the involved cutaneous area three or four times a day. Patients with VZV encephalitis or myelitis should be treated with IV acyclovir for 14 to 21 days at 10 to 12 mg per kg three times a day. Resistance of VZV to acyclovir has been reported, and refractory VZV CNS disease should be managed with foscarnet 60 to 90 mg IV twice a day for 10 to 21 days.
4. Outcome. Most patients with VZV radiculitis achieve resolution of the acute symptoms, although recurrences are common in immune suppressed individuals and may involve different dermatomes. The prognosis for progressive myelitis and encephalitis varies; however, limited anecdotal data suggest some patients respond to antiviral therapy.
G. Tuberculosis. Mycobacterium tuberculosis (MTB) causes tuberculous meningitis and cerebral mass lesions in HIV-infected patients. Tuberculous meningitis is more common and may evolve subacutely or chronically, often preceded by prodromal signs of systemic illness. Mass lesions include tuberculomas and cerebral abscesses that may evolve more acutely. It has been suggested that cerebral mass lesions are more frequent in HIV associated CNS tuberculosis. The pattern of pathology is influenced by the degree of immune suppression with less granuloma formation in those with lower CD4+ cells counts. Neurologic involvement is more common with immune suppression. In the United States, increased risk is associated with IV drug use, migration from countries with high MTB prevalence, and among individuals who live and work in close contact settings.
1. Clinical features. In patients with AIDS and MTB infection, the most common neurologic presentation is meningitis or meningoencephalitis marked by headaches, fever, myalgia, confusion, lethargy, cranial neuropathy, ataxia, seizures, or hemiparesis evolving over weeks. Contiguous extension of basal meningitis to blood vessels of the circle of Willis can result in vasculitis and cerebral infarction. Cerebral abscess formation results in focal symptoms, seizures, headaches, and signs of increased ICP. Tuberculous meningitis can also cause meningoradiculitis, myelitis, anterior spinal artery infarction, and epidural or intramedullary abscess formation. Tuberculous spondylitis can result in vertebral collapse with fever, back pain, and radiculopathy or compressive myelopathy.
2. Diagnosis. MRI may reveal focal abscesses in the brain that are indistinguishable from lesions of toxoplasmosis or CNS lymphoma. In MTB meningitis, areas of attenuation typical of infarction, meningeal thickening and enhancement, exudate in basilar cisterns, and hydrocephalus may be seen. CSF is often under increased pressure and reveals a mixed or predominantly lymphocytic pleocytosis, depressed glucose, and prominently elevated protein levels; however, benign CSF indices have been reported in some cases. Smears for acid-fast bacteria are uncommonly positive, although the yield improves somewhat with multiple specimens. CSF cultures may be negative in one-third of cases. Detection of MTB DNA by PCR and MTB antigen assays provide more rapid detection in CSF. Diagnosis of large tuberculous abscesses may require biopsy. Spinal MRI may reveal abscess formation and vertebral collapse in patients with meningitis or myelitis.
3. Therapy. Combinations of isoniazid 300 mg by mouth, rifampin 600 mg by mouth, ethambutol at 15 to 25 mg per kg a day by mouth and pyrazinamide at 15 to 25 mg per kg by mouth daily are recommended for the first 2 months, followed by INH and rifampin for the next 10 to 12 months in responders. Pyridoxine (50 mg per day) is added for patients taking isoniazid. Resistance of MTB to these agents is now observed more commonly, and isolates should be tested for sensitivity to the antibiotics employed. Resistance or lack of response to treatment should prompt infectious disease consultation to modify therapy. In patients with tuberculous meningitis, corticosteroids 0.3 to 0.4 mg/kg/day dexamethasone or 1 mg/kg/day prednisone are added for the first 3 weeks and then tapered over the next 3 to 5 weeks. IRIS is not uncommonly seen with reversal of immune suppression following cART (see III.J.).
4. Outcome. The mortality of AIDS-associated tuberculous meningitis has been reported to be as high as 33% and to be related to the degree of immune suppression. Patients with MTB meningitis need follow-up CSF studies 1 to 2 months after initiation of treatment and at completion of primary therapy to detect persistent infection from resistant organisms. Tuberculomas can be followed with serial imaging studies in the absence of life-threatening mass effects. Lesions that enlarge despite therapy should be reevaluated and considered for biopsy to detect resistant organisms or concurrent opportunistic processes.
H. Neurosyphilis. Although not strictly an opportunistic pathogen, overlapping risk factors and a potentially more aggressive course make Treponema pallidum infection a particular concern in patients with HIV infection. Increased frequency of CNS involvement and occasional failure of conventional therapy with emergence or recurrence of neurosyphilis despite standard courses of penicillin have been reported.
1. Clinical features. Meningitis, meningoradiculitis, meningovasculitis with infarctions of small vessels, meningomyelitis, and encephalitis can occur in patients with AIDS. Cranial neuropathy, headache, and fever may mark syphilitic meningitis, and polyradiculitis may result in a cauda equina syndrome similar to CMVRM. Luetic encephalitis and myelitis can be gradually or subacutely progressive. Mass lesions resulting from gumma formation may manifest with seizures, focal signs, and increased ICP.
2. Diagnosis. Aseptic meningitis with mononuclear pleocytosis and elevated protein associated with a positive venereal disease research laboratory (VDRL) test is considered diagnostic of neurosyphilis. A negative VDRL is not exclusionary of the diagnosis. Specific treponemal antibody assays in CSF, such as the direct fluorescent antibody—Treponemal Pallidum test and or the fluorescent treponemal antibody absorption test are more sensitive but less specific for neurosyphilis; however, they are exclusionary of neurosyphilis when negative in the CSF. Imaging studies may reveal infarctions in meningovascular syphilis, or masses in patients with gummas. Mass lesions are usually diagnosed at biopsy.
3. Therapy. Neurosyphilis should be treated with IV aqueous penicillin G at a dosage of 3 to 4 million units every 4 hours for 14 days. Procaine penicillin 2.4 million units intramuscularly once daily plus probenecid 500 mg orally four times a day for 14 days can alternatively be used in patients who are not allergic to sulfa. Some infectious disease specialists add 2.4 million units of intramuscular penicillin weekly for 3 weeks following the IV course. No other therapy has proven efficacy, and penicillin desensitization followed by one of the above regimens is preferred in patients with a history of penicillin allergy if possible. Ceftriaxone 2 g per day IV for 14 days may be an alternative treatment for patients severely allergic to penicillin who do not have cross-sensitivity to cephalosporins.
4. Outcome. Although the initial response is good, risk of recurrent neurosyphilis is increased in the setting of HIV infection. Patients with syphilitic meningitis should have CSF studies 3 months following the completion of treatment and at 6-month intervals until the CSF leukocyte count normalizes and the VDRL becomes non-reactive. Subsequent neurologic symptoms should prompt evaluation for recurrence.
I. Other opportunistic infections. Numerous other OIs have been described in HIV infected patients, and a fuller compilation is beyond the scope of this chapter. More extensive reviews are contained in the references below.
J. Immune reconstitution inflammatory syndrome. A potential consequence of the potency of current cART regimens is a rapid restoration of immune responsiveness, which may lead to clinical worsening during treatment, despite improving HIV disease markers, as a result of damage caused by an aggressive immune-mediated response. This is called IRIS and is most commonly seen with treatment of opportunistic infections in conjunction with institution or modification of cART. Some cases occur in the absence of OIs and are presumed to be an inflammatory response to HIV related antigens.
In some cases, a resident OI may be unmasked by the institution of cART and the vigorous immune response which follows, whereas in other instances, an initial improvement in an OI may be followed by clinical worsening, which may cause difficulties distinguishing between treatment failure of the OI and IRIS. Neurologic IRIS has been described with cryptococcus, toxoplasmosis, PML, CNS tuberculosis, CMV, VZV, EBV, and as a progressive encephalitis following initiation of cART when no OI is demonstrated.
Individuals naïve to cART, with low CD4+ counts and high HIV viral loads who experience rapid improvements in these measures appear to be most at risk. Onset usually occurs within 8 weeks of starting cART; however, some cases with longer intervals are reported. IRIS may occur without apparent symptoms detected by inflammatory activity on MRI, and may resolve spontaneously, or cause neurologic symptoms of such severity as to result in mortality. Pathologic reports of CNS IRIS have most commonly identified CD8+ lymphocyte infiltration from perivascular spaces with activated macrophages. MRI may show enlarged enhancing lesions with edema and mass effects suggestive of an inflammatory response in patients with CNS parenchymal disease.
1. Diagnosis. Diagnosis requires exclusion of recurrent or new concurrent infection or neoplasm to explain the clinical features. In cases where biopsy is pursued, a vigorous CD8+ inflammatory response in the absence of active infections suggests the diagnosis.
2. Therapy. There are no controlled studies addressing therapy. Both spontaneous resolution and resolution associated with corticosteroid therapy are reported. Current practice favors high-dose steroids for patients with severe neurologic symptoms and IRIS. Steroids may be required for several weeks or months and should be gradually tapered to prevent rebound inflammation on withdrawal.
Recommended Readings
Antinori A, Arendt G, Becker JT, et al. Updated research nosology for HIV-associated neurocognitive disorders. Neurology. 2007;69:1789–1799.
Canestri A, Lescure FX, Jaureguiberry S, et al. Discordance between cerebral spinal fluid and plasma HIV replication in patients with neurological symptoms who are receiving suppressive antiretroviral therapy. Clin Infect Dis. 2010;50:773–778.
Cysique LA, Vaida F, Letendre S, et al. Dynamics of cognitive change in impaired HIV-positive patients initiating antiretroviral therapy. Neurology. 2009;73:342–348.
Garvey L, Winston A, Walsh J, et al. Antiretroviral therapy CNS penetration and HIV-1-associated CNS disease. Neurology. 2011;76:693–700.
Gendelman H, Grant I, Everall IP, et al., eds. The Neurological and Neuropsychological Manifestations of HIV-1 Infection. 3rd ed. 2011.
Johnson T, Nath A. Neurological complications of immune reconstitution in HIV-infected populations. Ann N Y Acad Sci. 2010;1184:106–120.
Kaplan JE, Benson C, Holmes KK, et al. Guidelines for prevention and treatment of opportunistic infections in HIV-infected adults and adolescents. Morb Mortal Wkly Rep. 2009;58(RR-4):1–198.
Letendre S, Marquie-Beck J, Capparelli E, et al. Validation of the CNS penetration-effectiveness rank for quantifying antiretroviral penetration into the central nervous system. Arch Neurol. 2008;65:65–70.
Portegies P, Berger JR, eds. HIV/AIDS and the Nervous System. Handbook of Clinical Neurology. Vol 85, 3rd series. Amsterdam: Elsevier; 2007.