University of California, San Francisco Logo

University of California, San Francisco | About UCSF | Search UCSF | UCSF Medical Center

Neurologic
Neurologic Manifestations of HIV
transparent image
transparent image
transparent image
transparent image
HIV Neuropathogenesis
transparent image
transparent image
transparent imageEntry of HIV into the Central Nervous System
transparent image
transparent imagePathogenesis of AIDS Dementia Complex
transparent image
Overview of Clinical Neurologic Disease
transparent image
transparent image
transparent imageCerebral Symptoms and Signs
transparent image
transparent imageSyndromes Affecting Cord, Nerve Roots, and Muscle
transparent image
transparent imagePain
transparent image
Specific Neurologic Conditions
transparent image
transparent image
transparent imageNeuromuscular Disorders
transparent image
transparent image
transparent imageClassification of Neuromuscular Disorders
transparent image
transparent imageDistal Symmetric Polyneuropathy
transparent image
transparent imageMononeuropathy Multiplex
transparent image
transparent imageInflammatory Demyelinating Polyneuropathies
transparent image
transparent imageMitochondrial Toxicity: A Syndrome That May Mimic Guillain-Barré
transparent image
transparent imageProgressive Lumbosacral Polyradiculopathy
transparent image
transparent imageMyopathy
transparent image
transparent image
transparent imageSpinal Cord Disorders
transparent image
transparent image
transparent imageSubacute Myelopathies
transparent image
transparent imageAcute Myelopathies
transparent image
transparent image
transparent imageIntracranial Disorders
transparent image
transparent image
transparent imagePrimary HIV Infection of the Brain: HIV-1-Associated Dementia Complex
transparent image
transparent imageIntracranial Opportunistic Infections
transparent image
transparent imageNeoplasms
transparent image
transparent imageComplications of Systemic Diseases
transparent image
transparent image
Symptoms, Neurologic Signs, and Differential Diagnoses of Intracranial Disorders
transparent image
transparent image
transparent imageHeadache
transparent image
transparent imageSeizures
transparent image
transparent imageAltered Mental Status
transparent image
transparent imagePosterior Fossa Symptoms and Signs
transparent image
Diagnostic Studies
transparent image
transparent image
transparent imageComputed Tomography and Magnetic Resonance Imaging
transparent image
transparent imageLumbar Puncture
transparent image
transparent imageBrain Biopsy
transparent image
transparent image
References
transparent image
transparent image
Tables
Table 1.Neuromuscular Complications Associated with HIV Infection
transparent image
Table 2.Clinical Classification of the More Common Neuropathy Syndromes
transparent image
transparent image
Related Resources
transparent imageJournal Articles
transparent imageGuidelines and Best Practices
transparent imagePresentations, Interviews, and Roundtable Discussions
transparent imageSlide Sets
transparent image
transparent image
transparent image
transparent image
HIV Neuropathogenesis
transparent image

HIV is classified among the lentiviruses, a family of viruses characterized in part by their tendency to cause chronic neurologic disease in their animal hosts. It is not surprising, then, that neurologic complications of HIV infection are common and not confined to opportunistic infections. All levels of the neuraxis can be involved, including the brain, meninges, spinal cord, nerve, and muscle. Neurologic disease is the first manifestation of symptomatic HIV infection in roughly 10-20% of persons, while about 60% of patients with advanced HIV disease will have clinically evident neurologic dysfunction during the course of their illness.(1-3) The incidence of subclinical neurologic disease is even higher: autopsy studies of patients with advanced HIV disease have demonstrated pathologic abnormalities of the nervous system in 75-90% of cases.(1,4,5) In the United States and the European Union, where antiretroviral therapy is relatively available, peripheral neuropathy and HIV-associated cognitive dysfunction (including AIDS dementia) account for the greatest proportion of neurologic disease burden. In developing countries, opportunistic infections of the central nervous system (CNS) account for most of the reported neurologic morbidity and mortality in AIDS. Cryptococcal meningitis, fulminant bacterial meningitis, neurotuberculosis, toxoplasmosis, and neurosyphilis are common among HIV-infected individuals in Asia and Africa.

transparent image
Entry of HIV into the Central Nervous System
transparent image

HIV crosses the blood-brain barrier and enters the nervous system early, probably concomitant with initial systemic infection.(6) The virus has been cultured from brain, nerve, and cerebrospinal fluid (CSF) from persons at all stages of HIV disease, including those without neurologic signs or symptoms.(7,8) Positive HIV-1 cultures in CSF do not predict the presence or development of neurologic signs or symptoms later on. The development of neuroAIDS (neurologic manifestations of AIDS) depends on a number of factors, such as antiretroviral treatment history, degree of immunosuppression, and the molecular biology of the viral strain, particularly its neurovirulence.(9) Host factors, including genetic makeup, undoubtedly play a role in selective vulnerability to neuroAIDS, but are not yet well characterized.

The initial "seeding" of the nervous system by HIV-1 is usually asymptomatic, although acute aseptic meningitis, encephalitis, and inflammatory polyneuropathy have all occurred in this setting.(4)

Despite its potential to cause disease at all levels of the neuraxis, HIV-1 does not directly infect central or peripheral neurons, astrocytes, or oligodendroglial cells. Latent or low-level HIV infection in the CNS is maintained by virus-infected cells of the monocyte/macrophage lineage. "Indirect effects" of macrophage activation--such as dysregulation of cytokines and chemokines, free-radical (oxidative stress) injury, and secretion of soluble factors that are potently neurotoxic--have been implicated as effectors of nervous system injury in HIV.

Despite evidence of early infection of the CNS, symptoms of cognitive impairment typically occur late in symptomatic HIV disease, usually in the setting of severe immunosuppression.(10,11) However, the median CD4 cell count at diagnosis of dementia appears to be increasing, from 70 cells/µL in 1992-1995 to 170 cells/µL in 1997.(12)

transparent image
Pathogenesis of AIDS Dementia Complex
transparent image

The role of HIV-1 proliferation itself in the development of AIDS dementia complex (ADC) is controversial. Although viral strains that are particularly efficient at replicating in brain macrophages may play a role in the pathogenesis of brain injury,(13,14) a heavy "viral burden" in brain has not been linked consistently with clinical AIDS dementia.(15)

Some investigators hold that increased HIV-1 proliferation in the brain is necessary for the development of ADC. Others propose that a macrophage-initiated cascade of events can lead to brain dysfunction and clinical dementia, even in the absence of high viral load in the brain. Activated macrophages, whether infected with HIV or not, are capable of secreting potent neurotoxins, inducing pro-inflammatory cytokines, and generating oxygen free radicals that can damage cells and lead to neuronal dysfunction or death.(16-19) A particular subtype of monocyte/macrophages derived from the peripheral blood was found to be greatly increased among patients with AIDS dementia compared with both HIV-1-infected and -uninfected controls. Soluble factors from these macrophages were found to be highly neurotoxic--that is, they killed human brain cells in culture.(20)

Although the incidence of nearly all nervous system opportunistic infections has declined dramatically in the era of potent antiretroviral therapy, the impact on incidence and prevalence of HIV-associated cognitive impairment--including frank ADC--has been low. The prevalence of ADC in HIV-infected individuals with higher CD4 counts (200-350 cells/µL) actually appears to have increased since 1996.(12) Pathologically, the prevalence of HIV-associated brain disease, or encephalopathy, is rising despite suppressive antiretroviral therapy.(21)

Poor penetration of the blood-brain barrier by many of the antiretroviral drugs, particularly the protease inhibitors, has been suggested as a reason for the persistence of ADC. Unfortunately, there is currently no effective way to monitor successful suppression of CNS HIV infection, making selection of a CNS-penetrating antiretroviral regimen a matter of guesswork rather than clinical science. Patients with ADC commonly have no detectable virus in CSF. This does not exclude high viral burden in the brain, but rather emphasizes the limitations of CSF as a "window on the central nervous system." Nonetheless, HIV-1-infected macrophages in the CNS are considered an important anatomic reservoir for HIV, one capable of reseeding of the blood with replication-competent virus. Hence, antiretrovirals that cross the blood-brain barrier may be of benefit in limiting systemic reseeding of virus from the CNS compartment.

There is some evidence that, despite the poor CNS penetration of most antiretrovirals, effective antiretroviral therapy may attenuate the neurotoxicity of circulating monocytes/macrophages. Among individuals with ADC receiving effective antiretroviral regimens, macrophage-derived soluble factors were found to be less neurotoxic than observed prior to the availability of combination antiretroviral therapy.(20,22) Rather than killing neurons outright, macrophage secretions from subjects on effective HIV therapy cause a dysregulation of proteins critical to normal function. In other words, neurons appear to be "crippled," but not killed. Such changes in macrophage neurotoxicity among treated subjects may be a molecular correlate of a clinical change in ADC noted by some clinicians. Where antiretroviral therapy is available, ADC is typically a milder, more slowly progressing deterioration in mental function among HIV-infected patients, compared with the severe, rapidly progressing dementia seen earlier in the epidemic, and still seen among untreated individuals. These molecular and clinical observations are supported by newer imaging modalities, such as proton magnetic resonance spectroscopy, which show metabolic rather than structural changes in the brains of individuals with early-stage HIV-associated cognitive impairment.(23)

Despite a more insidious onset, other changes have been observed in the "new" ADC. Some HIV-infected individuals appear to have a dementia more akin to Alzheimer disease than typical ADC, with, for example, prominent disturbances in long-term memory. Is this simply a sign of the "graying" of the HIV-seropositive population? Greater than 10% of patients with AIDS in the United States are now over the age of 50--an age at which the incidence of Alzheimer disease begins to rise. Of potential significance is that some of the newer antiretroviral drugs themselves, by virtue of their effects on lipid metabolism and processing of amyloid, might theoretically increase the risk of Alzheimer disease. Chronic, low-grade brain inflammation, such as occurs in HIV-associated brain disease, may also play a role in vulnerability to Alzheimer disease.

Looking ahead, AIDS patients with dementia should be evaluated for cortical dysfunction as well as the subcortical cognitive dysfunction of "classical" ADC, to confirm whether or not the spectrum of cognitive dysfunction is widening to include an Alzheimer-disease phenotype. Quantitative assessment of cerebral amyloid plaques and tau protein-rich tangles--the hallmarks of Alzheimer disease--should be performed postmortem in patients with AIDS. On the molecular level, the effect, if any, of antiretrovirals on the processing of amyloid and amyloid-beta proteins needs to be elucidated.

As HIV/AIDS becomes a more chronic, otherwise "manageable" disease, current evidence indicates that ADC will increase in significance as a cause of major morbidity. Clinically and pathologically, it remains a frustrating "moving target." Research efforts in ADC undoubtedly will yield insights relevant to Alzheimer disease and other devastating neurodegenerative diseases.

transparent image
Overview of Clinical Neurologic Disease
transparent image
transparent image
Cerebral Symptoms and Signs
transparent image

Apart from dementia, HIV-infected patients are at risk for a wide range of neurologic diseases. Cerebral signs and symptoms are the most common. Global cerebral disease can present with altered mental status or generalized seizures, whereas focal disease often produces hemiparesis, hemisensory loss, visual field cuts, or disturbances in language use. Fungal, viral, and mycobacterial meningoencephalitides are the most common causes of global cerebral dysfunction, and progressive multifocal leukoencephalopathy (PML), primary CNS lymphoma, and toxoplasmosis account for the majority of focal presentations. As the epidemic has progressed, the epidemiology of CNS complications has changed. In general, availability of effective antiretroviral regimens has been associated with a dramatic decline in incidence and severity of opportunistic infections of the CNS. Even before the availability of these regimens, the incidence of CNS toxoplasmosis had declined among patients receiving trimethoprim-sulfamethoxazole prophylaxis against Pneumocystis. Unfortunately, antiretroviral regimens have not demonstrably decreased the prevalence of PML, and the incidence among individuals with higher CD4 counts may be increasing. However, the prognosis of this once uniformly fatal disease has improved dramatically, with long-term remissions now fairly common among patients receiving antiretroviral therapy.(24,25)

Human herpesvirus-6 and parvovirus B19 have been recognized as pathogens in patients with AIDS, and these viruses have been linked with meningoencephalitis, or brain inflammation; however, their importance in the spectrum of neuroAIDS has yet to be characterized, and is probably low.(26,27,28)

transparent image
Syndromes Affecting Cord, Nerve Roots, and Muscle
transparent image

Viral and, rarely, fungal and parasitic opportunistic infections can affect the spinal cord. Systemic lymphoma can infiltrate nerve roots and meninges, occasionally causing a mass lesion within the cord. In addition, HIV itself is associated with a spastic paraparesis similar to that seen with vitamin B12 deficiency. Peripheral nerve injury is very common, particularly a painful distal neuropathy seen late in HIV infection. About 35% of hospitalized patients with advanced HIV disease have peripheral neuropathy.(29,30) Among 272 HIV-infected outpatient subjects studied over time, 55% had signs, or both signs and symptoms, of distal neuropathy. The 1-year incidence of symptomatic distal neuropathy was estimated at 36%.(31)

Although myalgias or muscle pains are a frequent complaint, frank muscle disease is less common. Both inflammatory myopathies and a toxic myopathy secondary to zidovudine have been observed. More recently, a syndrome of acute neuromuscular weakness, often associated with lactic acidosis, has been described in association with several nucleoside analogue reverse transcriptase inhibitors, including zidovudine (AZT), stavudine (d4T), didanosine (ddI), and lamivudine (3TC), either alone or in combination. The first cases were reported to the U.S. Food and Drug Administration in mid-2001. Although the pathophysiology of this potentially fatal syndrome is not yet understood, the presence of lactic acidosis suggests an acute mitochondrial toxicity, or "mitochondropathy," possibly caused by the inhibition of mitochondrial DNA synthesis by nucleoside analogues. Anecdotally, the use of cofactors against lactic acidosis, such as thiamine, riboflavin, L-carnitine, vitamin C, and other antioxidants have been associated with lower mortality among the 60 patients described as of 2002.(32) Any patient on antiretroviral therapy presenting with a "Guillain-Barré-type" picture of ascending neuromuscular weakness should be tested for lactic acidosis and evaluated with electromyography and nerve conduction studies.

Among patients infected with HIV, serious neurologic disease may present with relatively trivial symptoms and signs. Therefore, a high index of suspicion must be maintained to detect disease early in these patients. A careful neurologic examination to attempt anatomic localization is necessary to guide further laboratory and imaging studies. Because multiple neurologic diseases often coexist in patients, close follow-up is needed even if a presumptive diagnosis has been made. A change in clinical condition often necessitates a thorough reevaluation.

transparent image
Pain
transparent image

There is growing awareness that pain from a variety of etiologies commonly complicates HIV disease. In general, patients with AIDS have pain comparable in prevalence and intensity to pain in patients with cancer, with similar mixtures of neuropathic and visceral-somatic etiologies. However, although efforts to improve malignant pain management have benefited many patients with cancer, pain in patients with AIDS is dramatically undertreated.

Aggressive pain treatment can be the single most important and most challenging intervention in the care of patients with HIV disease. In a recent U.S. study, only 15% of ambulatory AIDS patients with severe pain received adequate pain management.(33) The principles of pain assessment and treatment in the patient with HIV/AIDS are not fundamentally different from those in the patient with cancer and should be followed.(34,35)

These principles are described in the WHO analgesic ladder,(36) a well-validated, stepwise approach to pain management related to pain severity. Therapy ranges from nonopioid analgesics and adjuvants to systemic weak and strong opioids to intraspinal drug delivery for refractory severe pain. Opioids, except in quite high doses, can be ineffective in neuropathic pain; adjuvants (namely, tricyclics, anticonvulsants) are often more successful. Where neuropathic pain is refractory to such therapies, pain management specialists should be consulted.

A patient's previous substance abuse is a particularly strong risk factor for the undertreatment of pain by clinicians. Approaches to treatment in this difficult setting should be formulated with clear goals and limits, such that risks for both abuse and undermedication are minimized.(37)

transparent image
Specific Neurologic Conditions
transparent image
transparent image
Neuromuscular Disorders
transparent image

A wide range of peripheral nervous system disorders develop in patients with HIV infection, leading to pain, sensory symptoms, and muscle weakness (Table 1). Both "primary" HIV-1-associated nerve disorders, and those secondary to opportunistic processes are well described. In addition, certain antiretroviral drugs may cause or exacerbate peripheral neuropathies.

transparent image
Classification of Neuromuscular Disorders
transparent image

Four types of neuropathy are important to recognize in clinical practice, either because of their high prevalence or their therapeutic implications, or both. They are:

  1. Distal symmetric polyneuropathy (DSPN)

  2. Mononeuropathy multiplex

  3. Chronic inflammatory demyelinating polyneuropathy

  4. Progressive lumbosacral polyradiculopathy

Although there are also rare reports of motor neuron disease resembling amyotrophic lateral sclerosis,(38) its association with HIV infection is uncertain (see Table 1) and will not be discussed further in this chapter. Muscle diseases are discussed separately at the end of this chapter.

Depending on the study population and the method of case ascertainment, clinical, electrophysiologic, or pathologic evidence of peripheral neuropathy is present in about one-third to nearly 100% of patients with advanced HIV disease.(39) The incidence of neuropathy increases with declining CD4 cell count and advancing systemic HIV disease. Familiar causes of neuropathy, such as nutritional deficiency and diabetes mellitus, account for only a small percentage of the neuropathy in these patients. Toxicity of therapeutic drugs, notably ddI, zalcitabine (ddC), and d4T, is responsible for some cases of neuropathy, or for progression; however, antiretroviral toxicity is probably overdiagnosed as a primary cause of HIV-associated neuropathy. Of note, among 272 HIV-infected outpatient subjects studied over time, the use of antiretrovirals often suspected to cause a dose-related neuropathy was not associated with development of symptomatic neuropathy.(31)

Proper recognition of the different types of peripheral nerve dysfunction is essential for patient management. Except for the few neuropathies with known causes, most of these disorders are characterized on the basis of clinical features alone(Table 2). The rate of symptom progression, the degree of weakness relative to sensory loss, and the severity of immunosuppression guide the differential diagnosis. The electrophysiologic features of nerve conduction and electromyographic studies remain the gold standard for diagnosis, and may lead to different therapeutic options.

transparent image
Distal Symmetric Polyneuropathy
transparent image
transparent image
Incidence

Distal symmetric polyneuropathy (DSPN) is by far the most common neuropathy in HIV disease.(3,30,31,40)

In a cross-sectional study of hospitalized patients with advanced HIV disease, 35% had clinical and electrophysiologic evidence of this neuropathy. In a longitudinal study of outpatients, 55% had neuropathic signs or symptoms, and the estimated yearly incidence was 36%. Even among asymptomatic seropositive individuals, nerve conduction studies demonstrated polyneuropathy in 16%.

transparent image
Manifestations

DSPN can disable HIV-1-positive patients who are otherwise healthy. Associated pain and hypersensitivity can be intense, and is too often undertreated by physicians. Typical symptoms are tingling, numbness, and burning pain in the toes or over the plantar surface of the feet, often ascending over time. Neurologic examination shows bilateral depressed ankle-tendon reflexes and elevated vibratory threshold in the toes. There is often decreased appreciation of temperature distally. Brisk ankle reflexes suggest a diagnosis other than neuropathy or, at the very least, the presence of coexisting upper motor neuron disease (spinal cord or brain). Weakness, if present, is mild and usually restricted to the distal muscles, where muscle atrophy may also be observed. Severe or proximal weakness points to a different type of neuropathy (eg, polyradiculopathy), myopathy, or other neurologic diagnosis. Similarly, significant asymmetry in presentation usually suggests a focal neuropathy (eg, tarsal tunnel syndrome, other mononeuropathies) or other superimposed disorders. Electromyography and nerve conduction studies may be critical to localizing pathology and suggesting etiology.

transparent image
Pathogenesis

HIV-1-associated DSPN is a diagnosis of exclusion. Its pathophysiology, although not yet well characterized, is thought to be due to "indirect" effects of HIV-1 infection. HIV-1 virions are rarely detected in peripheral nerve tissue, even in patients with severe neuropathy. As in AIDS dementia and HIV-1-associated (vacuolar) myelopathy, theories of pathogenesis have focused on "friendly fire"--that is, products of immune-cell activation that may become neurotoxic. Tumor necrosis factor alpha in particular has been implicated, but other pro-inflammatory molecules are probably involved as well. The severity of neuropathy, in terms of both signs and symptoms, is associated with the levels of detectable plasma HIV RNA.(41) Pathologically, both large, myelinated fibers and small, unmyelinated fibers are damaged, accounting for the signs and symptoms of numbness, reflex loss, and pain.

transparent image
Differential Diagnosis

The clinical syndrome of DSPN is a common manifestation of many systemic diseases. Chronic alcoholism, neurotoxicity of therapeutic drugs, uremia, vitamin B12 deficiency, and diabetes mellitus all cause a similar, sometimes painful, polyneuropathy. In patients with HIV infection, vincristine, ddC, ddI, and d4T, among other drugs, may induce or exacerbate neuropathy. A temporal relationship with development of symptoms and a relatively more rapid onset (in terms of weeks to months, rather than months to years) may help to distinguish these toxic neuropathies from HIV-associated DSPN. Several studies of patients with advanced HIV disease have reported abnormally low serum vitamin B12 levels in 15-20% of subjects.(42-44) The significance of this apparent deficiency is not known, and the vast majority of patients with AIDS and DSPN have normal vitamin B12 levels. Because vitamin B12 deficiency can cause or exacerbate both myelopathy and neuropathy, however, it should be ruled out in all patients with either of these disorders. In DSPN, electromyographic and nerve conduction studies typically show a length-dependent sensorimotor polyneuropathy. Small or absent sural nerve action potentials are the most common finding. Electrodiagnostic tests help to confirm the diagnosis and assess the severity of the disorder, but they generally cannot distinguish the idiopathic DSPN from the polyneuropathies secondary to drug toxicity, vitamin B deficiency, or other causes.

transparent image
Treatment

Treatment of patients with DSPN is directed toward the neuropathic pain. We use, as first-line therapy, lamotrigine (25 mg, slowly increasing up to 250 mg) or desipramine (25 mg, slowly increasing up to 250 mg at bedtime). Amitriptyline (25-150 mg at bedtime) may also be used; however, sedation and anticholinergic effects may be dose limiting. Mexilitine (600-1200 mg/day) can be useful, as can phenytoin, carbamazepine, and other anticonvulsants. Gabapentin is used widely, but, in this author's experience, is relatively ineffective in more severe neuropathic pain syndromes. Potential drug-drug interactions and alterations in drug metabolism, particularly in conjunction with use of protease inhibitors, should be carefully considered. Patients should be monitored, as appropriate, for hepatotoxicity and leukopenia. Therapy is typically initiated at a low dosage and increased in increments over days to weeks until satisfactory therapeutic effect is achieved or adverse effects become limiting. These "adjuvant" agents provide partial relief in half to two-thirds of neuropathic pain patients, and dramatic relief in some. A number of "complementary" approaches to neuropathy and neuropathic pain syndromes are being tried by patients and clinicians. Although several are reasonable, none has been adequately studied. Acylcarnitine, magnesium and calcium supplementations are sometimes tried, and vitamin B12 injections given, despite normal B12 levels in blood. There is some evidence that vitamin B12 utilization pathways may be impaired in the setting of HIV disease, so that there may be a "functional" deficit in B12 despite normal serum levels.(45)

If vitamin B12 utilization is impaired, however, it is unlikely that supplementation will be of benefit. Amino acid supplements that bypass the B12 pathway, such as methionine or S-adenosyl methionine (SAM-E), theoretically could provide critical "methyl donors" needed for nerve fiber maintenance and repair. Controlled clinical trials are needed to investigate the safety and efficacy of these and other complementary approaches.

transparent image
Mononeuropathy Multiplex
transparent image
transparent image
Incidence

Mononeuropathy multiplex typically occurs in patients with symptomatic HIV-1 infection or in those with U.S. Centers for Disease Control and Prevention (CDC)-defined AIDS. The syndrome is uncommon, although accurate estimates of its incidence are not available.

transparent image
Pathogenesis

The pathogenesis of this syndrome is poorly understood. There may be two different disorders. Patients at an earlier stage of HIV-1 infection (CD4 >200 cells/µL) may have a self-limited mononeuropathy, usually involving only one or two nerves. An autoimmune etiology has been proposed.(46) In contrast, some evidence suggests that the mononeuropathy multiplex occurring in highly immunocompromised HIV-infected patients (CD4 <50 cells/µL) is often the result of infection of nerves or their vascular supply by cytomegalovirus (CMV).(47,48)

transparent image
Manifestations

Mononeuropathy multiplex typically presents as multifocal or asymmetric sensory and motor deficits in the distribution of peripheral nerves or spinal roots. Symptoms develop over weeks to months. Deep-tendon reflexes mediated by the affected nerves are diminished or absent, but diffuse areflexia does not occur. Cranial neuropathies may be a presenting feature. CMV-associated mononeuropathy multiplex can be extensive, involving several limbs or cranial nerves, or may preferentially involve the recurrent laryngeal nerve, resulting in hoarseness and vocal cord paresis. Electrophysiologic studies typically show a neuropathy with multifocal demyelination and axonal loss.

transparent image
Differential Diagnosis

The asymmetric neurologic signs and the prominent weakness separate this disorder from DSPN. Besides HIV, other etiologies of mononeuropathy multiplex include hepatitis B infection, diabetes, herpes zoster, and neoplastic infiltration of nerve. Entrapment neuropathies should be considered in disorders involving the ulnar, median, or tibial nerves, as cubital, carpal, and tarsal tunnel syndromes occur commonly in patients with AIDS wasting syndrome or extensive weight loss, and may also occur when human growth hormone is used to treat wasting or fat redistribution syndromes.

transparent image
Treatment

In our experience, mononeuropathy multiplex in patients with CD4 cell counts >200 cells/µL involves few nerves and follows a self-limiting clinical course. Clinical observation without specific treatment may be sufficient. Widespread and progressive weakness primarily occurs in patients with very low CD4 counts (typically <50 cells/µL). Although there are only anecdotal data to support the use of ganciclovir or foscarnet in such patients, we recommend empiric therapy because of the disabling nature of the disorder and its association with CMV.(48)

transparent image
Inflammatory Demyelinating Polyneuropathies
transparent image
transparent image
Incidence and Occurrence

Patients with HIV infection rarely may develop either acute inflammatory demyelinating polyneuropathy (Guillain-Barré syndrome, GBS), or chronic inflammatory demyelinating polyneuropathy (CIDP).(49) The incidence of these neuropathies is not known; GBS is probably no more common in the setting of HIV-1 than in the general population. However, GBS at seroconversion has been reported, and has been attributed to an autoimmune attack on nerves with resulting inflammation and destruction of myelin.

transparent image
Manifestations

Patients with inflammatory demyelinating neuropathies present with progressive, usually symmetric weakness in the upper and lower extremities. There is usually generalized areflexia. If the illness is monophasic with maximal neurologic dysfunction reached within the first month, it is, by definition, GBS. Patients with clinical progression of the syndrome after the first 4 to 6 weeks have, by definition, CIDP. Nerve conduction studies may show multifocal conduction slowing and conduction block and help establish the diagnosis of a demyelinating polyneuropathy. Electromyography typically shows signs of denervation in clinically weak muscles. CSF protein is usually elevated and, unlike the demyelinating neuropathies in the general population, a mononuclear pleocytosis of up to 50 cells/µL sometimes occurs.

transparent image
Treatment

Although no objective data on efficacy in the HIV-1-infected population are available, most centers treat these patients with either intravenous immune globulin (400 mg/kg/day for 5 days) or plasmapheresis (5 to 6 exchanges over 2 weeks) in a manner similar to that used for non-HIV-infected patients. In patients with CIDP, repeated treatment at monthly intervals may be needed to achieve clinical stabilization.(49)

transparent image
Mitochondrial Toxicity: A Syndrome That May Mimic Guillain-Barré
transparent image

A new syndrome, which may resemble Guillain-Barré, has been described in association with several NRTIs, including AZT, d4T, ddI, and 3TC, either alone or in combination. Although the pathophysiology of this potentially fatal syndrome is not yet understood, lactic acidosis suggests an acute mitochondrial toxicity, or "mitochondropathy," possibly caused by the metabolic effects of the nucleoside analogues. Anecdotally, the use of cofactors against lactic acidosis, such as thiamine, riboflavin, L-carnitine, vitamin C, and other antioxidants have been associated with lower mortality.(32)

Any patient on antiretroviral therapy presenting with a Guillain-Barré-type picture of ascending neuromuscular weakness should also be tested for lactic acidosis and evaluated with electromyography and nerve conduction studies.

transparent image
Progressive Lumbosacral Polyradiculopathy
transparent image

Progressive lumbosacral polyradiculopathy due to CMV infection is important to recognize because, unlike many other neurologic complications of AIDS, this serious disorder can be effectively treated if appropriately diagnosed. If unrecognized or untreated, CMV polyradiculopathy can be neurologically devastating or lethal.

transparent image
Incidence

CMV polyradiculopathy syndrome occurs in the setting of advanced systemic HIV disease in patients with very low CD4 cell counts (<50/µL). Even prior to the advent of effective antiretroviral therapy, the disorder was uncommon, being recognized in fewer than 2% of HIV-seropositive patients referred for neurologic consultation.(50) It is now quite rare in areas where antiretroviral therapy is generally available. A more benign or self-limited lumbosacral polyradiculopathy, without evidence of inflammation in spinal fluid, can occur in patients with higher CD4 counts.

transparent image
Pathogenesis

Autopsy studies have demonstrated CMV inclusions in astrocytes, neurons, and capillary endothelial cells in areas of necrosis around the lumbosacral roots and cauda equina. CMV is often recovered from the CSF, especially in those patients with polymorphonuclear pleocytosis. Other disorders reported to mimic this syndrome include neurosyphilis, toxoplasmosis of the conus medullaris, primary CNS lymphoma, and leptomeningeal metastasis from systemic lymphoma.(51-53)

transparent image
Manifestations

Progressive polyradiculopathy has a striking predilection for the lumbosacral roots, leading to neurologic deficits that are limited to the legs during the early stage of the syndrome. The presenting complaint is bilateral leg weakness that leads to difficulty with walking. Symptoms progress rapidly over several weeks. Flaccid paraplegia may develop within 1 to 2 weeks in some patients. Urinary retention and constipation or obstipation may be prominent, suggesting involvement of the lower sacral roots with sphincter disturbance. Deep tendon reflexes in the legs are suppressed or lost early. Back pain and subjective numbness or paresthesias are common, but sensory deficits are rarely severe. Sensory loss over the perineal or perianal areas (ie, the lower sacral dermatomes), if present, is characteristic of the syndrome.

transparent image
Differential Diagnosis

Loss of tendon reflexes and sensory symptoms and signs (even if mild) separate this disorder from the weakness due to myopathy or wasting syndrome. Weakness in the upper extremities, if any, occurs only late in the course of disease. Sphincter disturbances and the sparing of the upper extremities distinguish this syndrome from other neuropathies, such as mononeuropathy multiplex, chronic inflammatory demyelinating neuropathy, and GBS. CMV polyradiculopathy can be diagnosed with some confidence based on characteristic CSF findings, including polymorphonuclear CSF pleocytosis in conjunction with a convincing clinical presentation and progressive, areflexic leg weakness with early bowel and bladder (sphincter) disturbance. Lumbar puncture is probably the most important diagnostic test. In about half of affected patients, the CSF studies show a white cell count in excess of 500 cells/µL, with polymorphonuclear cells constituting at least 40-50% of the cells. Elevated protein and hypoglycorrhachia are common. CMV can be cultured from CSF in half to two-thirds of such cases. In others, often with a more benign clinical course, the CSF is characterized by a predominantly mononuclear pleocytosis in the range of 5 to 50 white blood cells/µL. CMV cultures are negative in the majority of such cases. Relatively bland CSF, however, does not rule out the diagnosis, and a high index of suspicion should be maintained. CSF diagnostic studies should include viral cultures, (nontreponemal syphilis testing (RPR or VDRL titer), and cytologic examination to look for the various causes reported in association with this syndrome. Where available, nucleic acid assays for CMV should be used.(51-53) Radiologic imaging, preferably magnetic resonance imaging (MRI), should be used to exclude compressive or space-occupying lesions of the cauda equina or lower thoracic spinal cord. MRI often reveals enhancement and thickening of lower spinal roots. Electromyography and nerve conduction studies are useful to localize the lesion to the spinal roots and to exclude other neurologic causes of weakness.

transparent image
Treatment

There is no controlled clinical trial to document the efficacy of ganciclovir or foscarnet. In practice, however, treatment successes are seen with either regimen or their combination.(54) Many clinicians treat these patients empirically before results of diagnostic studies are known. Early, empiric treatment is justified to preserve neurologic function, especially in patients with rapidly progressive leg weakness or characteristic CSF polymorphonuclear pleocytosis. Non-CMV causes of the polyradiculopathy syndrome, if identified, should be treated accordingly.

transparent image
Myopathy
transparent image
transparent image
Incidence and Occurrence

Symptomatic primary muscle disease is uncommon in patients with HIV infection. A polymyositislike syndrome occurs rarely, with few cases encountered even in large referral centers. A secondary myopathy attributable to the muscle toxicity of AZT emerged in the latter half of the 1980s with widespread use of the drug. In a study of 86 patients receiving AZT therapy for more than 6 months, 16% had persistently elevated serum creatine kinase, and 6% had symptomatic myopathy.(55)

transparent image
Pathogenesis

AZT probably causes mitochondrial dysfunction in muscle through its inhibition of the mitochondrial enzyme DNA polymerase gamma. In some myopathic patients treated with AZT, mitochondrial abnormalities are seen with either Gomori trichrome staining ("ragged-red fibers") or electron microscopy.(56,57) Little or no inflammatory infiltration occurs. The appearance of ragged-red fibers is a result of accumulation of abnormal mitochondria that were stained intensely red with trichrome. Whether the finding of ragged-red fibers is specific for the myopathy associated with AZT remains controversial.

The cause of the myopathies unassociated with AZT are unknown, but pathologic findings include rod body myopathy, both necrotizing and nonnecrotizing inflammatory myopathy, and type 2 muscle fiber atrophy found in HIV-1-associated muscle wasting syndrome. Immunologic factors likely play an important role in HIV-1-associated polymyositislike syndromes.(58-60)

transparent image
Clinical Manifestations

The hallmark of myopathy is diffuse, symmetric weakness of "proximal" muscles--hip or shoulder girdle muscles--with a sparing of sensory and autonomic functions. Difficulty with squatting, rising from a chair, or walking upstairs is often the presenting symptom of myopathy. Some patients have myalgia and muscle tenderness, but these complaints are also common in patients without myopathy. Neurologic examination reveals predominantly proximal weakness of the upper and lower limbs, although some patients may have prominent distal weakness as well. The clinical and laboratory features of HIV-associated myopathies are indistinguishable from those seen in the general population. Serum creatine kinase is almost always abnormally elevated.(56,57,58) Electromyography of clinically weak muscles shows fibrillation potentials, positive sharp waves, complex repetitive discharges, and a full recruitment of small, short-duration motor unit action potentials. The electromyography pattern is distinctive for myopathic disorders and is invaluable in establishing a diagnosis. The interpretation, however, requires an electromyographer experienced in the diagnosis of myopathy.

transparent image
Diagnosis and Differential Diagnosis

Preservation of tendon reflexes and sensory function helps distinguish myopathy from CIDP and other neuropathic causes of weakness. In most, but not all cases, creatinine phosphokinase levels will be elevated. As is often the case, however, more than one neurologic problem may be present and can complicate the examination. In the majority of cases, electromyography and muscle biopsy readily confirm the presence of a primary muscle disorder. Muscle biopsy may further assist in the differentiation among the different forms of myopathy. In addition to causing a syndrome of ascending neuromuscular weakness discussed above, antiretroviral-induced mitochondrial toxicity with lactic acidosis is often associated with muscle injury. Also, treatment with HMG-CoA reductase-type lipid-lowering agents ("statins"), often used to manage metabolic complications of antiretroviral therapy, can be associated with muscle pain, weakness, and muscle damage with enzyme elevations.

transparent image
Treatment and Management

In patients receiving AZT, discontinuation of the drug may result in clinical improvement of myopathy. Muscle pain and serum creatine kinase levels decrease first, followed by a more delayed improvement in strength. Some patients may tolerate rechallenging with lower doses of AZT, although the use of other antiretroviral therapy is probably preferable. Some patients, including some with ragged-red fibers on muscle biopsy, continue to deteriorate after cessation of AZT and respond only after initiation of steroid treatment,(56) suggesting a possible superimposed immunologic mechanism. Prednisone has also been used, apparently with some success, to treat those patients with polymyositis or rod body myopathy, although the natural history of these myopathies is not known and the relation of improvement to treatment is uncertain. We usually initiate prednisone at 60 to 80 mg/day and continue its administration until there is improvement in muscle strength. The dosage is then tapered to alternate-day dosing over several months, and prednisone eventually can be discontinued if there is no clinical relapse. Where lipid-lowering agents are suspected, immediate discontinuation is imperative.

transparent image
Spinal Cord Disorders
transparent image

Clinically significant spinal cord disorders are less common in HIV disease than are peripheral nervous system diseases. The neurologic signs of myelopathy, however, such as increased tone and hyperreflexia in the legs and Babinski signs (extensor plantar responses), may be elicited even in the absence of subjective complaints. In most cases, such asymptomatic signs reflect mild HIV-associated spinal cord disease that may or may not progress. Patients with symptomatic myelopathy usually complain first of clumsy gait and urinary hesitancy. On examination, one finds relatively symmetric leg weakness, sensory loss, particularly in vibration and position sense, spasticity and hyperreflexia of both legs, and Babinski signs. In clinical management, it is important to separate the acute from the more chronic myelopathies. More rapidly progressive neurologic deficits, especially if accompanied by back pain, spine tenderness, or a marked spinal sensory level, warrant immediate investigation with MRI or computed tomography (CT) myelogram to rule out cord compression.

transparent image
Subacute Myelopathies
transparent image
transparent image
Vacuolar Myelopathy
transparent image
Incidence and Occurrence

Strictly speaking, vacuolar myelopathy (VM) is a pathologic diagnosis. Characteristic pathology is identified in postmortem examination in as many as 55% of patients dying from AIDS.(61,62) Clinical myelopathy is less common, but is probably underdiagnosed.

transparent image
Pathogenesis

The pathologic finding of noninflammatory vacuolation of myelin, particularly in the lateral and posterior columns of the spinal cord, characterizes VM. Upper thoracic levels of the cord are affected most commonly, but cervical pathology is well described, and occasionally diffuse cord changes are seen. The physiologic mechanisms leading to these pathologic changes are unknown.(63) Direct invasion of spinal cord neural cells by HIV is not seen, even in severe cases. As in AIDS dementia, products secreted by activated macrophages have been implicated in pathogenesis. Tumor necrosis factor alpha, for example, a known neurotoxic pro-inflammatory cytokine, may play an important role in HIV-1-associated spinal cord disease.

Curiously, the myelopathy associated with HIV disease is nearly identical clinically and pathologically to that seen in severe cobalamin (vitamin B12) deficiency (subacute, combined systems disease). However, despite the fact that low vitamin B12 levels are seen in up to 20% of AIDS patients, those with HIV-1-associated myelopathy rarely have B12 deficiency. Many clinicians routinely provide monthly injections of B12 to HIV-1-positive patients with myelopathy; although this practice is innocuous, evidence of clinical benefit is lacking. However, there is evidence that vitamin B12 is not utilized normally in the setting of HIV disease for the stabilization of nerve fibers. Vitamin B12-dependent transmethylation of myelin basic protein is critical to nerve fiber survival and maintenance, and this process has been shown to be deficient in HIV-seropositive subjects with myelopathy. This metabolic defect may result in a "functional" vitamin deficiency, despite normal B12 levels in blood.(45)

transparent image
Manifestations

Vacuolar myelopathy typically presents as subacute progression of motor and sensory deficits over several months. Paresthesias or numbness of the limbs, if present, is sometimes difficult to distinguish from symptoms of peripheral neuropathy; moreover, the two conditions often coexist in patients with advanced HIV disease. Brisk tendon reflexes suggest spinal cord (or brain) involvement, whereas peripheral neuropathy is associated with depressed reflexes, especially those of the Achilles tendons. A patient with both processes might have brisk knee reflexes and absent ankle jerks.

transparent image
Differential Diagnosis

Because VM also occurs in patients with AIDS dementia complex, and both conditions cause spasticity and paraparesis, it may be clinically difficult to separate spinal cord disease from cerebral involvement of motor pathways. Brain MRI demonstrating extensive bilateral white matter changes supports a cerebral etiology. The diagnosis of VM in the setting of HIV disease is one of exclusion. The evaluation should include radiologic imaging of the spinal cord (and brain, if indicated). MRI is typically normal in patients with VM, although areas of increased T2 signal may be seen rarely. CSF studies may be normal or may show nonspecific abnormalities such as low-grade mononuclear pleocytosis and mild elevation of protein content. Such changes are also seen in asymptomatic HIV-1-seropositive patients, and so have little diagnostic sensitivity or specificity.

transparent image
Treatment

The clinical course is typically one of slow progression, and most patients remain ambulatory. A more fulminant course may be seen, however, with wheelchair dependence within a few months. Upper extremities are affected very late, if at all. Baclofen (10-30 mg three times daily) or tizanidine (4 mg three times daily) may attenuate leg spasticity and reduce leg cramps. Painful dysesthesias may be treated with "neuropathic pain" adjuvants, such as lamotrigine or desipramine. As noted above, the vast majority of patients with this condition have normal vitamin B12 levels; however, there may be a defect in utilization of B12. Amino acid supplements that bypass the B12 pathway, such as methionine or S-adenosyl methionine (SAM-E), could theoretically provide the "methyl donors" normally supplied by B12 metabolism, which are critical for nerve fiber maintenance. Controlled clinical trials are needed so that the safety and efficacy of such complementary approaches may be better understood.

transparent image
HTLV-1-Associated Myelopathy

Another rare but important retroviral cause of subacute myelopathy is human T-lymphotropic virus type I (HTLV-1) infection. The diagnosis of HTLV-1-associated myelopathy (also known as "tropical spastic paraparesis") should be considered in patients from the high-risk epidemiologic groups (eg, previous transfusion, injection drug use, and residence in known endemic areas such as Japan, the Caribbean islands, and parts of Central and Latin America). Endemic areas have also been identified in the United States and include parts of Texas and New Orleans.(64,65) Serology for anti-HTLV-1 antibodies can be assayed. Interferon-alfa is being investigated for the treatment of HTLV-1-associated myelopathy.

transparent image
Acute Myelopathies
transparent image

The causes of acute myelopathies include spinal cord compression from lymphomatous metastasis,(1,66) tuberculous or bacterial spinal abscess,(67) and acute infections by herpes zoster or other DNA viruses.(68-70) In addition, a rare acute myelopathy at the time of seroconversion to HIV has been reported.(71) This is not surprising, given that acute or "transverse" myelitis can complicate a number of viral syndromes. In the experience of the author, by far the most common cause of subacute myelopathy in patients with HIV is non-HIV-associated cervical spine disease (eg, cervical spinal stenosis, disk disease, degenerative joint disease, and so on. The assumption that myelopathy in a seropositive individual "must" be HIV related can lead to missing relatively common treatable, non-HIV-related conditions.

transparent image
Neurologic Emergency: Spinal Cord Compression

In patients with acute back pain and rapidly developing neurologic deficits such as leg weakness and numbness, or bowel and bladder dysfunction, spinal cord compression must be ruled out. Neurologic examination, including sensory examination of the trunk for a sensory level to temperature or pinprick, should be performed to establish the probable level of the lesion for diagnostic imaging. MRI of the appropriate spinal cord segments or myelography with follow-up CT scan are the diagnostic tests of choice. If radiologic studies are negative, the CSF should be evaluated for evidence of infectious and neoplastic causes. In addition to routine CSF studies, mycobacterial cultures and cytologic examination for malignant cells should be performed. CSF nucleic acid assays for CMV, herpes varicella-zoster virus (VZV), herpes simplex virus (HSV), and tuberculosis (TB) are useful emerging tools for diagnosis of treatable conditions.(72) Prognosis for recovery depends on the neurologic function at the time of initiation of treatment.

transparent image
Intracranial Disorders
transparent image

The CNS disorders in the setting of HIV disease can be divided into four general categories: a) primary infection of the brain by HIV; b) opportunistic infections by parasitic, fungal, viral, and bacterial organisms; b) CNS neoplasms; and d) complications of systemic disorders.

transparent image
Primary HIV Infection of the Brain: HIV-1-Associated Dementia Complex
transparent image

HIV-1-associated dementia complex (AIDS dementia, or ADC) has been variously called AIDS dementia complex, HIV-associated dementia (HAD), AIDS encephalopathy, HIV encephalitis, and multinucleated giant-cell encephalitis. This devastating complication of HIV-1 infection is discussed briefly above (Pathogenesis of ADC), and more completely in the chapter "AIDS Dementia Complex".

transparent image
Intracranial Opportunistic Infections
transparent image
transparent image
Toxoplasma gondii
transparent image
Incidence and Presentation

CNS toxoplasmosis has been the most common cause of intracerebral mass lesion in HIV-infected patients. Its incidence has declined dramatically among patients receiving PCP prophylaxis, and further declined among patients treated with effective antiretroviral therapy. Earlier reports described frequencies of 3-40%, reflecting the considerable regional variation in exposure to the parasite.(1,3,73) Most of the cases in the United States are probably a result of reactivation of latent infection. Toxoplasmic encephalitis in the absence of immunoglobulin G antibodies to Toxoplasma has been documented;(74-76) however, this is probably quite rare with newer assays. Toxoplasmosis causes a multifocal cerebritis, and initial symptoms and signs are often both diffuse and focal. They include confusion, headache, personality change, generalized or focal seizures, hemiparesis, hemisensory loss, or other focal neurologic deficits.

CT scan of the brain usually shows multiple ring-enhancing lesions with predilection for cortex and deep gray-matter structures such as the basal ganglia. The cerebellum and brain stem are less commonly involved. Radiologic appearance can vary markedly; single lesions and lesions with diffuse enhancement, as well as nonenhancing lesions can appear. In fact, other common cerebral lesions can be radiologically indistinguishable from toxoplasmosis. MRI is more sensitive than CT, which can underestimate the number of lesions.(77) If tissue diagnosis is indicated, MRI can often be helpful in localizing a lesion most accessible for biopsy. The differential diagnosis of cerebral focal lesions in patients with AIDS should include lymphoma, progressive multifocal leukoencephalopathy (rarely enhances), other masses of infectious etiology such as cryptococcal cerebritis and tuberculoma, and, in some cases, stroke. CSF examination in toxoplasmosis is nondiagnostic; it can be normal, or it can show a mononuclear pleocytosis and elevated protein. CSF antibodies to Toxoplasma are not sensitive for Toxoplasma encephalitis.

transparent image
Treatment

The treatment of toxoplasmosis is discussed in the chapter "Toxoplasmosis and HIV".

transparent image
Cryptococcus neoformans

Cryptococcus neoformans is another CNS opportunistic infection that has become rare among individuals receiving effective antiretroviral therapy. It usually presents as a subacute meningitis.(78-80) Clinical manifestations can be remarkably benign, with vague malaise or nausea alone. More commonly, headache and fever are the presenting features. An acute confusional state can be seen, as can cranial nerve palsies. Stiff neck (meningeal sign) is absent in up to 70% of cases. In fact, some patients may have a completely normal physical examination. Hence, clinicians must maintain a high index of suspicion for cryptococcal disease, particularly in the setting of new onset of headache.

CT or MRI is usually normal or reveals only atrophy. Uncommonly, cryptococcomas occur, particularly in the basal ganglia due to spread of the organisms from the basal cisterns by way of the lenticulostriate arteries. These lesions do not enhance after contrast administration. Over the past several years, we have observed severe cryptococcal cerebritis in patients previously "successfully" treated for cryptococcal meningitis. Focal meningeal and parenchymal enhancement is seen on MRI, and patients typically present with seizure or altered mental status.

CSF can be normal or show mononuclear pleocytosis, elevated protein, low glucose, and high opening pressure. India ink staining may reveal fungus, but it is relatively insensitive. Determination of CSF cryptococcal antigen (CRAG) titer is essential because this may be the only CSF abnormality; latex agglutination of CSF for cryptococcal antigen has a sensitivity of 90-95%.

The treatment of cryptococcal meningitis is discussed in the chapter "Cryptococcus and HIV".

transparent image
Aseptic Meningitis

Patients with aseptic meningitis often present initially with headache, occasionally in association with altered mental status or cranial neuropathies. Many patients with this syndrome probably have primary HIV meningoencephalitis.(6,81) The meningitis can manifest at the time of seroconversion and can recur spontaneously or become chronic.(1) Because of the high incidence of CSF abnormalities in HIV-infected patients, regardless of symptoms (see Diagnostic Studies: Lumbar Puncture), interpretation of CSF in this population can be difficult. In investigating symptoms such as headache, altered mental status, and cranial neuropathy, aseptic meningitis must be a diagnosis of exclusion.

transparent image
Progressive Multifocal Leukoencephalopathy

Progressive multifocal leukoencephalopathy (PML) is caused by JC virus, a ubiquitous polyoma virus that affects approximately 4-8% of patients with advanced HIV disease. With effective antiretroviral therapy, the prognosis for those who develop PML has improved dramatically, with long-term remission being fairly common. PML is a subacute or chronic progressive illness most often characterized by focal neurologic findings, such as hemiparesis, gait abnormalities, and visual field cuts, as well as changes in mental status and personality. Dementia, encephalopathy, and coma can occur with fulminant disease. Seizures are uncommon, but not rare.(82) If focal deficits are not prominent, it can be difficult clinically to distinguish PML from ADC. CT or MRI usually reveals focal or diffuse lesions in the white matter, particularly in the parieto-occipital region. The brainstem or cerebellum may be solely involved in up to 15% of cases. Single lesions are not uncommon in patients with HIV disease, however, making "multifocal leukoencephalopathy" something of a misnomer in this population; and gray-matter involvement, though unusual, is well described. With rare exceptions, the lesions do not enhance, nor do they cause tissue edema or mass effect. Pathologically, infection is confined to oligodendrocytes and results in demyelination with little or no inflammation. Routine CSF evaluation is nondiagnostic and is usually normal or reveals only nonspecific changes, such as mild pleocytosis or protein elevation. CSF PCR detection of JC virus DNA has become a useful tool in the diagnosis of PML, and is available in some commercial laboratories.(83) Diagnosis should be based on clinical and radiographic features, supported by PCR. Sensitivity of PCR will vary depending on the laboratory and the primers used; hence, while a positive test is confirmatory, a negative CSF PCR for JC virus should not exclude the diagnosis.

transparent image
PML versus HIV Encephalitis

Occasionally clinical and radiographic features of PML are quite similar to those of AIDS dementia with its radiographic counterpart, HIV encephalitis. Clinically, focal findings strongly favor PML, as does rapid progression of symptoms. Radiographically, asymmetry and hypointensity of lesions on T1-weighted MRI, involvement of the subcortical U-fibers, and relative sparing of the periventricular white matter all favor a diagnosis of PML.

transparent image
Treatment and Prognosis of PML

In the absence of antiretroviral therapy, PML is characterized by progressive decline over the course of 4 to 5 months until death. Stabilization of symptoms, either without treatment or in the setting of antiretroviral therapy, occurs in some patients with relatively high CD4 counts (>200 cells/µL), for whom PML is the CDC AIDS-defining illness. Improvement and stabilization for months to years is now fairly common among patients treated with antiretroviral therapy, particularly those who achieve complete suppression of HIV in the blood.(24,25)

Some patients who undergo a decline in status despite combination antiretroviral therapy or who cannot tolerate antiretrovirals may improve or stabilize on cidofovir treatment, using the same regimen as for CMV retinitis (see chapter "Cytomegalovirus and HIV"). This approach has not been studied adequately in controlled clinical trials, and remains experimental. Ocular hypotension and renal injury are important adverse events associated with cidofovir, and must be closely monitored.(84)

transparent image
Immune Reconstitution Syndrome and PML

There have been several reports of severe worsening of PML on initiation of antiretroviral therapy, thought to be due to "immune reconstitution" syndrome. Marked inflammation--otherwise rare in PML--has resulted in rapid neurologic deterioration and, in some cases, death. Patients with PML should be monitored closely in the first 4 to 6 weeks after initiation of highly active antiretroviral therapy (HAART) for neurologic worsening. In the setting of rapid deterioration, an MRI or CT scan with contrast should be obtained. A trial of corticosteroids is reasonable in the setting of marked inflammation and mass effect.

transparent image
Viral Encephalitis

Among the opportunistic viral infections of the CNS, the most important are the herpes viruses: herpes simplex types 1 and 2 (HSV-1 and -2), herpes varicella-zoster (VZV), and CMV. Each can cause a meningoencephalitis with mental status changes and focal neurologic findings. Diagnosis is complicated by the low yield of CSF viral cultures in herpesvirus encephalitis in general. Sensitive CSF PCR assays have been developed for each of these conditions, however, and, where available, can greatly aid diagnosis.

transparent image
Herpes Simplex Virus

(Also see chapter "Herpes Simplex Virus and HIV").

In general, the onset of headache, fever, and seizures should, in the absence of other clear etiologies, prompt empiric treatment for herpes simplex encephalitis with acyclovir (10.0 to 12.5 mg/kg intravenously every 8 hours). Interestingly, HSV encephalitis is rarely reported among patients with AIDS. Also, in contrast to its fulminant course in immunocompetent persons, HSV infection in patients with advanced HIV disease is often insidious in onset and chronic in duration. Skin or mucosal lesions are absent in the majority of patients. CT or MRI scans may reveal edema, focal hemorrhage, or contrast enhancement in the characteristic locations--medial temporal lobes and inferior frontal lobes--especially if coronal images are obtained. However, diffuse lesions also occur. CSF often shows a lymphocytic pleocytosis and elevated protein; in addition, red blood cells may be a prominent though nonspecific finding. Glucose levels are usually normal. Electroencephalogram may show diffuse slowing, common to all encephalitides, or periodic lateralized epileptiform discharges or other focal abnormalities. Definitive diagnosis often requires brain biopsy, but CSF PCR may reduce the need for tissue diagnosis.(85)

transparent image
Herpes Varicella-Zoster Virus

(Also see chapter "Varicella-Zoster Virus and HIV").

Herpes varicella-zoster infection of the CNS is associated with meningoencephalitis, cranial nerve palsies, myelitis, leukoencephalopathy, ependymitis, or cerebral vasculitis leading to strokes and transient ischemic attacks (TIAs). Zoster encephalitis is probably underdiagnosed among patients with AIDS. Clinical suspicion should be high in AIDS patients with stroke or TIAs. Neurologic signs and symptoms can precede or follow the rash, or be unassociated with a rash, present or past. CSF usually reveals only nonspecific, mild pleocytosis and protein elevation. VZV viral cultures of CSF and CSF PCR for VZV should be performed, where available.(86) Positive PCR or culture results justify high-dose intravenous acyclovir treatment. CT or MRI scans may demonstrate cerebral ischemia or combined hemorrhagic and ischemic changes.

If skin lesions are present, immunofluorescence of biopsied tissue should be performed. Acyclovir (10.0 to 12.5 mg/kg intravenously every 8 hours) for 14 to 21 days has, in our experience, resulted in excellent recovery in zoster encephalitis. Where vasculitis is suspected, and confirmed with MR or conventional angiography, steroids or other anti-inflammatory immunosuppressants may be required.

transparent image
Cytomegalovirus

(Also see chapter "Cytomegalovirus and HIV").

Because CMV is ubiquitous in patients with advanced HIV disease, it can be difficult to determine what role, if any, CMV is playing in CNS disease. Cells bearing CMV inclusion bodies are a common finding in the brains of patients with HIV disease at autopsy, regardless of presence or absence of neurologic symptoms. Occasionally, severe necrotizing CMV ependymitis or meningoencephalitis is seen in tissue specimens, as is necrotizing involvement of spinal roots. CT and MRI scans are usually normal or reveal only nonspecific changes, even in biopsy-proven CMV encephalitis. Occasionally, an ependymitis is evident on imaging but is not diagnostic for CMV infection. Similarly, CSF examination is nondiagnostic and cultures are usually negative, even in pathologically proven CMV encephalitis.(87) If available, nucleic acid amplification testing (PCR or bDNA) for CMV should be performed on CSF; a positive test is highly suggestive of actual CNS disease., Because CMV involvement of the brain is usually patchy, even brain biopsy may yield a false-negative result. Evidence of systemic CMV infection--retinal, gastrointestinal, or, rarely, pulmonary--should be sought aggressively in any patient with HIV infection and signs and symptoms of acute meningoencephalitis for which no other convincing etiology is found.

Therapeutic response to ganciclovir has been documented in patients with spinal root involvement.(88) A small clinical series of patients with CMV encephalitis described response to treatment with ganciclovir or foscarnet in 3 of 5 patients.(54)

transparent image
Fungal Encephalitis

Candida albicans, which commonly infects the oral mucosa of patients with HIV disease, can cause a meningoencephalitis, usually in the setting of fungemia. Microabscesses are the usual pathologic findings in the brain. Mucormycosis, especially among injection drug users, and aspergillosis have been reported causes of meningoencephalitis in patients with advanced HIV disease, as have coccidioidomycosis and histoplasmosis in patients from endemic areas, such as the southwestern United States and the Ohio Valley, respectively.(6) Diagnosis usually requires demonstration of fungus from biopsied tissues.

transparent image
Neurosyphilis

(Also see chapter "Syphilis and HIV").

It is unclear whether infection with HIV is an independent risk factor for the development of neurosyphilis. Although some authors have suggested that neurosyphilis is both more fulminant and more difficult to eradicate in the setting of HIV disease,(89,90) luetic neurologic disease has always encompassed a broad spectrum of presentations and clinical courses, and clinical evidence does not support the theory that HIV alters the natural history of Treponema pallidum infection.(77) Manifestations of neurosyphilis include meningitis, cerebral arteritis, and cerebritis, as well as optic neuropathy and deafness. Evaluation of HIV-infected patients with a positive serum treponemal antibody test (FTA-ABS or MHATP) meeting diagnostic criteria for late latent syphilis or syphilis of unknown duration should include lumbar puncture to evaluate for neurosyphilis. Current CDC recommendations also suggest lumbar puncture in the setting of primary or secondary syphilis when accompanying signs or symptoms suggest ophthalmic involvement (eg, uveitis) or neurologic involvement (eg, headache, altered mental status, meningeal signs).(91)

In the absence of neurologic signs or symptoms, a positive CSF VDRL in the setting of abnormal spinal fluid establishes the diagnosis of latent neurosyphilis. Unfortunately, the sensitivity of the CSF VDRL in the setting of HIV disease is unknown but estimated at only 70% at best. A negative CSF VDRL does not exclude the diagnosis.(92) A CSF pleocytosis (usually 10-400 cells/µL) and mildly elevated protein (46-200 mg/dL) with or without a positive CSF VDRL may be the only findings. One should probably err on the side of caution, and AIDS patients with abnormal CSF and a positive peripheral syphilis serology--even with negative CSF VDRL--should receive a course of at least 10 days of intravenous aqueous penicillin G, 4 million units every 4 hours. Repeat lumbar puncture with normalization of CSF is evidence of the efficacy of treatment; however, CSF abnormalities due to HIV infection alone can complicate interpretation. In contrast, a positive CSF VDRL in the setting of normal CSF poses another interpretive dilemma, particularly in a severely lymphopenic patient with advanced HIV disease. T pallidum has been recovered from CSF of patients with otherwise normal spinal fluid.(93) In patients already treated for primary or secondary syphilis, either empiric therapy for neurosyphilis or careful interval neurologic and CSF evaluations are reasonable approaches.

transparent image
Neoplasms
transparent image
transparent image
Systemic Neoplasms

Although Kaposi sarcoma (KS) is the most common systemic neoplasm in HIV disease, it rarely spreads to the CNS. Among the systemic cancers, non-Hodgkin lymphoma is the most important cause of neurologic dysfunction in HIV disease and invades the CNS by spreading along the leptomeninges. Common signs and symptoms include cranial nerve palsies and polyradiculopathy, and, less commonly, myelopathy due to epidural metastasis with spinal cord compression.(94) Intraparenchymal mass lesions are uncommon. Cytologic examination of CSF, often requiring multiple large-volume (10-20 mL) taps, is essential for the diagnosis. CSF must be delivered immediately for analysis to minimize cell lysis.

transparent image
Central Nervous System Lymphoma

Primary CNS lymphoma (PCNSL) is a fairly common cause of cerebral mass lesions in patients with advanced HIV disease.(95) The most common signs and symptoms are confusion, lethargy, and personality changes, usually with focal deficits, such as hemiparesis, hemisensory loss, ataxia, and aphasia. Seizures are less common, but not rare.

On CT or MRI, lesions can be single or multiple, and typically enhance, either diffusely or in a ring pattern, after injection of contrast. About half the lesions are associated with edema and mass effect, but the degree of swelling is often mild relative to the size of the tumor(s). The most common locations are in the periventricular white matter, and in the deep gray matter. Primary CNS lymphoma can be indistinguishable radiologically from toxoplasmosis; however, a single lesion on MRI (which is more sensitive than CT for detecting multiple lesions) in a patient with AIDS favors the diagnosis of lymphoma.(96) Definitive diagnosis requires brain biopsy or positive CSF cytology. Special assays to detect clonal markers in CSF may aid in the diagnosis. Prior to the availability of effective antiretroviral treatment, a common initial approach to contrast-enhancing brain lesions in the setting of HIV was a 10- to 14-day trial of antitoxoplasma therapy with careful clinical and radiologic reevaluation. However, given the decline in incidence of toxoplasmosis where antiretroviral drugs are available, the index of suspicion for PCNSL should be higher in individuals receiving effective antiretroviral treatment, and a definitive diagnosis based on CSF or brain biopsy should be more aggressively pursued. Whole-brain radiation (4,000 to 5,000 cGy over 3 weeks) prolongs survival in some patients with advanced HIV disease.(97) The tumor is radiosensitive, but its recurrence rate is high.(94,98) In general, treated patients have modestly improved survival and often succumb to opportunistic infections rather than to lymphoma.(96) Dexamethasone, which is lympholytic as well as effective against tumor-associated edema, may be used to control symptoms. There is some evidence that prognosis of PCNSL has improved in the era of effective antiretroviral therapy, and the incidence has declined.(99)

transparent image
Complications of Systemic Diseases
transparent image
transparent image
Metabolic Encephalopathy

Metabolic encephalopathy occurs frequently in patients with advanced HIV disease. Adverse reactions to therapeutic drugs, hypoxia, electrolyte imbalance, and multiorgan failure are common etiologies. Efavirenz can cause a (usually) transient encephalopathy for a few weeks after initiation of therapy. In the cachectic patient or in patients with significant liver disease or history of protracted vomiting, Wernicke encephalopathy, due to thiamine deficiency, should be considered.(100)

transparent image
Stroke

Cerebral infarction and TIAs are seen infrequently in HIV-1-infected patients, with a reported incidence ranging from 0.5% to 8.0%.(101) Based on a case control study, this incidence is less than that among age-matched young adults with other terminal illnesses.(102) Among patients with advanced HIV disease, cerebral ischemic disease is more common than hemorrhagic stroke. One cause of stroke is cardiac disease resulting in cardiogenic emboli. Cerebral vasculitis, particularly that due to VZV or syphilitic arteritis, as well as vasculopathies due to chronic meningitis, or amphetamine or cocaine use, may cause thrombotic stroke in patients with HIV disease. Hemorrhage is occasionally seen in the setting of zoster vasculitis, thrombocytopenia, or, rarely, metastatic KS.

transparent image
Symptoms, Neurologic Signs, and Differential Diagnoses of Intracranial Disorders
transparent image
transparent image
Headache
transparent image

Headache is a common and difficult clinical problem in patients with HIV disease. Although many patients undoubtedly have "benign" headaches, headaches may also herald a wide range of CNS disorders. Meningitis, encephalitis, cerebral vasculitis, and mass lesions can all present with headache. New headache or significant change in pattern of headache warrants evaluation including imaging by CT or MRI followed by a lumbar puncture, unless contraindicated by the presence of mass lesions. Lumbar puncture need not await CT or MRI unless the patient has altered mental status, papilledema, or a focal neurologic examination. The likelihood of HIV-related causes increases with more severe immune deficiency (current or recent CD4 <200 cells/µL). Clinicians should measure opening CSF pressure, and special studies should include cryptococcal antigen titers and CSF VDRL. CSF can be frozen for later PCR analysis. Clinical and preliminary laboratory evaluation should guide further testing. For example, in the setting of unexplained cranial neuropathies, CSF cytology should be included among the examinations ordered, whereas an extremely low CSF glucose (<35 mg/dL) should lead to stains and cultures for acid-fast bacteria.

transparent image
Seizures
transparent image

Seizures can accompany ADC or can be manifestations of any of the opportunistic or neoplastic intracranial complications of advanced HIV disease previously discussed.(103) The most common causes, in descending order of frequency, are cerebral mass lesions, encephalitis (including HIV-associated dementia), and meningitis. In about 20% of patients, no definite etiology for seizures can be found despite thorough neurologic, radiologic, and laboratory evaluation.(103) Treatment with anticonvulsant medications such as phenobarbital, phenytoin, carbamazepine, or valproic acid, provides excellent symptomatic control, although seizures due to mass lesions can be refractory to anticonvulsant therapy. Patients with advanced HIV disease appear to have an increased risk of adverse reactions to anticonvulsants, particularly phenytoin. In addition, liver disease may be exacerbated, particularly by valproic acid, and severe lymphopenia is a contraindication to the use of carbamazepine. Protease inhibitors may markedly alter metabolism of many drugs; anticonvulsant drug levels may need to be carefully monitored. A patient with seizures or episodes of confusion or loss of consciousness may need to be reported to the Public Health Department. State legislation varies on the requirements for reporting by physicians, but in some states it is mandatory. In most states, patients with seizures must not operate a motor vehicle unless seizures are controlled for at least 6 months. An exception may be granted if a reversible metabolic abnormality or drug toxicity caused the seizure and is not expected to recur.

transparent image
Altered Mental Status
transparent image

Acute encephalopathy is distinguished from dementia by the rapid progression of symptoms and the frequent association of a depressed level of alertness. Opportunistic infections and neoplasms can present with progressive cognitive decline and personality changes similar to ADC, but focal deficits are usually more prominent and the clinical course more rapid than in ADC.

Decline in mental status in HIV-infected patients warrants full physical examination, evaluation of electrolytes and renal and hepatic function, syphilis serology, measurement of vitamin B12 level, toxicology screen, and neurologic evaluation, including diagnostic imaging of the brain and, unless contraindicated, lumbar puncture. Review of prescribed and nonprescribed medications as well as recreational drug and alcohol use is essential.

Neuropsychiatric testing should be considered where depression (pseudodementia) is in the differential diagnosis. If altered mentation is episodic and the sensorium clears within 24 hours without specific treatment, suspicion of drug toxicity or a postictal encephalopathy should be raised. An electroencephalogram can be useful if epileptiform activity is demonstrated, but a normal study does not rule out a seizure disorder.

transparent image
Posterior Fossa Symptoms and Signs
transparent image

Isolated involvement of the posterior fossa (cerebellum and brainstem) is uncommon in HIV-associated conditions, but may occur in PML, toxoplasmosis, or lymphoma. Manifestations include vertigo, diplopia, headache, cerebellar ataxia, and cranial nerve deficits. If the brainstem parenchyma is involved, hemiparesis and hemisensory loss can be prominent.

transparent image
Diagnostic Studies
transparent image
transparent image
Computed Tomography and Magnetic Resonance Imaging
transparent image

Although MRI is more sensitive than CT in detecting CNS pathology,(77) CT with double-dose contrast is an excellent alternative in the evaluation of HIV-infected patients with signs and symptoms of intracranial disease. There is no pathognomonic radiologic appearance for any of the CNS disorders seen in patients with advanced HIV disease. Several patterns, however, are clinically helpful. Widespread white-matter abnormalities without contrast enhancement or mass effect suggest either PML or HIV encephalitis. Lesions associated with the latter tend to be more diffuse, less well demarcated, and more prominent in the frontal regions, whereas lesions of PML tend to be discrete and, in patients with AIDS, to favor occipital-parietal regions of the brain. Zoster encephalitis can resemble PML radiographically.

Periventricular contrast enhancement can be seen with either CMV or zoster ventriculitis. Focal cerebral lesions with surrounding edema and mass effect are most commonly caused by either abscesses (especially those of toxoplasmosis), or primary CNS lymphoma. Either can show ring, nodular, or diffuse enhancement, and either can produce single or multiple lesions. A solitary lesion on MRI, while not definitive, would favor a diagnosis of lymphoma.(104) Enlarged ventricles are usually the result of atrophy (hydrocephalus ex vacuo); frank hydrocephalus occurs with mass lesions that obstruct CSF flow or as the result of previous meningitis, most commonly cryptococcal or tuberculous.

transparent image
Lumbar Puncture
transparent image

Abnormal CSF findings, such as mild elevations in white blood cell count and protein and mild decrease in glucose concentration, are frequent in the setting of HIV disease at all stages, including among asymptomatic HIV-infected persons with well-preserved immunologic function.(105) These nonspecific findings complicate the interpretation of CSF indices in the setting of neurologic signs and symptoms. In one large retrospective study of HIV-infected outpatients who underwent lumbar puncture for the "classic" indications of headache, fever, and altered mental status, alone or in combination, CSF abnormalities were found in 45%. Definitive diagnosis, however, was reached based on lumbar puncture in only 8%.(106) In contrast, the diagnostic yield of lumbar puncture was 40% in another study in which a specific neurologic deficit, cranial neuropathy, was the reason for CSF examination.(107)

Despite difficulties in interpretation and low yields in many instances, lumbar puncture remains unsurpassed as a means of detecting treatable CNS diseases such as cryptococcal, tuberculous, syphilitic, or lymphomatous meningitis. Recent validation of CSF PCR assays provide additional tools in the diagnosis of PML, CMV, HSV, VZV, and TB.(85)

To avoid possible herniation, lumbar puncture should not be performed in patients with altered mental status, papilledema, or a focal neurologic examination until the presence of a mass lesion has been ruled out by CT or MRI brain imaging.

transparent image
Brain Biopsy
transparent image

Biopsy is a reliable method for making a definitive diagnosis of intracranial disorders presenting as focal lesions on brain imaging, such as toxoplasmosis, lymphoma, and PML. Because the incidence of toxoplasmosis has declined dramatically in the setting of antiretroviral therapy, it is reasonable to consider brain biopsy early, rather than pursuing an empiric course of toxoplasmosis treatment, in patients receiving effective antiretroviral therapy. Brain biopsy should be strongly considered in patients with focal brain lesions who are either neurologically unstable or have only a solitary lesion on brain MRI, or who have negative antitoxoplasma serology. Nevertheless, the risks and benefits of brain biopsy must be carefully evaluated for each individual case, taking into account not only clinical factors, laboratory evaluation, and imaging studies, but, above all, the patient's particular situation and wishes.

transparent image
transparent image

References

transparent image
1.   Levy RM, Bredesen DE, Rosenblum ML. Neurological manifestations of the acquired immunodeficiency syndrome (AIDS): experience at UCSF and review of the literature. J Neurosurg. 1985 Apr;62(4):475-95.
transparent image
2.   Koppel BS, Wormser GP, Tuchman AJ, Maayan S, Hewlett D Jr, Daras M. Central nervous system involvement in patients with acquired immune deficiency syndrome (AIDS). Acta Neurol Scand. 1985 May;71(5):337-53.
transparent image
3.   Snider WD, Simpson DM, Nielsen S, Gold JW, Metroka CE, Posner JB. Neurological complications of acquired immune deficiency syndrome: analysis of 50 patients. Ann Neurol. 1983 Oct;14(4):403-18.
transparent image
4.   de la Monte SM, Ho DD, Schooley RT, Hirsch MS, Richardson EP Jr. Subacute encephalomyelitis of AIDS and its relation to HTLV-III infection. Neurology. 1987 Apr;37(4):562-9.
transparent image
5.  Rosenblum ML, Levy RM, Bredesen DE. AIDS and The Nervous System. New York: Raven Press, 1988.
transparent image
6.   Resnick L, Berger JR, Shapshak P, Tourtellotte WW. Early penetration of the blood-brain-barrier by HIV. Neurology. 1988 Jan;38(1):9-14.
transparent image
7.   Resnick L, diMarzo-Veronese F, Schupbach J, Tourtellotte WW, Ho DD, Muller F, Shapshak P, Vogt M, Groopman JE, Markham PD, et al. Intra-blood-brain-barrier synthesis of HTLV-III-specific IgG in patients with neurologic symptoms associated with AIDS or AIDS-related complex. N Engl J Med. 1985 Dec 12;313(24):1498-504.
transparent image
8.   McArthur JC, Cohen BA, Farzedegan H, Cornblath DR, Selnes OA, Ostrow D, Johnson RT, Phair J, Polk BF. Cerebrospinal fluid abnormalities in homosexual men with and without neuropsychiatric findings. Ann Neurol. 1988;23 Suppl:S34-7.
transparent image
9.  McGuire D, Greene WC. Neurological damage in HIV infection. In: Lever AML, ed. The Molecular Biology of HIV/AIDS. New York: John Wiley & Sons, 1996;127-142.
transparent image
10.   Miller EN, Selnes OA, McArthur JC, Satz P, Becker JT, Cohen BA, Sheridan K, Machado AM, Van Gorp WG, Visscher B. Neuropsychological performance in HIV-1-infected homosexual men: The Multicenter AIDS Cohort Study (MACS) Neurology. 1990 Feb;40(2):197-203.
transparent image
11.   Goethe KE, Mitchell JE, Marshall DW, Brey RL, Cahill WT, Leger GD, Hoy LJ, Boswell RN. Neuropsychological and neurological function of human immunodeficiency virus seropositive asymptomatic individuals. Arch Neurol. 1989 Feb;46(2):129-33.
transparent image
12.   Dore GJ, Correll PK, Li Y, Kaldor JM, Cooper DA, Brew BJ. Changes to AIDS dementia complex in the era of highly active antiretroviral therapy. AIDS. 1999 Jul 9;13(10):1249-53.
transparent image
13.   Ho DD, Pomerantz RJ, Kaplan JC. Pathogenesis of infection with human immunodeficiency virus. N Engl J Med. 1987 Jul 30;317(5):278-86.
transparent image
14.   Chiodi F, Valentin A, Keys B, Schwartz S, Asjo B, Gartner S, Popovic M, Albert J, Sundqvist VA, Fenyo EM. Biological characterization of paired human immunodeficiency virus type 1 isolates from blood and cerebrospinal fluid. Virology. 1989 Nov;173(1):178-87.
transparent image
15.   An SF, Giometto B, Scaravilli F. HIV-1 DNA in brains in AIDS and pre-AIDS: correlation with the stage of disease. Ann Neurol. 1996 Oct;40(4):611-7.
transparent image
16.   Glass JD, Fedor H, Wesselingh SL, McArthur JC. Immunocytochemical quantitation of human immunodeficiency virus in the brain: correlations with dementia. Ann Neurol. 1995 Nov;38(5):755-62.
transparent image
17.   Johnson RT, Glass JD, McArthur JC, Chesebro BW. Quantitation of human immunodeficiency virus in brains of demented and nondemented patients with acquired immunodeficiency syndrome. Ann Neurol. 1996 Mar;39(3):392-5.
transparent image
18.   Price RW, Staprans S. Measuring the "viral load" in cerebrospinal fluid in human immunodeficiency virus infection: window into brain infection? Ann Neurol. 1997 Nov;42(5):675-8.
transparent image
19.   Giulian D, Yu J, Li X, Tom D, Li J, Wendt E, Lin SN, Schwarcz R, Noonan C. Study of receptor-mediated neurotoxins released by HIV-1-infected mononuclear phagocytes found in human brain. J Neurosci. 1996 May 15;16(10):3139-53.
transparent image
20.   Pulliam L, Gascon R, Stubblebine M, McGuire D, McGrath MS. Unique monocyte subset in patients with AIDS dementia. Lancet. 1997 Mar 8;349(9053):692-5.
transparent image
21.   Neuenburg JK, Brodt HR, Herndier BG, Bickel M, Bacchetti P, Price RW, Grant RM, Schlote W. HIV-related neuropathology, 1985 to 1999: rising prevalence of HIV encephalopathy in the era of highly active antiretroviral therapy. J Acquir Immune Defic Syndr. 2002 Oct 1;31(2):171-7.
transparent image
22.   Kusdra L, McGuire D, Pulliam L. Changes in monocyte/macrophage neurotoxicity in the era of HAART: implications for HIV-associated dementia. AIDS. 2002 Jan 4;16(1):31-8.
transparent image
23.   Tracey I, Carr CA, Guimaraes AR, Worth JL, Navia BA, Gonzalez RG. Brain choline-containing compounds are elevated in HIV-positive patients before the onset of AIDS dementia complex: A proton magnetic resonance spectroscopic study. Neurology. 1996 Mar;46(3):783-8. Erratum in: Neurology 1996 Jun;46(6):1787.
transparent image
24.   Berger JR, Levy RM, Flomenhoft D, Dobbs M. Predictive factors for prolonged survival in acquired immunodeficiency syndrome-associated progressive multifocal leukoencephalopathy. Ann Neurol. 1998 Sep;44(3):341-9.
transparent image
25.   Clifford DB, Yiannoutsos C, Glicksman M, Simpson DM, Singer EJ, Piliero PJ, Marra CM, Francis GS, McArthur JC, Tyler KL, Tselis AC, Hyslop NE. HAART improves prognosis in HIV-associated progressive multifocal leukoencephalopathy. Neurology. 1999 Feb;52(3):623-5.
transparent image
26.   Soldan SS, Berti R, Salem N, Secchiero P, Flamand L, Calabresi PA, Brennan MB, Maloni HW, McFarland HF, Lin HC, Patnaik M, Jacobson S. Association of human herpes virus 6 (HHV-6) with multiple sclerosis: increased IgM response to HHV-6 early antigen and detection of serum HHV-6 DNA. Nat Med. 1997 Dec;3(12):1394-7.
transparent image
27.   Ito M, Baker JV, Mock DJ, Goodman AD, Blumberg BM, Shrier DA, Powers JM. Human herpesvirus 6-meningoencephalitis in an HIV patient with progressive multifocal leukoencephalopathy. Acta Neuropathol (Berl). 2000 Sep;100(3):337-41.
transparent image
28.   Bossolasco S, Marenzi R, Dahl H, Vago L, Terreni MR, Broccolo F, Lazzarin A, Linde A, Cinque P. Human herpesvirus 6 in cerebrospinal fluid of patients infected with HIV: frequency and clinical significance. J Neurol Neurosurg Psychiatry. 1999 Dec;67(6):789-92.
transparent image
29.   Hall CD, Snyder CR, Messenheimer JA, Wilkins JW, Robertson WT, Whaley RA, Robertson KR. Peripheral neuropathy in a cohort of human immunodeficiency virus-infected patients. Incidence and relationship to other nervous system dysfunction. Arch Neurol. 1991 Dec;48(12):1273-4.
transparent image
30.   So YT, Holtzman DM, Abrams DI, Olney RK. Peripheral neuropathy associated with acquired immunodeficiency syndrome. Prevalence and clinical features from a population-based survey. Arch Neurol. 1988 Sep;45(9):945-8.
transparent image
31.   Schifitto G, McDermott MP, McArthur JC, Marder K, Sacktor N, Epstein L, Kieburtz K; Dana Consortium on the Therapy of HIV Dementia and Related Cognitive Disorders. Incidence of and risk factors for HIV-associated distal sensory polyneuropathy. Neurology. 2002 Jun 25;58(12):1764-8.
transparent image
32.   Falco V, Rodriguez D, Ribera E, Martinez E, Miro JM, Domingo P, Diazaraque R, Arribas JR, Gonzalez-Garcia JJ, Montero F, Sanchez L, Pahissa A. Severe nucleoside-associated lactic acidosis in human immunodeficiency virus-infected patients: report of 12 cases and review of the literature. Clin Infect Dis. 2002 Mar 15;34(6):838-46.
transparent image
33.   Breitbart W, Rosenfeld BD, Passik SD, McDonald MV, Thaler H, Portenoy RK. The undertreatment of pain in ambulatory AIDS patients. Pain. 1996 May-Jun;65(2-3):243-9.
transparent image
34.   Breitbart W, Dibiase L. Current perspectives on pain in AIDS. Oncology (Huntingt). 2002 Jul;16(7):964-8, 972; discussion 972, 977, 980, 982.
transparent image
35.   Breitbart W, Dibiase L. Current perspectives on pain in AIDS. Oncology (Huntingt). 2002 Jun;16(6):818-29, 834-5.
transparent image
36.  World Health Organization. Clinical practice guidelines. Washington DC: U.S. Department of Health and Human Services AHCPR Pub. #94-0592. 1994;14.
transparent image
37.   Breitbart W, McDonald MV. Pharmacologic pain management in HIV/AIDS. J Int Assoc Physicians AIDS Care. 1996 Jul;2(7):17-26.
transparent image
38.   Verma RK, Ziegler DK, Kepes JJ. HIV-related neuromuscular syndrome simulating motor neuron disease. Neurology. 1990 Mar;40(3 Pt 1):544-6.
transparent image
39.   Wiley CA. Neuromuscular diseases of AIDS. FASEB J. 1989 Nov;3(13):2503-11.
transparent image
40.   Cornblath DR, McArthur JC. Predominantly sensory neuropathy in patients with AIDS and AIDS-related complex. Neurology. 1988 May;38(5):794-6.
transparent image
41.   Simpson DM, Haidich AB, Schifitto G, Yiannoutsos CT, Geraci AP, McArthur JC, Katzenstein DA; ACTG 291 study team. Severity of HIV-associated neuropathy is associated with plasma HIV-1 RNA levels. AIDS. 2002 Feb 15;16(3):407-12.
transparent image
42.   Kieburtz KD, Giang DW, Schiffer RB, Vakil N. Abnormal vitamin B12 metabolism in human immunodeficiency virus infection. Association with neurological dysfunction. Arch Neurol. 1991 Mar;48(3):312-4.
transparent image
43.   Burkes RL, Cohen H, Krailo M, Sinow RM, Carmel R. Low serum cobalamin levels occur frequently in the acquired immune deficiency syndrome and related disorders. Eur J Haematol. 1987 Feb;38(2):141-7.
transparent image
44.   Harriman GR, Smith PD, Horne MK, Fox CH, Koenig S, Lack EE, Lane HC, Fauci AS. Vitamin B12 malabsorption in patients with acquired immunodeficiency syndrome. Arch Intern Med. 1989 Sep;149(9):2039-41.
transparent image
45.   Di Rocco A, Bottiglieri T, Werner P, Geraci A, Simpson D, Godbold J, Morgello S. Abnormal cobalamin-dependent transmethylation in AIDS-associated myelopathy. Neurology. 2002 Mar 12;58(5):730-5.
transparent image
46.   Lipkin WI, Parry G, Kiprov D, Abrams D. Inflammatory neuropathy in homosexual men with lymphadenopathy. Neurology. 1985 Oct;35(10):1479-83.
transparent image
47.   Small PM, McPhaul LW, Sooy CD, Wofsy CB, Jacobson MA. Cytomegalovirus infection of the laryngeal nerve presenting as hoarseness in patients with acquired immunodeficiency syndrome. Am J Med. 1989 Jan;86(1):108-10.
transparent image
48.   Said G, Lacroix C, Chemouilli P, Goulon-Goeau C, Roullet E, Penaud D, de Broucker T, Meduri G, Vincent D, Torchet M, et al. Cytomegalovirus neuropathy in acquired immunodeficiency syndrome: a clinical and pathological study. Ann Neurol. 1991 Feb;29(2):139-46.
transparent image
49.   Cornblath DR, McArthur JC, Kennedy PG, Witte AS, Griffin JW. Inflammatory demyelinating peripheral neuropathies associated with human T-cell lymphotropic virus type III infection. Ann Neurol. 1987 Jan;21(1):32-40.
transparent image
50.   de Gans J, Tiessens G, Portegies P, Tutuarima JA, Troost D. Predominance of polymorphonuclear leukocytes in cerebrospinal fluid of AIDS patients with cytomegalovirus polyradiculomyelitis. J Acquir Immune Defic Syndr. 1990;3(12):1155-8.
transparent image
51.   So YT, Olney RK. Acute lumbosacral polyradiculopathy in acquired immunodeficiency syndrome: experience in 23 patients. Ann Neurol. 1994 Jan;35(1):53-8.
transparent image
52.   Kayser C, Campbell R, Sartorious C, Bartlett M. Toxoplasmosis of the conus medullaris in a patient with hemophilia A-associated AIDS. Case report. J Neurosurg. 1990 Dec;73(6):951-3.
transparent image
53.   Lanska MJ, Lanska DJ, Schmidley JW. Syphilitic polyradiculopathy in an HIV-positive man. Neurology. 1988 Aug;38(8):1297-301.
transparent image
54.   Cohen BA. Prognosis and response to therapy of cytomegalovirus encephalitis and meningomyelitis in AIDS. Neurology. 1996 Feb;46(2):444-50.
transparent image
55.   Till M, MacDonell KB. Myopathy with human immunodeficiency virus type 1 (HIV-1) infection: HIV-1 or zidovudine? Ann Intern Med. 1990 Oct 1;113(7):492-4.
transparent image
56.   Dalakas MC, Illa I, Pezeshkpour GH, Laukaitis JP, Cohen B, Griffin JL. Mitochondrial myopathy caused by long-term zidovudine therapy. N Engl J Med. 1990 Apr 19;322(16):1098-105.
transparent image
57.   Mhiri C, Baudrimont M, Bonne G, Geny C, Degoul F, Marsac C, Roullet E, Gherardi R. Zidovudine myopathy: a distinctive disorder associated with mitochondrial dysfunction. Ann Neurol. 1991 Jun;29(6):606-14.
transparent image
58.   Simpson DM, Bender AN. Human immunodeficiency virus-associated myopathy: analysis of 11 patients. Ann Neurol. 1988 Jul;24(1):79-84.
transparent image
59.   Simpson DM, Bender AN, Farraye J, Mendelson SG, Wolfe DE. Human immunodeficiency virus wasting syndrome may represent a treatable myopathy. Neurology. 1990 Mar;40(3 Pt 1):535-8.
transparent image
60.   Lange DJ. AAEM minimonograph #41: neuromuscular diseases associated with HIV-1 infection. Muscle Nerve. 1994 Jan;17(1):16-30.
transparent image
61.   Petito CK, Navia BA, Cho ES, Jordan BD, George DC, Price RW. Vacuolar myelopathy pathologically resembling subacute combined degeneration in patients with the acquired immunodeficiency syndrome. N Engl J Med. 1985 Apr 4;312(14):874-9.
transparent image
62.   Dal Pan GJ, Glass JD, McArthur JC. Clinicopathologic correlations of HIV-1-associated vacuolar myelopathy: an autopsy-based case-control study. Neurology. 1994 Nov;44(11):2159-64.
transparent image
63.   Rosenblum M, Scheck AC, Cronin K, Brew BJ, Khan A, Paul M, Price RW. Dissociation of AIDS-related vacuolar myelopathy and productive HIV-1 infection of the spinal cord. Neurology. 1989 Jul;39(7):892-6.
transparent image
64.   Dixon AC, Dixon PS, Nakamura JM. Infection with the human T-lymphotropic virus type I. A review for clinicians. West J Med. 1989 Dec;151(6):632-7.
transparent image
65.   Johnson RT, McArthur JC. Myelopathies and retroviral infections. Ann Neurol. 1987 Feb;21(2):113-6.
transparent image
66.   Ziegler JL, Drew WL, Miner RC, Mintz L, Rosenbaum E, Gershow J, Lennette ET, Greenspan J, Shillitoe E, Beckstead J, Casavant C, Yamamoto K. Outbreak of Burkitt's-like lymphoma in homosexual men. Lancet. 1982 Sep 18;2(8299):631-3.
transparent image
67.   Doll DC, Yarbro JW, Phillips K, Klott C. Mycobacterial spinal cord abscess with an ascending polyneuropathy. Ann Intern Med. 1987 Feb;106(2):333-4.
transparent image
68.   Dix RD, Bredesen DE, Erlich KS, Mills J. Recovery of herpesviruses from cerebrospinal fluid of immunodeficient homosexual men. Ann Neurol. 1985 Nov;18(5):611-4.
transparent image
69.   Britton CB, Mesa-Tejada R, Fenoglio CM, Hays AP, Garvey GG, Miller JR. A new complication of AIDS: thoracic myelitis caused by herpes simplex virus. Neurology. 1985 Jul;35(7):1071-4.
transparent image
70.   Tucker T, Dix RD, Katzen C, Davis RL, Schmidley JW. Cytomegalovirus and herpes simplex virus ascending myelitis in a patient with acquired immune deficiency syndrome. Ann Neurol. 1985 Jul;18(1):74-9.
transparent image
71.   Denning DW, Anderson J, Rudge P, Smith H. Acute myelopathy associated with primary infection with human immunodeficiency virus. Br Med J (Clin Res Ed). 1987 Jan 17;294(6565):143-4.
transparent image
72.   Weber T, Frye S, Bodemer M, Otto M, Luke W. Clinical implications of nucleic acid amplification methods for the diagnosis of viral infections of the nervous system. J Neurovirol. 1996 Jun;2(3):175-90.
transparent image
73.   Luft BJ, Remington JS. AIDS commentary. Toxoplasmic encephalitis. J Infect Dis. 1988 Jan;157(1):1-6.
transparent image
74.  Israelski DM, Dannemann BR, Remington JS. Toxoplasmic encephalitis in patients with AIDS. In: Sande MA, Volberding PA, eds. The Medical Management of AIDS. Philadelphia: WB Saunders 1990:241-266.
transparent image
75.   McArthur JC. Neurologic manifestations of AIDS. Medicine (Baltimore). 1987 Nov;66(6):407-37.
transparent image
76.   Porter SB, Sande MA. Toxoplasmosis of the central nervous system in the acquired immunodeficiency syndrome. N Engl J Med. 1992 Dec 3;327(23):1643-8.
transparent image
77.   Levy RM, Mills CM, Posin JP, Moore SG, Rosenblum ML, Bredesen DE. The efficacy and clinical impact of brain imaging in neurologically symptomatic AIDS patients: a prospective CT/MRI study. J Acquir Immune Defic Syndr. 1990;3(5):461-71.
transparent image
78.   Chuck SL, Sande MA. Infections with Cryptococcus neoformans in the acquired immunodeficiency syndrome. N Engl J Med. 1989 Sep 21;321(12):794-9.
transparent image
79.   Dismukes WE. Cryptococcal meningitis in patients with AIDS. J Infect Dis. 1988 Apr;157(4):624-8.
transparent image
80.   Zuger A, Louie E, Holzman RS, Simberkoff MS, Rahal JJ. Cryptococcal disease in patients with the acquired immunodeficiency syndrome. Diagnostic features and outcome of treatment. Ann Intern Med. 1986 Feb;104(2):234-40.
transparent image
81.   Ho DD, Rota TR, Schooley RT, Kaplan JC, Allan JD, Groopman JE, Resnick L, Felsenstein D, Andrews CA, Hirsch MS. Isolation of HTLV-III from cerebrospinal fluid and neural tissues of patients with neurologic syndromes related to the acquired immunodeficiency syndrome. N Engl J Med. 1985 Dec 12;313(24):1493-7.
transparent image
82.   Berger JR, Kaszovitz B, Post MJ, Dickinson G. Progressive multifocal leukoencephalopathy associated with human immunodeficiency virus infection. A review of the literature with a report of sixteen cases. Ann Intern Med. 1987 Jul;107(1):78-87.
transparent image
83.   McGuire D, Barhite S, Hollander H, Miles M. JC virus DNA in cerebrospinal fluid of human immunodeficiency virus-infected patients: predictive value for progressive multifocal leukoencephalopathy. Ann Neurol. 1995 Mar;37(3):395-9. Erratum in: Ann Neurol 1995 May;37(5):687.
transparent image
84.   Segarra-Newnham M, Vodolo KM. Use of cidofovir in progressive multifocal leukoencephalopathy. Ann Pharmacother. 2001 Jun;35(6):741-4.
transparent image
85.   Antinori A, Ammassari A, De Luca A, Cingolani A, Murri R, Scoppettuolo G, Fortini M, Tartaglione T, Larocca LM, Zannoni G, Cattani P, Grillo R, Roselli R, Iacoangeli M, Scerrati M, Ortona L. Diagnosis of AIDS-related focal brain lesions: a decision-making analysis based on clinical and neuroradiologic characteristics combined with polymerase chain reaction assays in CSF. Neurology. 1997 Mar;48(3):687-94.
transparent image
86.   Burke DG, Kalayjian RC, Vann VR, Madreperla SA, Shick HE, Leonard DG. Polymerase chain reaction detection and clinical significance of varicella-zoster virus in cerebrospinal fluid from human immunodeficiency virus-infected patients. J Infect Dis. 1997 Oct;176(4):1080-4.
transparent image
87.   Vinters HV, Kwok MK, Ho HW, Anders KH, Tomiyasu U, Wolfson WL, Robert F. Cytomegalovirus in the nervous system of patients with the acquired immune deficiency syndrome. Brain. 1989 Feb;112 ( Pt 1):245-68.
transparent image
88.   Kim YS, Hollander H. Polyradiculopathy due to cytomegalovirus: report of two cases in which improvement occurred after prolonged therapy and review of the literature. Clin Infect Dis. 1993 Jul;17(1):32-7.
transparent image
89.   Hook EW 3rd. Syphilis and HIV infection. J Infect Dis. 1989 Sep;160(3):530-4.
transparent image
90.   Johns DR, Tierney M, Felsenstein D. Alteration in the natural history of neurosyphilis by concurrent infection with the human immunodeficiency virus. N Engl J Med. 1987 Jun 18;316(25):1569-72.
transparent image
91.   Sexually transmitted diseases treatment guidelines 2002. Centers for Disease Control and Prevention. MMWR Recomm Rep. 2002 May 10;51(RR-6):1-78.
transparent image
92.   Hook EW 3rd, Marra CM. Acquired syphilis in adults. N Engl J Med. 1992 Apr 16;326(16):1060-9.
transparent image
93.   Lukehart SA, Hook EW 3rd, Baker-Zander SA, Collier AC, Critchlow CW, Handsfield HH. Invasion of the central nervous system by Treponema pallidum: implications for diagnosis and treatment. Ann Intern Med. 1988 Dec 1;109(11):855-62.
transparent image
94.  So YT, Choucair A, Davis RL, et al. Neoplasms of the central nervous system in acquired immunodeficiency syndrome. In:Rosenblum ML, Levy RM, Bredesen DE, eds. AIDS and the Nervous System. New York: Raven Press, 1988.
transparent image
95.   So YT, Beckstead JH, Davis RL. Primary central nervous system lymphoma in acquired immune deficiency syndrome: a clinical and pathological study. Ann Neurol. 1986 Nov;20(5):566-72.
transparent image
96.   Ciricillo SF, Rosenblum ML. Use of CT and MR imaging to distinguish intracranial lesions and to define the need for biopsy in AIDS patients. J Neurosurg. 1990 Nov;73(5):720-4.
transparent image
97.   Baumgartner JE, Rachlin JR, Beckstead JH, Meeker TC, Levy RM, Wara WM, Rosenblum ML. Primary central nervous system lymphomas: natural history and response to radiation therapy in 55 patients with acquired immunodeficiency syndrome. J Neurosurg. 1990 Aug;73(2):206-11.
transparent image
98.   Formenti SC, Gill PS, Lean E, Rarick M, Meyer PR, Boswell W, Petrovich Z, Chak L, Levine AM. Primary central nervous system lymphoma in AIDS. Results of radiation therapy. Cancer. 1989 Mar 15;63(6):1101-7.
transparent image
99.   Chow KU, Mitrou PS, Geduldig K, Helm EB, Hoelzer D, Brodt HR. Changing incidence and survival in patients with aids-related non-Hodgkin's lymphomas in the era of highly active antiretroviral therapy (HAART). Leuk Lymphoma. 2001 Mar;41(1-2):105-16.
transparent image
100.   Schwenk J, Gosztonyi G, Thierauf P, Iglesias J, Langer E. Wernicke's encephalopathy in two patients with acquired immunodeficiency syndrome. J Neurol. 1990 Nov;237(7):445-7.
transparent image
101.   Engstrom JW, Lowenstein DH, Bredesen DE. Cerebral infarctions and transient neurologic deficits associated with acquired immunodeficiency syndrome. Am J Med. 1989 May;86(5):528-32.
transparent image
102.   Berger JR, Harris JO, Gregorios J, Norenberg M. Cerebrovascular disease in AIDS: a case-control study. AIDS. 1990 Mar;4(3):239-44.
transparent image
103.   Holtzman DM, Kaku DA, So YT. New-onset seizures associated with human immunodeficiency virus infection: causation and clinical features in 100 cases. Am J Med. 1989 Aug;87(2):173-7.
transparent image
104.   Grant I, Atkinson JH, Hesselink JR, Kennedy CJ, Richman DD, Spector SA, McCutchan JA. Evidence for early central nervous system involvement in the acquired immunodeficiency syndrome (AIDS) and other human immunodeficiency virus (HIV) infections. Studies with neuropsychologic testing and magnetic resonance imaging. Ann Intern Med. 1987 Dec;107(6):828-36. Erratum in: Ann Intern Med 1988 Mar;108(3):496.
transparent image
105.   Appleman ME, Marshall DW, Brey RL, Houk RW, Beatty DC, Winn RE, Melcher GP, Wise MG, Sumaya CV, Boswell RN. Cerebrospinal fluid abnormalities in patients without AIDS who are seropositive for the human immunodeficiency virus. J Infect Dis. 1988 Jul;158(1):193-9.
transparent image
106.   Hollander H, McGuire D, Burack JH. Diagnostic lumbar puncture in HIV-infected patients: analysis of 138 cases. Am J Med. 1994 Mar;96(3):223-8.
transparent image
107.  Engstrom JW, Lewis E, McGuire D. Cranial neuropathy and the acquired immunodeficiency syndrome. Neurology 1991;41:374.
transparent image
transparent image