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.
| Entry of HIV into the Central Nervous System|
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)
| Pathogenesis of AIDS Dementia Complex|
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.
| Neuromuscular Disorders|
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.
| Classification of Neuromuscular Disorders|
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:
Distal symmetric polyneuropathy (DSPN)
Chronic inflammatory demyelinating polyneuropathy
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.
| Distal Symmetric Polyneuropathy|
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%.
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.
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.
| 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.
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.
| Mononeuropathy Multiplex|
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.
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)
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.
| 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.
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)
| Inflammatory Demyelinating Polyneuropathies|
| 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.
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.
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)
| Mitochondrial Toxicity: A Syndrome That May Mimic Guillain-Barré |
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.
| Progressive Lumbosacral Polyradiculopathy|
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.
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.
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)
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.
| 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.
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.
| 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)
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)
| 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.
| 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.
| 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.
| Spinal Cord Disorders|
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.
| Subacute Myelopathies|
| Vacuolar Myelopathy|
| 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.
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)
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.
| 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.
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.
| 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.
| Acute Myelopathies|
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.
| 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.
| Intracranial Disorders|
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.
| Primary HIV Infection of the Brain: HIV-1-Associated Dementia Complex|
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".
| Intracranial Opportunistic Infections|
| Toxoplasma gondii|
| 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.
| 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".
| 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.
| 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.
| 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.
| 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)
| 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.
| 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.
| 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)
| 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.
(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)
| 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.
(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.
| 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.
| 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)
| Complications of Systemic Diseases|
| 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)
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.