MEDICAL MANAGEMENT OF AIDS PATIENTS

0025-7125/92 $0.00 + .20

CENTRAL AND PERIPHERAL NERVOUS SYSTEM ABNORMALITIES Bruce James Brew, MBBS, FRACP

Infection with the human immunodeficiency virus type 1 (HIV-l) is often associated with a number of neurologic complications that may involve each part of the neuraxis. 9 This article classifies the complications in a clinical framework and discusses ana to mic site and etiologic agent. Prior to detailed consideration of these complications, certain principles should be outlined. First, these sequelae are "time locked" to the degree of advancement of HIV-l infection. That is, particular disorders are largely, and in some cases exclusively, related to the level of immune compromise. A conceptual framework for this is presented in Tables 1 and 2, where in broad terms it can be appreciated that the dementia, for example, is associated with advanced HIV-l infection whereas demyelinating neuropathy is a feature of an earlier stage of HIV-l infection. Systemic HIV-l infection is currently staged in approximate terms according to the CD4 cell count, and it is useful to apply this to the neurologic complications. In the early and clinically "latent" phases of the infection, the CD4 cell count is usually normal. Only rarely is seroconversion associated with a fall in CD4 cell counts that then return to normal after several months. 18 The next phase of the illness approximates CD4 cell counts between 2S0/mm3 and SOO/mm3 , while the advanced stage is characterized by counts below 2S0/mm3 • The second principle is that of "parallel tracking," by which it is meant that multiple levels of the neuraxis may be involved simultaneFrom the National Centre in HIV Epidemiology and Clinical Research, St. Vincent's Medical Centre; and the University of New South Wales, KenSington, Sydney, Australia THE MEDICAL CLINICS OF NORTH AMERICA VOLUME 76 • NUMBER 1 • JANUARY 1992

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Table 1. CENTRAL NEUROLOGIC COMPLICATIONS OF HIV-1 INFECTION AS A FUNCTION OF ADVANCEMENT OF HIV-1 INFECTION SystemiC Disease Stage Complication

Early

Acute encephalitis Subacute syndromes Aseptic meningitis HIV-1 headache AIDS dementia complex Asymptomatic infection Opportunistic infection Primary CNS lymphoma Metastatic systemic lymphoma Seizures Transient neurologic disorders

Clinically Latent

Early-Late

Late

~---------?----------~

ously. Thus, in the evaluation of a patient it may not be pertinent to search for a single disease that leads to peripheral neuropathy, hemiparesis, and seizures. Such a patient is more likely to have, for example, an HIV -1 related peripheral neuropathy existing in parallel with an opportunistic infection such as cerebral toxoplasmosis. Understanding of this concept then highlights the "background" neurologic signs such as impaired fine finger movements, primitive reflexes, brisk leg jerks, and mild peripheral neuropathy that are so common in patients with advanced HIV-1 infection and that serve as a substrate upon which the signs of an opportunistic infection are "grafted." The third principle is that of "diagnostic flexibility." Not infrequently, patients develop complications in addition to those that were previously diagnosed. This is especially relevant to demented patients Table 2. PERIPHERAL NEUROLOGIC COMPLICATIONS OF HIV-1 INFECTION AS A FUNCTION OF ADVANCEMENT OF HIV-1 INFECTION Systemic Disease Stage Complication Acute demyelinating neuropathy Chronic demyelinating neuropathy Mononeuropathies Mononeuritis multiplex Autonomic neuropathy Sensorimotor neuropathy Distal painful sensory neuropathy Noninflammatory myopathies Polymyositis

Early

Clinically Latent

Early-Late

Late

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who initially respond to antiretroviral therapy and begin to relapse. It is not sufficient to say that such patients show progressive dementia. It behooves the clinician to be flexible, to consider when appropriate an additional complication, and to reinvestigate the patient for other disorders such as toxoplasmosis and lymphoma. With these principles in mind, this review will briefly consider the early manifestations of neurologic involvement by HIV-1 and then the aspects of more advanced involvement. EARLY NEUROLOGIC INVOLVEMENT BY HIV-1

In this section the neurologic sequelae of initial HIV -1 infection are described along with those complications that may occur later but while the patient is still systemically well. Acute Syndromes and a Multiple Sclerosis-like Illness

Shortly after the glandular fever-like illness that is associated with initial infection by HIV-1,17 patients may develop a variety of neurologic disorders.8 Aseptic meningitis, encephalitis, cerebellar syndrome, brachial plexopathy, and neuropathy have all been described. Cerebrospinal fluid (CSF) analysis often reveals a mild mononuclear pleocytosis and raised protein. Other investigations such as computed tomography (CT) of the brain have been normal. Patients with these manifestations appear to do well over time. The pathogenesis of this group of disorders remains speculative as no autopsy studies have been performed. Probably, however, they are in part similar to the postinfectious encephalitides that have an auto immune basis for tissue damage. In the later phase of HIV-1 infection, but while the patient is still systemically well, rare patients may develop a syndrome very similar to multiple sclerosis. 2 , 39 It is still not clear whether this represents the concurrence of two disorders in the one patient; however, it is conceivable that it is related to HIV-1 and that it has an auto immune pathogenesis since it occurs at the time when other auto immune phenomena such as immune thrombocytopenic purpura occur. Aseptic MeningitiS and HIV-1 Headache

During the early phase of HIV -1 infection, aseptic meningitis may also occur, sometimes in combination with cranial neuropathies, especially in nerves V, VII, and VIII. 42, 51 Patients may have an acute presentation with a nonspecific headache over several days or a chronic form in which such headaches have been present in indolent fashion for months. 42 More recently, Brew et al have drawn attention to the fact that both acute and chronic nonspecific headaches may occur

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without a raised CSF cell count.7 It seems likely that headaches occurring with and without CSF pleocytosis are in fact the same disorder and that the CSF pleocytosis is a "background" abnormality (see below) that is not pathogenetically associated with the disorder. Low doses of amitriptyline are effective in managing the headaches, and it has been proposed that their pathogenesis is at least in part related to disturbed serotonin metabolism secondary to the systemic or local production of cytokines. Asymptomatic Neurologic Involvement

As opposed to the minority of individuals who develop neurologic complications at this stage of HIV-1 infection, the vast majority of individuals are asymptomatic. When they are investigated for other reasons, however, several abnormalities are often found. Perhaps the most important controversial finding at this stage of HIV -1 infection is that of neuropsychological dysfunction. Several groups have documented impaired neuropsychological test performance in the absence of any symptoms,38, 85 whereas other larger studies have not shown any deficit. 44 , 56, 57 Clearly, some of the discrepancy between these studies rests in the confounding influences of substance abuse, anxiety, and depression. Furthermore, asymptomatic HIV-1 infected patients are a heterogeneous group and some are at more advanced phases of the illness than others. Future studies will need to categorize patients according to the degree of advancement of HIV-1 infection by CD4 cell count and other surrogate markers. At the present time, all that can be said is that on a population basis, there is no definite evidence for functionally significant neuropsychological impairment. In distinction to the controversial presence of neuropsychologic abnormalities, there are frequent anomalies in the CSF of asymptomatic patients. Often aseptic meningitis is seen with a mild mononuclear pleocytosis usually of less than 100 mononuclear cells and elevated proteinY HIV-1 may be recovered from the CSF in a small percentage of patients and rarely p24, the core protein of HIV-1, may be found in the CSF. 15 , 55 Furthermore, when electrophysiologic tests are performed, abnormal results are not infrequent. The electroencephalogram is variably abnormal. Some workers have reported abnormalities,49 while others have not found any disturbance. 56 At present, there appears to be no resolution of these discrepancies. Somatosensory evoked potentials have also been found to be abnormal, 80 pointing to subclinical involvement of the spinal cord, usually in the thoracic area. Additionally, at least one study has found that long latency potentials may be abnormal-as well as the saccadic and pursuit systems of eye movements 24-in this group of patients. 37 Whether these disturbances have definite prognostic significance for the later development of conditions such as dementia is not known at the present time. It is apparent from these studies that the nervous system is

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commonly involved subclinically at this phase of the illness and this may interfere with the interpretation of other test abnormalities. For example, "background" CSF abnormalities of raised cell count and protein may make the interpretation of syphilis serology difficult. 41 Demyelinating Neuropathies

In the peripheral nervous system, a demyelinating neuropathy may occur acutely or chronically .19,67 The clinical presentation is identical to that of the non-HIV infected population, but investigations reveal a mild CSF mononuclear pleocytosis in contradistinction to the classic "albumino-cytologique dissociation" of Guillain-Barre syndrome. While speculative, it seems likely that the CSF pleocytosis represents the subclinical aseptic meningitis so common in HIV-l infected individuals. That is, the pleocytosis is an asymptomatic "background" abnormality brought to clinical attention by the chance occurrence of the neuropathy. Treatment with plasmapheresis is the same as in non-HIV-l infected patients and the response does not seem to be any different. LATE NEUROLOGIC INVOLVEMENT BY HIV-1

This section first considers the central nervous system disturbances directly related to HIV-l, followed by a discussion of the effects on the peripheral nervous system. The last section briefly discusses certain opportunistic infections and syphilis that are not covered elsewhere in this volume. AIDS Dementia Complex

As HIV-l infection advances and patients develop symptoms of what was previously termed "AIDS-related complex" (unexplained fevers, weight loss, and diarrhea), subacute dementia often in association with myelopathy (see below) frequently occurs. Alternately and perhaps more commonly, patients may develop the dementia and yet still be systemically well with CD4 cell counts between 2S0/mm3 and SOO/mm3 • With further progression of systemic HIV-l infection, the dementia becomes both more common and more severe. As it is difficult to distinguish between a cerebral and a spinal cord cause for leg weakness, the term AIDS dementia complex (ADC) has been used to describe the clinical syndrome. This is similar to other terms such as "HIV encephalopathy," "AIDS encephalopathy," and "subacute encephalitis." However, it is distinct from the pathologic term "HIV-l encephalitis," which is applicable only to a subgroup of ADC patients and is associated with demonstration of productive HIV-l infection of the brain.

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The dementia is characterized by disturbances in three spheres of functioning, namely cognition, motor function, and behavior. 61 Dysfunction often occurs in each of these, but the cognitive and motor disturbances are most closely linked. Patients complain of decreased concentration manifested as losing track of the conversation while speaking to people and having to reread a paragraph or page to get it to "sink in." Additionally, they complain of forgetfulness, usually for day-to-day events. Some patients note that their thoughts are slowed. Conjoined to these symptoms are motor complaints of clumsiness, sloppy handwriting, tremor, and poor balance, especially with rapid head turns. Less frequently, patients may be socially withdrawn and apathetic. It is not until late in the illness that insight is impaired, so patients can often accurately report these difficulties. Notably lacking are such cortical symptoms as aphasia, alexia, and agraphia, thereby distinctly stamping the disorder as a subcortical dementia. Complaints develop subacutely over a number of weeks to months; only rarely do some patients have a more fulminant presentation over days to weeks. In such cases, it usually becomes apparent that symptoms had been present for several weeks but were ignored by the patient. The prevalence of ADC has been variably estimated, with groups reporting rates ranging from 40% to 90%.9 This discrepancy is probably the consequence of the heterogeneity of the studied populations since patients vary in the degree of advancement of HIV-l disease. Another potential explanation is the failure to adequately exclude patients who had such confounding factors as fatigue, anxiety, and depression. One recent report has found a minimum prevalence of 30% in patients who had already been diagnosed as having AIDS. There were another 13% who were impaired on neuropsychological testing but who were excluded because of the presence of confounding conditions. 64 It is certainly conceivable that these patients had underlying dementia in addition to the confounding conditions, though it is not presently possible to diagnose ADC in such patients. Physical signs may be sparse at the beginning of the illness. The mini-mental state examination is often normal, although responses are delayed. Saccadic and pursuit eye movements are often slowed and inaccurate. Primitive reflexes such as the snout response are common and fine finger movements are slowed. Deep tendon reflexes are frequently brisker in the lower limbs, and not infrequently the ankle jerks may be depressed or absent as a consequence of a conjoined peripheral neuropathy. Similarly, sensory disturbance may be a result of neuropathy. Tandem gait is commonly abnormal. As the disorder progresses, patients become globally demented, mute, paraparetic, and incontinent of urine and feces. In order to stage ADC, a scheme has been developed that stratifies patients from 0 through 4 (Table 3).70 In addition to this scheme, the World Health Organization has developed a similar classification,87 although dementia is not recognized until stage 2. Investigations are essentially exclusionary as certain treatable infec-

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Table 3. PRICE AND BREW STAGING SCHEME FOR AIDS DEMENTIA COMPLEX Stage 0 (normal): Normal mental and motor function. Stage 0.5 (subclinical): Minimal or equivocal symptoms without impairment of work or activities of daily living (ADL). "Background" neurologic signs such as slowed fine finger movements and primitive reflexes may be present. Stage 1 (mild): Cognitive or motor deficit that compromises the performance of the more demanding aspects of work or ADL. Patients can walk without assistance. Stage 2 (moderate): Cognitive deficit makes the patient unable to perform work or the more demanding aspects of ADL. The patient may require a single prop for ambulation. Stage 3 (severe): Cognitive deficit makes it possible for the patient to perform only the most rudimentary tasks. The patient cannot follow news or sustain a conversation of any complexity. The patient requires a walker or personal support for ambulation. Stage 4 (end-stage): Cognitive deficit has reached the point where the patient has virtually no understanding of surroundings and is virtually mute. The patient is paraparetic or paraplegic, often with double incontinence. Adapted from Price RW, Brew BJ: The AIDS dementia complex. J Infect Dis 158:1079-1083,1988.

tions may exacerbate ADC to the point that its clinical manifestations overshadow those of the precipitant infection. CT brain scan almost always demonstrates cerebral atrophy, and magnetic resonance imaging may reveal T2-weighted periventricular abnormalities that are either patchy or diffuse. 45 However, these neuroradiologic abnormalities may occur in patients who are not demented. 56 CSF analysis may reveal the "background" abnormalities that occur in nondemented patients, but significant mononuclear pleocytosis may also be present. This may depend on the degree of immune compromise. Significant cell counts are usually found in individuals whose immune system is relatively preserved. In addition to abnormalities of cell count and protein, HIV1 antibodies may be found 73 and HIV-l itself may be culturedy,63 However, HIV-l antibodies are not found in every ADC patient and virus can be cultured from only approximately 30% of ADC patients. 63 The core protein of HIV-l, p24, is also infrequently found; approximately 50% of severely demented patients will not have detectable p24 in the CSF. 63, 69 Certain immunologic markers provide an objective correlate of ADC. Elevated CSF concentrations of ~2-microglobulin (~2M) (the invariant light chain of the major histocompatibility complex class 1),5 neopterin6 (a product of activated macrophages), and quinolinic acid40 are cross-sectionally related to both the presence and severity of ADC in patients without confounding illnesses such as other neurologic opportunistic infections or lymphoma. While ~2M and neopterin are markers of immune activation, quinolinic acid may itself be implicated in the pathogenesis of ADC since it is a neurotoxin acting through the N-methyl-D-aspartate receptor. 77 The neuropathology of ADC is characterized by four sets of abnormalities that often overlap. However, the precise interrelationships between these sets are unknown. 10, 48, 60 Most common is white

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matter pallor and gliosis with minimal or no inflammatory infiltrates. These changes are predominantly subcortical in location and may be found in patients who are either normal or mildly demented. Productive infection by HIV-1 is almost always absent. Less frequent is the finding of perivascular inflammatory infiltrates of multinucleated giant cells, again in a subcortical distribution. This finding correlates with the presence of significant ADC and with a limited degree of productive HIV -1 infection as demonstrated by immunohistochemical detection of HIV-1 p24 and in situ hybridization. Rarely, the pathology may be characterized by vacuolation throughout the white matter, the clinical correlate of which has yet to be delineated. Lastly, cortical atrophy with neuronal loss has been described, though how commonly this occurs and its relationship to clinical status are currently unknown. 48 Several anecdotal case reports 89 and a placebo-controlled triaP have demonstrated that ADC improves after treatment with zidovudine (ZDV). However, the optimal dose is not known. Since approximately 30% of ZDV crosses the blood-brain barrier,88 it is reasonable to expect that doses higher than those used for systemic infection would be necessary. The time needed for a maximal response is also unknown in precise terms, but from the ZDV placebo trial it would seem to be of the order of 8 weeks. Of similar concern is the possibility that the low doses of ZDV currently in use may not protect the patient against ADC at a later date. Moreover, only one report has attempted to examine the relationship between CSF abnormalities (anti-HIV-1 antibody, HIV-1 culture, and p24) and clinical response to an antiretroviral agent such as ZDV.63 CSF anti-HIV-1 antibody did not change with treatment, CSF culture became negative in 4 of 10 samples, and CSF p24 became negative in the one previously positive sample. ZDV did reduce the CSF concentrations of (32M, neopterin, and quinolinic acid, which was coincident with both neurologic and neuropsychological improvement. 63 From present data, two factors appear to determine response to ZDV: the dose used and the presence of macrophage-tropic strains of HIV-1 in the CSF. Because the optimal dose for ADC is unknown, most physicians would recommend the highest tolerable dose, usually 1 gl day. It is known from a small series of patients that some have macrophage-tropic strains of HIV-1Y Furthermore, preliminary data suggest that such strains occur much more commonly in the CSF of patients with ADC. 32 The efficacy of ZDV to inhibit HIV-1 replication in the macrophage is contentious: some studies show decreased efficacy,74 whereas one study shows efficacy in an in vitro system. 65 Thus, the presence of macrophage-tropic strains may influence the degree of response to antiretroviral intervention, but no in vivo studies have been performed. Other antiretroviral agents may also be beneficial in the treatment of ADC. Preliminary data on dideoxyinosine (ddI) suggest that it is effective in improving the neuropsychological deficits found in HIV-1 infected children. 12 Because ddI has limited penetration across the

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blood-brain barrier,S! the comparative efficacy of ddI and ZDV might be expected to favor ZDV. Another nucleoside analogue, dideoxycytidine (ddC), is being used in HIV-1 infection, but as it has poor CSF penetration33 it may not be an optimal agent for ADC treatment. Several newer antiretroviral agents, the non-nucleoside analogues, as well as the protease and tat inhibitors, are soon to enter clinical trials and hold promise of systemic and neurologic efficacy. The pathogenesis of ADC remains speculative, but certain "building blocks" can be used to gain a preliminary understanding of the disorder; vacuolar myelopathy seems to be a distinct disturbance and will be discussed separately. First, subclinical involvement of the nervous system is common throughout the long course of HIV-1 infection. Second, ADC is largely a feature of advanced HIV-1 disease when significant immunodeficiency exists. Third, there is a superficially paradoxical correlation between ADC severity and certain markers of immune activation, namely, 132M and neopterin. That is, ADC is related to increased immune activity in the form of cytokines at a time of decreased immune function. This is paralleled in the systemic circulation in AIDS when on the one hand there is profound immunodeficiency and on the other there is overactivity of the more "primitive" components of the immune system. 35 Fourth, pathology is largely restricted to the subcortical areas of the brain. While it is true that cortical changes of neuronal loss may be found, these have not been correlated with clinical deficit and seem at the moment unlikely to be significant when one considers the serial data from positron emission tomography studies of patients with ADC. 76 Moreover, certain parts of the brain seem peculiarly susceptible to the pathologic changes, especially the globus pallidus. 22 The fifth critical point is that productive infection of the brain is restricted to the mononuclear and macrophage cells and microglia. That is, the only resident brain cell that is infected is the ontogenetic equivalent of the macrophage, the microglial cell. Controversy still exists as to whether endothelial cells and oligodendroglia are infected; however, most investigators agree that while astrocytes can be infected in vitro, astrocytic infection in vivo does not occur. The sixth major point is that there is a clinical-virologic dissociation between the clinical severity of ADC and the amount of productive HIV-1 infection found at autopsy.22 Thus, it is not uncommon for patients to have severe ADC and disproportionately little in the way of demonstrable infection. Indeed, some cases of pediatric ADC show no evidence of infection despite the presence of severe dementia. 82 As to whether latent infection of the brain is important in pathogenesis, data exist from only one group that found a marked clinical-virologic dissociation. 36 Lastly, macrophage-tropic strains of HIV-1 seem to be more common in patients with ADC. 32 These considerations lead to several fundamental conclusions: (1) the viral burden in the brain is not the explanation of the clinical deficit; (2) host-mediated responses seem likely as candidate toxins; and (3)

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alternately or in addition, certain viral products may be involved in tissue damage. In order to better understand the pathogenesis of ADC, a model has been developed incorporating these points71 which has been modified to include more recent data. In essence, it is proposed that as systemic HIV -1 disease advances and there is progressive loss of CD4 cells, central nervous system infection can no longer be kept in check. Compensatory mechanisms are activated that result in the production of various cytokines that over time lead to central nervous system dysfunction. Additionally, the previously controlled central nervous system infection, which is likely located in the subcortical areas of the brain and the meninges, increases and becomes amplified by the circulating infected cells from the systemic circulation. The tissue damaged by the cytokines then becomes secondarily infected both by the now unchecked local brain infection and by the systemically circulating infected cells. Moreover, as the CD4 cell count falls, distinctly macrophage-tropic strains of HIV -1 are selected and these preferentially infect microglial cells. Indeed, such strains can productively infect microglial cells in primary culture. 83 As to specific mechanisms of tissue damage, there are at least two possibilities for which some evidence exist. Quinolinic acid has been shown to be increased in the CSF of patients with ADC,40 and it is known to be a neurotoxin acting through the N-methyl-D-aspartate receptor. 77 It is therefore possible that quinolinic acid is involved in tissue damage by way of release from imported infected cells or resident brain cells. Second, gp 120, the envelope glycoprotein of HIV-1, is also a neurotoxin,4 and it possibly also contributes to dysfunction. Preliminary evidence suggests that gp 120 may be produced in excess of whole virions so as to explain the clinical-virologic dissociation (Pinching A: personal communication). In approximately one-third of patients,66 there may also be a vacuolar myelopathy manifesting as a spastic paraparesis without a definite sensory level. Posterior column type sensory loss, namely, proprioception and vibration disturbance, is common and dominant over pinprick or light touch abnormalities. While the features of this myelopathy may exist alone and as such may be recognized when investigations have excluded other causes, the disorder often coexists with the dementia making it clinically difficult to ascertain whether the leg weakness is a result of the dementia or the myelopathy. Vacuolar myelopathy is pathologically characterized by changes that are very similar to those of subacute combined degeneration of the cord, although serum vitamin Bl2 levels are normal. In detail, there is degeneration of the posterior and lateral columns of the spinal cord along with separation of the myelin lamellae on electron microscopy. Lipid-laden macrophages are infrequent and probably secondary to tissue damage rather than instrumental in causation. Recent studies have demonstrated that this disorder is probably not the result of productive HIV-1 infection. 75 The spinal cord may also be affected by multinucleated cell infiltrates leading to a multinucleated cell myelitis,

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the spinal cord equivalent of the multinucleated cell encephalitis. This disorder is related to productive viral infection and not infrequently coexists with vacuolar myelopathy. Reports showing productive infection in the spinal cords of patients with vacuolar myelopathy seem to be from patients who have both vacuolar myelopathy and multinucleated cell myelitis. ll , 84 Response of either of these disturbances to antiretroviral therapy is unknown; however, anecdotal experience suggests that vacuolar myelopathy does not respond, whereas multinucleated cell myelitis does. These observations clearly need to be substantiated further. Peripheral Neuropathy

At the late stage of HIV-1 infection, involvement of the peripheral nervous system may take the form of a mononeuritis multiplex or a distal predominantly sensory neuropathy.62 The mononeuritis multiplex, first described by Lipkin et al,52 seems to occur when the CD4 cell count is below normal but not at the level where opportunistic infection might be expected «2S0/mm3). The disorder is rare and may require corticosteroids and chemotherapy for control. More common than mononeuritis multiplex is distal predominantly sensory neuropathy. Initially, this is characterized by subjective shading to temperature in the legs with absent or depressed ankle jerks and minimal or no symptoms. With time, the patients develop tingling or numbness in the feet, which may gradually spread to the knees. Less often are the hands involved. By and large, the neuropathy remains a dominantly sensory disturbance with little functional weakness. In a small proportion of patients, a painful distal sensory neuropathy develops that advances to the point where it is difficult for the patient to walk. 20 Treatment of the peripheral neuropathy is purely symptomatic. When pain is prominent, capsaicin cream may be useful and low doses of amitriptyline may also be beneficial. In the more advanced phase of HIV-1 infection, a small number of patients develop a clinically significant autonomic neuropathy.34 This may lead to postural hypotension, diarrhea, and sudden arrhythmias with the risk of death. 21 Once again, treatment is purely symptomatic with the use of agents such as fludrocortisone for stabilization of blood pressure. Myopathies

Myopathies that may be related to HIV-1 infection are still a poorly defined group. Rarely, patients may develop a nemaline rod type of myopathy, but the timing of this complication in relation to the degree of advancement of HIV-1 infection is unclear. 79 Similarly, an HIV-1 related polymyositis may also occur rarely, but its precise timing has

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not been delineated. 26 The management of such patients is often difficult as chemotherapy may exacerbate the underlying immunodeficiency. Treatment with intravenous gamma globulin may provide an avenue of treatment without further compromise of the immune system as it seems to do in other neurologic diseases. 16 The most important myopathy in HIV-1 infected individuals at the moment is that related to ZDV. The myopathy usually develops after 1 year on therapy and is manifest as wasting of the buttock muscles with associated leg weakness, though symptoms may be mild. 25 This is a mitochondrial myopathy with inhibition of gamma DNA polymerase by ZDV.I Preliminary data analysis suggests that this complication is related to the use of high doses of ZDV. Patients taking ZDV should have creatine kinase (CK) levels monitored on a regular basis so that ZDV can be decreased or ceased when serum CK increases. If the complication is recognized early, there is every reason to expect improvement and in some cases resolution. Seizures

Recently, it has become appreciated that seizures may occur in HIV-1 infection, not only as a result of an underlying opportunistic infection but also as a result of HIV-1 infection. 86 Such seizures have a high relapse rate, thereby making it important to commence indefinite therapy after the first seizure. 43 Most often treatment with phenytoin will be adequate. However, approximately 14% of patients develop a rash to the drug, necessitating a new anticonvulsant such as carbamazepine or clonazepam. Transient Neurologic Deficits and Strokes

Cerebrovascular complications may also occur in HIV -1 infection, often as the result of an underlying opportunistic infection or lymphoma or occasionally secondary to marantic endocarditis. However, it is becoming increasingly clear that some patients may have transient neurologic deficits without an underlying conditionY These usually do not lead to clinically apparent strokes, but at autopsy some 20% of patients have evidence of small areas of infarction in the basal ganglia. 59 The pathogenesis of these vascular events is unknown; however, it is conceivably related in part to the presence of anticardiolipin antibody, which has already been demonstrated in HIV-1 infected patients. 54 Treatment at the moment is no different from that used in the nonHIV-1 infected patient. Opportunistic Infections and Neoplasms

Opportunistic infections and neoplasms are discussed elsewhere in this issue, but mention will be made here of those complications

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that have distinct neurologic aspects or that have neurologic involvement as their only clinical expression. Cytomegalovirus

Cytomegalovirus (CMV) may affect the nervous system in two ways and seems to be a complication of very advanced HIV-l disease in that it is usually a consideration when CD4 cell counts are less than SO/mm3 • 23 First, a polyradiculopathy mainly affecting the legs with some spinal cord involvement may occur. 30 This is a rare complication,58 but its importance lies in the fact that it may respond to treatment if recognized at an early stage. Usually patients complain of an ascending numbness in both legs associated with leg weakness. Later, a degree of bladder disturbance is seen with an onset over a few days to weeks. Deep tendon reflexes are lost in the legs, and there is evidence of distal sensory loss with leg weakness. The hands are affected only if the disorder goes unrecognized. There is no definitive method of making the diagnosis; however, when the patient is further investigated, CSF analysis reveals a polymorphonuclear pleocytosis in the absence of any other identifiable organism. Presently, the sensitivity of CMV culture from CSF is unknown. In any case, the time required for a positive culture makes it of little practical significance. Treatment is with intravenous ganciclovir, which is modeled on therapy used in CMV retinopathy.29, 58 However, treatment is purely empirical since the disorder is rare and there have been no controlled studies to determine optimal dose and duration of induction. Patients are routinely placed on maintenance therapy indefinitely on the assumption that CMV will recur off treatment. The other disorder that CMV may cause is a poorly defined encephalitis that can develop over days to 1 to 2 weeks. 9 The clinical picture is marked by progressive obtundation, fevers, and seizures. CT brain scan is usually unremarkable, but CSF analysis shows a polymorphonuclear pleocytosis in the absence of any other identifiable cause. Once again, treatment is with ganciclovir, but data on its efficacy are unavailable. Progressive Multifocal Leukoencephalopathy

Progressive multifocal leukoencephalopathy is another rare disorder whose clinical picture is that of a multifocal deficit with onset over several weeks. Consciousness is almost always preserved and fevers are not part of the presentation. CT brain scan reveals areas of hypodensity without mass effect and usually without enhancement. Magnetic resonance scan of the brain is helpful, not only by showing more lesions more clearly but also by demonstrating that they are confined to the white matter and that the cortex is spared. 9 There is no

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proven therapy for this disorder, but several anecdotal reports have suggested the efficacy of cytosine arabinoside. 68 Presently, controlled trials are underway to address this issue. Syphilis

Some evidence indicates that syphilis may have a more aggressive course in AIDS patients, with neurologic complications occurring at an earlier time, and that the complications may be atypical. 3, 46, 47 Patients have been described who have presented with meningovascular syphilis after seemingly adequate treatment for primary syphilis,46 In addition to meningovascular syphilis, a polyradiculopathy has also been described. 50 Despite these disturbing reports, it should be remembered that such treatment failures did occur before AIDS and that unusually short times to progression have been recorded. 78 What is more important, however, is that the diagnosis of neurosyphilis in these patients may be exceptionally difficulf 7 since both HIV-1 and syphilis may have similar clinical manifestations and both frequently lead to CSF abnormalities. Certainly neurosyphilis may occur with a negative CSF VDRL and on occasion a negative FTA. 28,53 From a practical view point, clinical suspicion should be high in AIDS patients. If neurosyphilis is suspected, benzathine penicillin should be avoided since it has poor CSF penetration and intramuscular procaine penicillin or intravenous penicillin should be considered. APPROACH TO DIAGNOSIS

Having considered the above information, one may approach the patient in the following manner. First, the HIV-1 serologic state has to be determined if possible. If the patient refuses to have an HIV-1 test, certain clinical clues can enable the physician to assess the likelihood of patient infection. Most importantly, information can be gleaned from the history as to whether the patient has been involved in high risk behavior. Second, there may be clinical clues: the presence of Kaposi's sarcoma in covert sites such as the roof of the mouth, oral thrush, or oral hairy leukoplakia. Third, the peripheral blood count may show an anemia with leukopenia and lymphopenia. Additionally, the biochemical screen may show a raised total protein. Having established the likelihood of infection, it is then useful to have some idea as to the stage of the HIV-1 disease by assessing the CD4 cell count. If, however, it is clinically imperative to have an idea of the degree of advancement of HIV -1 disease before waiting several days for a CD4 cell count to become available, the patient should be asked about AIDS-related symptoms such as fevers, weight loss, and diarrhea. Furthermore, the presence of Kaposi's sarcoma, oral thrush, oral hairy leukoplakia, cachexia, and seborrheic dermatitis point to an advanced stage of HIV1 infection.

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Table 4. OPPORTUNISTIC CONDITIONS OF THE NERVOUS SYSTEM ACCORDING TO CLINICAL PRESENTATION Focal

Nonfocal

Toxoplasmosis Primary brain lymphoma Progressive multifocal leukoencephalopathy Herpes simplex virus 1 and 2 encephalitis Varicella zoster virus Tuberculous brain abscess Meningovascular syphilis Metastatic lymphoma Miscellaneous (aspergillosis, histoplasmosis, etc)

Cytomegalovirus radiculomyelopathy Cytomegalovirus encephalitis Tuberculous meningitiS Herpes simplex virus I and II encephalitis

After assessment of the HIV -1 status of the patient and its degree of advancement, the physician must then consider the ana to mic site of involvement. For disorders affecting the brain, this is best categorized into those that lead to a dominantly focal disturbance and those leading to a dominantly nonfocal disorder (Table 4). Clearly, such a classification is arbitrary and in individual cases distinction may become blurred. Nonetheless, the guiding principle is whether the presentation is dominantly focal or nonfocal. In considering the various possibilities, it is very useful to keep in mind that certain disorders are rarely, if ever, associated with nervous system involvement. The two most important of these are Kaposi's sarcoma and Mycobacterium aviumintracellulare. While it is correct that Kaposi's sarcoma may metastasize to the nervous system, it is exceptionally rare. Mycobacterium infection may involve the meninges or brain, but again such an occurrence is exceptionally uncommon. References 1. Arnaudo E, Dalakas M, Shanske S, et al: Depletion of muscle mitochondrial DNA in

AIDS patients with zidovudine-induced myopathy. Lancet 337:508-509, 1991 2. Berger JR, Sheremata W A, Resnick L, et al: Multiple sclerosis-like illness occurring with human immunodeficiency virus infection. Neurology 39:324-329, 1989 3. Berry CD, Hooton TM, Collier AC, et al: Neurologic relapse after benzathine penicillin therapy for secondary syphilis in a patient with HIV infection. N Engl J Med 316:1587-1589, 1987 4. Brenneman DE, Westbrook CL, Fitzgerald S, et al: Neuronal cell killing by the envelope protein of HIV and its prevention by vasoactive intestinal peptide. Nature 335:639-642, 1988 5. Brew Bl, Bhalla RB, F1eischer M, et al: Cerebrospinal fluid beta-2 microglobulin in patients infected with human immunodeficiency virus type 1. Neurology 39:830-834, 1989 6. Brew Bl, Bhalla RV, Paul M, et al: CSF neopterin in HIV-1 infection. Ann Neurol 28:556-560, 1990

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Address reprint requests to Bruce James Brew, MBBS National Centre in HIV Epidemiology and Clinical Research St. Vincent's Medical Centre Victoria Street Darlinghurst, Sydney, Australia 2010