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(Stroke. 2000;31:2117.)
© 2000 American Heart Association, Inc.
Original Contributions |
Cerebral Infarction in Adult AIDS Patients
Observations From the Edinburgh HIV Autopsy Cohort
From the Neurology Unit (M.D.C.), Department of Medicine, University of the Witwatersrand, Johannesburg, South Africa; the Department of Pathology (G.A.L.), University of Wales College of Medicine, Cardiff, Wales; and the Department of Pathology (Neuropathology) (J.E.B.), the Department of Clinical Neurosciences (C.P.W.), the Virus Evolution Group, Laboratory for Clinical and Molecular Virology (P.S.), and the Regional Infectious Disease Unit (R.D.B.), University of Edinburgh, Edinburgh, Scotland.
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Abstract |
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Background and Purpose—Autopsy series of patients with AIDS have found a 4% to 29% prevalence of cerebral infarction. Little is known of the prevalence of cerebral infarction when not associated with non-HIV central nervous system (CNS) infection, lymphoma, or cardioembolic sources. Clinical correlation has seldom been available. We describe the pathological and clinical features of patients from the Edinburgh HIV Cohort Study found to have had cerebral infarcts without evidence of non-HIV CNS infection, CNS lymphoma, or cardioembolic sources at autopsy.
Methods—From 183 autopsy cases, 26 without evidence of opportunistic cerebral infection or lymphoma were selected. These 26 cases went through a second selection process in which the presence of cerebral infarction, in the absence of the conditions mentioned, was verified. Histology and clinical records for the remaining patients were reviewed.
Results—Ten (5.5%) cases fulfilled the inclusion criteria and demonstrated similar hypoxic-ischemic lesions. Small-vessel thickening was seen in all cases, and perivascular space dilatation, rarefaction, and pigment deposition, with vessel wall mineralization and perivascular inflammatory cell infiltrates, were seen in some cases. Vasculitis was not found. One patient had had a transient ischemic attack, and no patient had had a stroke.
Conclusions—Cerebral infarcts in HIV-infected patients are not common in the absence of cerebral non-HIV infection, lymphoma, or embolic sources. We found an HIV-associated vasculopathy with similar features in all risk groups. In AIDS patients presenting with stroke or transient ischemic attack, potentially treatable causes, such as cerebral coinfection or tumor, should be sought.
Key Words: acquired immunodeficiency syndrome • cerebral infarction • pathology
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Introduction |
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TopAbstractIntroductionSubjects and MethodsResultsDiscussionReferences |
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Human immunodeficiency virus (HIV) invades the central nervous system (CNS) early.1 2 Any neurological manifestations may result from opportunistic infections, neoplasia, the immunological and metabolic response to HIV, iatrogenic causes, or corisk factors (eg, injection drug use), or they may be related directly to HIV itself.2 3 Indeed, postmortem neuropathological series reveal that CNS abnormalities occur in up to 90% of patients with advanced AIDS.2 4 5 In a clinical series, up to 70% of HIV-infected patients eventually develop neurological manifestations.6 Cerebral infarction in an HIV-infected patient may, at least in theory, result from any one of the causes listed in Table 1
,7 8 but a strokelike
clinical presentation is unusual, occurring in 
1%, with
cerebral hemorrhage constituting 32% of the
cases.9 On the other hand, autopsy series in adults have
found a much higher prevalence of cerebral infarction (4% to
29%),9 12 16 28 43 44 45 46 but the majority of studies do not
distinguish between cerebral infarcts associated with, and therefore
potentially caused by, non-HIV CNS infection, CNS lymphoma, or
cardioembolic sources and cerebral infarcts occurring in the absence of
these conditions.5 11 12 14 44 45 46 47 48 49 50 Furthermore, patient
risk factors for cerebral infarction, including drug misuse, are seldom
described,17 22 45 47 48 50 and no clinical correlation
has been available or very little is known about the patient’s
clinical course before
death.11 12 14 16 17 22 28 44 45 46 47 49 50 51 Therefore, it is
far from clear whether HIV itself causes cerebral infarction and (if it
does) whether the patients experience a stroke, transient
ischemic attack (TIA), or other neurological symptoms that are
indicative of neurovascular disease before
death.8
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The principal aims of the present study were (1) to establish whether cerebral infarcts occurred in the Edinburgh HIV autopsy cohort, in the absence of causes other than possibly HIV infection itself; (2) to describe the pathological characteristics of any cerebrovascular lesions; and (3) to retrospectively correlate the autopsy findings with relevant clinical features (in particular, symptoms and signs that would have been in keeping with neurovascular disease) and vascular risk factors.
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Subjects and Methods |
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TopAbstractIntroductionSubjects and MethodsResultsDiscussionReferences |
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Study Design and Population
We performed an observational pathology study of patients from the Edinburgh HIV Cohort Study, with clinical correlation. The Edinburgh HIV Cohort52 53 at the time of the study consisted of 1372 HIV-infected patients (28% homosexual patients, 48% intravenous drug users, 4% patients with blood product–related HIV, 17% heterosexual patients, and 3% patients with other or unknown risk factors for HIV infection), all prospectively followed up, of whom 535 had died. One hundred eighty-three (34%) of the patients (25% homosexual patients, 65% intravenous drug users, 5% heterosexual patients, and 5% other) had a full neuropathological post mortem. Forty-four of the 183 cases in the autopsy cohort were pre-AIDS cases; ie, they had not developed AIDS. Autopsies were requested on all patients, and results were not biased by dementia or other underlying clinical illness. There is virtually no overlap between the 2 major "at-risk" groups, with only 1 homosexual patient having been an injection drug user.
Methods
After formalin fixation, the brain was coronally sliced and
blocked according to an established protocol to include all areas of
the cerebrum, brain stem, and cerebellum.52 Sections of
the frontal lobe (in all cases) and additional blocks including
temporal and occipital cortex and basal ganglia (in most cases) were
stained immunohistochemically by use of an antibody to HIV p24 core
protein (Du Pont; diluted 1:200 and with microwave pretreatment,
immersed in 0.01 mol/L citric acid for 3x5 minutes).
Case selection was performed in 2 stages. First, all 183 autopsy reports were screened, and 157 cases were not selected for further detailed review if (1) the report clearly documented normal brain tissue; (2) an opportunistic cerebral infection was detected, such as toxoplasmosis, fungal infection, cytomegalovirus, varicella-zoster virus, herpes simplex virus, or mycobacterium; or (3) cerebral lymphoma was found. Cases with criteria 2 and 3 above were excluded because these conditions are all accepted causes of cerebral infarction in HIV-infected patients.4 11 12 16 17 18 19 20 21 22 23 26 27 54 Second, the CNS histology in the remaining 26 cases then went through another selection process, in which we checked that cases indeed had pathologically verified cerebral infarcts without pathological evidence of non-HIV cerebral infection, lymphoma, hemorrhage, traumatic injury, or potential sources of cerebral emboli. Sixteen cases were excluded for the following reasons (number of cases in parentheses): no infarcts or ischemic lesions seen on CNS pathology review (n=9), primary intracerebral hemorrhage (n=2), non-HIV viral encephalitis (n=1), basal meningitis (n=1), cerebral abscess (n=1), bacterial endocarditis with vegetations (n=1), and extensive head trauma (n=1). All histology on the remaining 10 cases was reviewed in detail, with the site and number of infarcts, their morphological features, any associated vessel abnormalities, and evidence of HIV encephalitis documented.
HIV-1 proviral load was determined in fresh, frozen, frontal lobe tissue from 9 of the 10 cases by nested polymerase chain reaction with the use of conserved primers from the pol region, followed by competitive polymerase chain reaction with the use of templates constructed from pol sequences.52 In 8 cases, this was performed separately on gray and white matter.
Clinical Review
For the 10 selected cases, all hospital and clinical records
were reviewed, including general practitioner (family
doctor) letters, clinical notes, inpatient notes, nursing notes, and
laboratory and radiology reports. The following clinical details were
elicited: patient demographic details, length of clinical follow up,
risk factors for HIV, intravenous and other drug misuse at
the time of death and before death, prescribed medications, disease
stage, vascular risk factors including family history of vascular
disease, documented diagnosis of ischemic heart disease,
cardiac failure or arrhythmia, peripheral vascular
disease, hypertension (defined as requiring treatment or based on a
clinical diagnosis made during the final admission), diabetes mellitus
(based on treatment or diagnosis documented in the clinical
record), and hypercholesterolemia
(requiring treatment, dietary modification, or documented in the
clinical record). Furthermore, any history of pulmonary
embolism, deep venous thrombosis, emboli to any site, or significant
hypoxia (PaO2 <50
mm Hg on arterial blood gas measurement) during the last
admission was noted. Detail was then sought on any history of
neurological problem at any time, including the nature of the onset,
history and examination findings, investigations performed,
neurological and psychiatric opinion sought, and relation to the onset
of a diagnosis of AIDS dementia complex. Records of investigations
were reviewed with emphasis on inflammatory markers (erythrocyte
sedimentation rate and C-reactive protein), tests of
blood coagulation, cholesterol levels, serology for any of
the infective conditions listed in Table 1
, and chest x-ray
reports. ECGs were reviewed, and all neuroradiological reports
performed at any time were reviewed in the context of any documented
neurological signs and symptoms.
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Results |
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Ten cases out of 183 autopsies (5.5%) fulfilled all the inclusion criteria. Relevant pathological findings and frontal lobe viral load estimates are shown in Table 2
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Gray Matter Lesions
The histological appearance of gray matter lesions
(Figure 1) was similar in all but one
case (case 1). Typical lesions were multiple and small, composed of
palely stained and rarefied brain tissue, with loss of neurons and
variable numbers of associated reactive astrocytes and microglial
cells. Some lesions were noncavitated, whereas others were completely
cavitated, with other lesions exhibiting a spectrum of degrees of
cavitation between these 2 extremes. Foamy macrophages were
seen in small numbers in a proportion of lesions, depending on the
histological age of the lesion and the degree of tissue
damage. Thus, macrophages were most conspicuous in subacute
or resolving lesions with extensive tissue necrosis and cavitation. The
histological age of lesions varied from old (at least 3
months) to acute (
1 day); this variation was apparent both between
and within cases. Thus, in some cases, lesions were of a similar
histological age; in some, the appearances suggested
2 "crops" of lesions; and in others, a wide range of lesion ages
was seen. The number of lesions per brain varied, with a clear
predilection for neocortex and basal ganglia. Neocortical lesions were
relatively evenly distributed throughout all 4 lobes. In 2 cases, there
was an apparent clustering of lesions in superficial cortical layers 2
and 3 (cases 4 and 9), whereas in others, there was an apparent
preference for deeper cortical layers (cases 3 and 7). Less commonly,
lesions were identified in the thalamus (4 cases), cerebellum (2
cases), and brain stem (1 case). In case 1, the appearances were
somewhat different, in that there was a small, old, solitary, linear,
cavitated infarct in the parietal cortex.
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In no case was there evidence of global, hemispheric, or regional vessel territory infarction, wedge-shaped cortical infarction, or intracerebral or subarachnoid hemorrhage. In 3 cases (cases 1, 6, and 10), focal lesions were superimposed on recent, more widespread, hypoxic-ischemic changes, which were interpreted as being due to agonal global cerebral circulatory insufficiency. These were most severe in case 6, in which a dilated cardiomyopathy, congestive cardiac failure, and hypoperfusion were dominant clinical features latterly.
White Matter Lesions
Generalized white matter rarefaction and gliosis with U-fiber
sparing was a conspicuous feature in case 8, whereas white matter
pallor and edema were seen in case 6 as a manifestation of agonal
hypoperfusion. All other cases exhibited a mild to moderate degree of
focal white matter rarefaction. There was a single focal white matter
infarct in case 10.
Vessel Pathology
Leptomeningeal vessels and main arteries on the circle of Willis
showed either no atherosclerosis (8 cases) or mild
intimal thickening only (cases 1 and 10). Penetrating
intracerebral vessels showed a mild to moderate degree
of concentric hyaline thickening in 9 of the 10 cases; thickening was
most severe in case 5. This was patchily distributed: in 3 cases, it
was most conspicuous in the basal ganglia (cases 1, 4, and 9); in 2
cases, it was most conspicuous in the deep white matter (cases 3 and
8); and in 4 cases, it appeared evenly distributed in the cortex, white
matter, and deep gray structures (cases 2, 5, 6, and 7). The cerebellum
in all cases was relatively spared, and in case 10, there was no
significant small-vessel thickening. These relatively mild structural
vessel wall changes were accompanied by variable degrees of
perivascular space dilatation and parenchymal rarefaction, the severity
of which paralleled the severity and distribution of small-vessel
thickening. Similarly, small perivascular deposits of pigment were a
feature in all cases; their presence was again correlated with a
small-vessel thickening and perivascular space dilatation and
rarefaction. Microvessel mineralization was observed in 4 cases (cases
1, 6, 7, and 9), particularly in the basal ganglia, with 3 of these 4
patients being drug users. Small numbers of perivascular inflammatory
cells, both lymphocytes and macrophages, were present in 5
cases, with 4 of them being drug users. Representative
vessel pathology is shown in Figure 2.
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In no case was there evidence of vasculitis. Small-vessel occlusion was not observed, with the exception of one possible intravascular thrombus in a small penetrating artery in the basal ganglia of case 2 and in a single neocortical penetrating artery in case 5. Fibrinoid necrosis of occasional neocortical and basal ganglia microvessels was a feature only in case 6; this brain was unusual in that it showed severe agonal global hypoxic-ischemic damage.
Other Brain Pathology
By definition, no brain harbored pathology due to trauma, tumor,
or opportunistic infection. Multinucleate giant cells were identified
in the brains of 1 homosexual patient, 4 drug users, and the sole
hemophiliac patient. In these 6 cases, HIV was identified by use of p24
immunohistochemistry, thus fulfilling the criteria for the
histological diagnosis of HIV
encephalitis.55 Other features included focal
leptomeningeal thickening and varying degrees of cerebral atrophy,
which were present in all cases.
Clinical Features
Patient characteristics are summarized in Table 3. In case 10, the only hemophiliac
patient, despite a detailed general practitioner’s summary
of the past medical history, hospital/clinic follow-up notes were
available for only 2 weeks before death, whereas for the remaining 9
cases, lengthy follow-up (20 to 224 months, mean 75 months) was
available. Vascular risk factors were not common for the group as a
whole (Table 3). Cardiac disease was present in only 1
patient (case 6), in whom there was no evidence of intracardiac
thrombus or vegetation at post mortem. Despite 5 patients having been
previous injection drug users, only 2 (cases 6 and 8) were misusing
drugs at the time of death. One patient (case 6) had been using oral
dihydrocodeine and diazepam, and another (case 8) had been using
injection as well as oral drugs (dihydrocodeine, temazepam, diazepam,
and methadone). None of the 10 patients had used heroin or cocaine
during the 6 months before death. All patients died before the
introduction of protease inhibitors into clinical practice
in Edinburgh, and anti-retroviral medication was limited to zidovudine
and didanosine, although only 2 patients were on anti-retroviral
medication at the time of death (cases 1 and 7). Patients were on
numerous prescribed medications in the months before death, but none of
these have been associated with cerebral infarction or
vasculopathy.
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All patients had advanced AIDS (Table 3). Two patients had
positive syphilis serology (although neither had evidence of vasculitis
or meningitis at autopsy), and 7 had positive cytomegalovirus serology,
although only 1 patient had circulating IgM antibodies. Hepatitis B or
C serology was positive in 7 patients, and low platelet counts were
present in 5, but none had histological evidence of
intravascular thrombi, hemorrhage, or other tissue changes in
keeping with cryoglobulinemia or disseminated intravascular
coagulation. A full coagulation profile, including proteins C and S,
was available for 1 patient (case 4) only. Plasma fibrinogen was raised
in 1 patient (case 9) but was measured only in 5.
Cholesterol levels were not available for any of the
patients. No obvious source of emboli was found at post mortem in any
patient.
Five of the 10 patients had no neurovascular symptoms or signs. In the
remaining 5 patients (Table 4), a
clinically evident stroke did not occur, and a diagnosis of TIA was
made in only 1 patient (case 4). One other patient (case 9) had
radiological evidence of basal ganglia infarction but no clinical
stroke syndrome. Cognitive changes were noted in 3 patients (cases 6,
8, and 9), and diagnoses of AIDS dementia complex were made 2, 1, and 4
years before death, respectively.
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Discussion |
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TopAbstractIntroductionSubjects and MethodsResultsDiscussionReferences |
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We found histopathological evidence of cerebral infarction in
1
in 20 of a large autopsy series of adult HIV cases (7% if one
considers only AIDS patients), after patients with cerebral
opportunistic infections, lymphoma, non-HIV infections, or sources of
cerebral emboli (all potential causes of cerebral infarction) had been
excluded. They all (drug users, homosexuals not using drugs, and 1
hemophiliac patient) had evidence of a nonvasculitic vasculopathy with
the same histopathologic features. The presence of the vasculopathy and
the extent of cerebral infarction were not associated with viral load.
Despite these pathological findings, only 1 patient had had a TIA
clinically, and no patient had had a clinically evident stroke. All
patients with evidence of cerebral infarction had AIDS and were thus
severely immunocompromised. Reviews of AIDS neuropathology have documented cerebral infarction in 4% to 29% of HIV-infected patients,9 12 16 17 28 44 45 46 but few studies have assessed how many patients had cerebral infarction in the absence of potential causes, such as cerebral opportunistic infections, lymphoma, or emboli from nonbacterial infective endocarditis.9 23 Some studies, however, have described their histopathologic findings, patient characteristics, and selection criteria in sufficient detail to enable us to work out the proportion of their patients with "isolated" cerebral infarcts and would have fulfilled (as far as we can assess) our selection criteria.16 28 43 51 The combined total of the 4 studies51 (22 of 356 patients fulfilling our selection criteria) gives a proportion of HIV-associated cerebral infarct cases (6%) that closely approximates our own. Variations in individual studies may reflect population differences, variation in patient selection for autopsy, or the small number of cases.
The vascular lesions in all our 10 cases were characterized by hyaline small-vessel thickening, perivascular space dilatation, rarefaction, and pigment deposition, with vessel wall mineralization and perivascular inflammatory cell infiltrates also seen in some cases. There were only occasional intravascular thrombi. Such changes are similar to those described by Mizusawa et al,28 although in their study opportunistic cerebral infection was a feature in 9 of 24 brains. Similar microvessel changes have also been described in an AIDS-related leukoencephalopathy attributed to HIV-1 infection.56 Mineralization of vessels has been noted previously in AIDS brains,22 57 particularly in children,58 and again has been suggested to be a direct effect of HIV on vessel walls.57 We did not see convincing evidence of vasculitis. This may reflect a different prevalence of varicella-zoster or herpes simplex infection because those viruses are said to mediate vasculitic pathologies,19 22 26 but this may also reflect different pathological criteria for the diagnosis of vasculitis. Thus, although vasculitis has been reported in the nervous system in HIV,28 17 30 31 34 59 its relation to HIV itself is unclear.55 60 Vasculitis must be distinguished from perivascular lymphocyte cuffing55 and should be diagnosed only when inflammatory cells are seen within the vessel wall and are associated with mural damage.
Several of the neuropathological features we describe are consistent with the effects of focal or diffuse blood-brain barrier breakdown, such as hyaline vessel wall thickening, perivascular space dilatation, rarefaction, and pigment deposition. Damage to the blood-brain barrier in HIV brains with leakage of serum protein has been reported,61 62 63 usually as a chronic diffuse phenomenon but also as a fatal, acute, relapsing variant.64 These vessel features are also commonly seen in aging non-HIV brains (cerebral arteriolosclerosis), exacerbated principally by hypertension and diabetes mellitus. However, none of the patients in this series were elderly, hypertensive, or diabetic.
Although small-vessel pathology similar to what we describe may be seen in HIV-negative drug-abuser brains (authors’ unpublished data, 1999), the fact that no vascular lesion was seen exclusively in any one HIV risk group suggests that in this series the changes are more likely a consequence of HIV infection itself. It has been claimed that HIV infects vascular endothelial cells,61 65 66 although this is disputed.56 67 68 Indeed, infection of endothelial cells with consequent blood-brain barrier breakdown has been advanced as at least a theoretically possible mechanism of HIV entry into the CNS.23 69 70 71 More specifically, HIV infection of vessel walls has been linked to focal blood-brain barrier breakdown56 and to vessel mineralization.57 Similar, though not identical, vascular changes have been found in HIV-infected patients in the pre-AIDS stage72 73 ; these changes are possibly the result of a lymphocyte T-cell reaction during early infection with HIV. In our series, neither the presence and distribution of HIV encephalitis nor the viral load was correlated with the number or distribution of the cerebral infarcts, although the small number of cases makes this correlation uncertain.
Altered vasoreactivity, alone or in combination with any of the above-mentioned factors, may, at least in theory, have contributed to the development of microinfarcts. Disturbed vasoreactivity in patients with HIV has recently been reported.29 Temporary vasospasm was one of the possible mechanisms involved in a recent study describing incomplete lacunar infarcts74 in non-HIV brains; incomplete lacunar infarcts are small foci of incompletely infarcted brain in deep gray structures that are similar in many respects to the microinfarcts that we describe in the brains of AIDS patients.
What else may have contributed to the cerebral infarcts in our patients? Two patients had positive syphilis serology, but in the absence of meningitis or vasculitis, this is unlikely to be relevant. None of the patients had significant atherosclerosis of their medium or large vessels, and there were no other arterial or cardiac sources of cerebral emboli detected during life or at autopsy. Other investigators have associated cerebral infarcts in HIV-infected patients with hepatitis B42 (hepatitis B or C serology was positive in 6 of our patients), as well as with a prothrombotic state related to protein S deficiency,35 36 antiphospholipid antibodies,39 40 or disseminated intravascular coagulopathy.4 11 12 We have protein S levels, which were normal, for only 1 patient, and none of our patients had antiphospholipid antibodies measured. Thus, the theoretical possibility of "hypercoagulability" remains, although intravascular thrombi, recent or organized, were seen only rarely in this and other autopsy series, even in those cases with very recent infarcts. The fact that "crops" of small cerebral infarcts of similar histological age were seen in some brains might suggest showers of microemboli or a transient hypercoagulable state, but this remains speculative. Infarcts were not a feature in other organs at autopsy, militating against cardiac embolism or a generalized hypercoagulable state.
We could not demonstrate a clear correlation between the pathological changes and clinical features of stroke or TIA in our patients. Five patients had no neurovascular symptoms at any stage. One patient had experienced recurrent anterior circulation TIAs that started 11 months before death, but no etiology was found on investigation on 2 separate occasions, although an angiogram was not performed. The diagnosis was changed to migraine on review by a neurologist because the attacks were slow in onset and were associated with headache, but the diagnosis was reversed again after a typical left partial anterior circulation TIA. As the TIAs resolved after the introduction of ganciclovir, one might speculate that the patient had a cytomegalovirus-induced vasculitis that was treated with ganciclovir. Alternatively, the cessation of the TIAs may have been entirely coincidental. None of our patients received highly active anti-retroviral therapy because they came to autopsy before the introduction of the newer anti-retroviral agents.
Several patients presented diagnostic difficulty not only to the attending physicians (cases 1, 2, 3, and 9) but also to the neurologists to whom they were referred (cases 1, 3, and 9). All 4 patients (cases 1, 2, 3, and 9) had recurrent transient neurological symptoms. One patient was diagnosed as having atypical migraine, and in the other 3 patients, the symptoms were thought to be seizure-related, although in 2 of them, a diagnosis of atypical migraine was entertained at some point. Recently, recurrent transient neurological deficits similar to those noted in our patients have been found to occur in clinical cohorts27 75 76 and have been linked to antiphospholipid antibodies27 77 or protein S deficiency.27
In conclusion, the present study suggests that cerebral infarcts in HIV-infected patients are not common in the absence of cerebral opportunistic infection, lymphoma, non-HIV infection, or embolic sources. We confirm the existence of an HIV-associated vasculopathy but highlight that this vasculopathy shows similar histopathologic features in all risk groups irrespective of drug use, hepatitis serology, or even syphilis serology. The possible relation of this vasculopathy to direct HIV infection of vessel walls should be further investigated. Finally, the present study supports the approach that in AIDS patients presenting with a stroke or TIA, potentially treatable causes, such as cerebral coinfection or tumor, be excluded before assuming that the cause is HIV itself, be that as a result of a vasculopathy or some as yet unrecognized pathogenic mechanism.
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Acknowledgments |
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Dr Lammie is funded by the Medical Research Council (MRC), UK, and the Edinburgh Brain and Tissue Resource is funded by a grant to Dr Bell (9708080) from the MRC, UK. The authors would like to thank Frances Brannan for providing expert technical support for the MRC HIV Brain Bank, Dr Alison Richardson for help with the Edinburgh HIV register, and Prof Peter Sandercock for constructive criticism.
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Footnotes |
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Reprint requests to M.D. Connor, FCP(SA), Neurology Unit, Department of Medicine, Faculty of Health Sciences, Medical School, 7 York Rd, Parktown 2193, South Africa.
Received February 16, 2000; revision received June 5, 2000; accepted June 6, 2000.
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