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Brain imaging in acquired immunodeficiency syndrome dementia complex
Brain Imaging in Acquired Immunodeficiency Syndrome Dementia Complex Elissa Lipcon Kramer and Joseph J. Sanger Human immunodeficiency virus (HIV) infections are accompanied by many different types of neurological complications. Opportunistic infections and neoplasms, particularly lymphoma, are often an underlying cause for these complications in patients w i t h acquired immunodeficiency syndrome (AIDS). Frequently, these can be detected by cerebrospinal fluid (CSF) examination, double-dose contrast transmission computed t o m o g r a p h y (CT), a n d / o r magnetic resonance imaging (MRI). It has become apparent t h a t the HIV itself is responsible for a significant percentage of neurological disease in t h e HIVseropositive individual. The onset may be subtle and may occur before t h e onset of frank immunosuppression. Diagnosis of HIV encephalitis or AIDS dementia c o m p l e x (ADC) is complicated by the f r e q u e n t coexistence of opportunistic infections. Structural neuroimaging (CT or MRI) shows a t r o p h y and in some
WIDE SPECTRUM of central nervous system (CNS) complications is found in the patient with human immunodeficiency virus (HIV) infection. Opportunistic infections and neoplasms, particularly CNS lymphoma, constitute a significant problem in these immunocompromised patients, but it also has become clear that the HIV virus itself is responsible for a syndrome of dementia. This dementia is accompanied by cognitive and motor abnormalities, and is observed in a large number of HIVseropositive individuals with or without other complications of HIV infection. This has been termed HIV encephalopathy, HIV subacute encephalitis, ] or acquired immunodeficiency syndrome (AIDS) dementia complex (ADC). 2 Although clinically there is a characteristic presentation, this presentation may overlap with other CNS complications of AIDS. Neuroimaging modalities such as computed tomography (CT) or magnetic resonance imaging (MRI) may be suggestive, but inconclusive and/or unrevealing, particularly early in the disease. On the other hand, functional neuroimaging modalities, both positron emission tomography (PET) and singlephoton emission computed tomography (SPECT), hold the potential for detecting HIV encephalitis in its early stages, because ADC causes functional abnormalities before gross anatomical changes are detectable with noninvasive means.
case w h i t e m a t t e r abnormalities, but imagingpathological correlation suggests t h a t these modalities are relatively insensitive t o the presence of HIV brain i n f e c t i o n . Functional n e u r o i m a g i n g , b o t h lefluorodeoxyglucose positron emission t o m o g r a p h y (PET) for evaluation of glucose metabolism and !z31 iodoamphetamine or m"Tc-HMPAO single-photon emission computed t o m o g r a p h y (SPECT) for evaluation of cerebral perfusion, can demonstrate abnormalities in t h e subcortical gray m a t t e r structures and the cerebral c o r t e x in patients w i t h ADC. These abnormalities may be observed early in the course of ADC even w h e n MRI is negative and the patient is relatively asymptomatic. Also, PET and SPECT may be useful to f o l l o w progression of t h e dementia or response t o therapy. 9 1990 b y W.B. Saunders Company.
A
INCIDENCE OF NEUROPSYCHIATRIC COMPLICATIONS
Neurological complications may occur in 30% l of patients with AIDS. Toxoplasmosis is a common cause of brain abscess in these patients and has been found in 10% to 13% 1'3 of patients with CNS complications. Progressive multifocal leukoencephalopathy caused by the Papova virus has been found in 2% to 6% T M of AIDS patients with CNS disease. Cryptococcus neoformans may cause meningitis. Other infections, including Mycobacterium avium intracellulare, herpes encephalitis (zoster or simplex), and Candida albicans I may be encountered. Primary CNS lymphoma occurs in about 6% ] of patients. Somewhat more common is involvement from a systemic neoplasm, again usually lymphoma. Peripheral neuropathies consistent with a demyelinating process also have been reported in 16% of one series of patients with AIDS-related neurological abnormalities ] and in 38% in an-
From the Division of Nuclear Medicine, Department of Radiology, N Y U Medical Center/Bellevue Hospital Center, New York, NY. Address reprint requests to Elissa Lipcon Kramer, MD, Division of Nuclear Medicine H W 215, NYU Medical Center, 560 First Ave, New York, N Y 10016. 9 1990 by W.B. Saunders Company. 0001-2998/90/2004-0006505.00/0
Seminars in Nuclear Medicine, Vol XX, No 4 (October), 1990: pp 353-363
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other series of patients with HIV-related lymphadenopathy syndrome: The ADC, which is believed secondary to direct infection of the brain by the HIV, comprises a larger percentage of CNS complications than opportunistic infections and neoplasms in AIDS patients) In one series of patients with a full-blown AIDS picture, ADC occurred in 11% 1 and constituted 36% (18 of 50) of the neurological complications. Navia et al 2 found clinical evidence of ADC in 65% of a series of 70 AIDS patients assessed clinically. Grant et al 6 found neuropsychometric impairment in 87% of AIDS patients. Approximately half of the patients with lymphadenopathy syndrome studied have shown neuropsychometric evidence of A D C : '6 Furthermore, ADC may occur even in the absence of evidence of immunodeficiency and opportunistic infections. 7 An increased incidence (44%) of neuropsychometric impairment has been found in subjects who are HIV seropositive but without any other markers of immune deficiency.6 In children, HIV encephalopathy presents as a slowing of milestone achievement and deterioration in cognitive function. The infection has been estimated to occur in 75% of AIDS-infected children: Autopsy data suggest a higher incidence of HIV brain involvement. At autopsy, the presence of HIV-infected cells in the brain has been identified in 23% to 61% 9"13 of AIDS patients with neurological abnormalities. Others have found virus present in cerebrospinal fluid (CSF), brain, or spinal cord in 73% of autopsied AIDS patients with neurological manifestations) 4 There are a variety of presentations of primary HIV viral infection of the brain for which there is both clinical and pathological evidence. The dementia complex, as described previously, has been observed in HIV-seropositive patients at all stages of HIV infection. In the early phases of HIV infection, probably at the time of seroconversion, a transient acute meningitis may occur in 5%-10%) '15'16 This may be associated with a flu-like syndrome (fever, myalgias, rash). Although other viruses may cause aseptic meningitis in the AIDS patient, HIV seems to be the most frequent infectious agent. 17A more chronic, indolent form of meningitis manifesting only w i t h headache and CSF pleocytosis has been described) 8 Chronic pleocytosis in patients with
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long-standing seropositivity has also been noted. 18 Vacuolar myelopathy, which causes progressive spastic paraparesis with gait ataxia, leg weakness, and incontinence, has also been described. 19 The myelopathy occurs in association with dementia. 2~ Primarily, the pathology affects the lateral and posterior columns of the spinal cord. At pathological examination, vascular infarcts are also observed. Leptomeningeal thickening may be present consistent with a meningitis. 9 However, most common is the subacute encephalopathy that is associated with ADC. Grossly, the brains of patients with ADC are atrophic, weighing less than brains of nondemented HIVseropositive individuals. However, Navia et al 2~ did not find a correlation between brain weight and severity of dementia in their study. The histological hallmark of ADC is multinucleated giant cells of monocytic origin.I~176These are usually seen in a perivascular distribution, but may also be parenchymal. Reactive astrocytosis is also a part of the histological presentation. 2~ This primarily involves the white matter and subcortical gray matter. 9'11'2~ Cerebellar and pontine involvement also has been described by several authors. 2~ Only infrequently is a predominant involvement of cortical gray matter noted. The involvement of the white matter is manifest by vacuolization, pallor, and areas of demyelinization.22 Microglial nodules occur frequently. These contain microglia, astrocytes, and macrophages. Navia et al 2~ found these to be associated with cytomegalovirus (CMV) inclusions, and Vazeux et al ll have not found a high concentration of HIV-infected cells in these microglial nodules, suggesting that nodules may be more associated with CMV infections than HIV. Very recently, Chrysikopoulos et a123 have described microglial nodules in HIV encephalitis without direct association with CMV. HIV has been found to be concentrated in more loosely scattered monocytes, microglial cells, macrophages, or endothelial cells, m21'24"26 Although it is known that the HIV virus is trophic for CD4 + cells, HIV has been most often localized to C D 4 - microglia) 1 It has been proposed that monocytes serve as a reservoir of the virus and serve as the m , : a n ~ of retrovirus entrance h~Lc:the br4i~7~.~7 [~ecau~e oi" ~b~f~?rcq;.~ent associa~.k,n n.,~g,:dbetwe~r, t.:.,.:~'~-,r., ~ a~d x~:P'~ ,; i:t 1-1~e ....
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brain, it has been suggested that the immune response to an opportunistic infection (like CMV) may underly or increase the initial entrance of the already infected monocytes into the brain. Another explanation for the presence of viralladen macrophages in the brain has been the transformation of infected microglia into macrophages with multinucleated cell formation.H The affect on the brain may be due to virusactivation of monocytes or macrophages with subsequent production or release of monokines, for example, tumor necrosis factor, which may have toxic effects on the surrounding tissue. 28 A third possibility proposed is that HIV infection occurs by infection of the endothelial cells with breakdown in the blood-brain barrier, 26 permitting entrance of toxic substances. Less likely is the possibility of direct neuronal infection by HIV, because viral antigen is so rarely identified in neural cells) s CLINICAL MANIFESTATIONS
ADC, which has been termed a subcortical dementia, is characterized by progressive cognitive impairment with behavioral and motor abnormalities.2 The neuropsychiatric manifestations vary greatly. Patients may present with frank delirium, 14delusional states, 29 or a picture easily confused with depressionJ 2 The early manifestations of loss of cognitive function include forgetfulness, inattentiveness, slowed mentation, and confusion.2 On mental status testing, both verbal and motor responses may be slowed. Neuropsychometric testing reported by Grant et al 3~found abnormalities most frequently in tests of problem solving, speeded information processing, and memory, particularly in new information retrieval. Others have found abnormalities in language, verbal cognitive skills, motor speed, and rapid visual scanning) Patients are frequently unable to draw a clock. 3~The behavioral manifestations are marked most commonly by apathy and social withdrawal. These may be difficult to distinguish from depression in these patients. Dysphoria and organic psychoses also have been noted in early ADC. 2 The most common motoric findings are leg weakness, loss of balance, and loss of fine motor control, with handwriting difficulty a frequent complaint.2 On physical examination, gait ataxia is commonly found as well as leg weakness and hyperreflexia.2 Tremor
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on sustension and abnormalities in smooth eye movement and saccadic eye movement may be noted. As the encephalopathy progresses, the cognitive abnormalities become all-encompassing. Patients become withdrawn from their surroundings, with psychomotor slowing a prominent feature. Although they may seem lethargic, patients with advanced ADC generally may be easily roused. Motor abnormalities typically progress with increasing leg weakness that may lead to paraplegia and incontinence. Myoclonus and seizures may be more prevalent. In the very end-stage of encephalopathy, the patients may be unresponsive and mute. LABORATORY
Examination of CSF in patients who are HIV seropositive frequently shows anti-HIV antibodies. 1'2'32It has been suggested that the ratio of serum antibodies to CSF antibodies increases with more advanced manifestations of HIV infection (ie, AIDS v AIDS-related complex [ARC]), but the presence or increase in anti-HIV antibodies is not specific for dementia.32 Commonly, protein levels are elevated (in 67% of patients in one series). 28 A mononuclear pleocytosis may be identified in 25% of patientsJ '2'7'2s The presence of virus in the CSF also is not specific for HIV encephalitis,33'34 However, the presence of HIV- 1 core antigen has been correlated with the presence of dementia.34 Electroencephalography usually shows nonspecific, generalized slowing, 7'8 but this is not usually helpful in distinguishing AIDS dementia complex from other causes of dementia. NEUROIMAGING
Structural neuroimaging plays an important role in the evaluation of the HIV-seropositive patient with psychiatric and/or neurological complaints. In HIV encephalitis/ADC, CT may show only atrophy. Post et a135 found cortical atrophy on CT in 20 of 21 patients with neurological symptoms and AIDS, and ventricular enlargement due to atrophy in 13 of 21 subjects. Snider et al I found cortical atrophy in 80% of their series of AIDS patients with neurological problems. CT may also show low-density parenchymal lesions without any mass effect. Presumably, some of this may be on the basis of
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demyelination. 35 CT has also demonstrated cortical gray matter low-density lesions. 35 Even in the absence of neurological deficits, atrophy may be detected on CT. Navia et al 2 reported on 38 AIDS patients. All of these studies showed cortical atrophy and ventricular dilatation. Three of these patients were without clinical evidence of dementia at the time of the CT. In addition to atrophy, M R I has been successful in demonstrating parenchymal changes, particularly in the white matter. 23 Although several patterns of abnormal signal have been identified on brain MRI in patients with AIDS, the patterns on T-2-weighted images most commonly associated with ADC are multiple, small, highsignal-intensity lesions in a bilateral and subcortical distribution, or more patchy, confluent, high-signal intensity involving the white matter of the brain. 6'23'36"39 Others have described increased signal in the periventricular white matter that becomes more diffuse and widespread with progression of dementia .39Quantification of white matter in the brains of AIDS patients with dementia has shown decreased volumes of white m a t t e r compared with at-risk, noninfected subjects. 4~ It is now generally accepted that MRI is more sensitive to brain parenchymal changes due to HIV infection than CT. 2'14'35'38Four of five AIDS patients with positive MRI had negative CTs 35 and Levy et al ~4 have found that 29% to 35% of patients with normal CTs have abnormal M R I studies. MRI abnormalities due to HIV may precede AIDS. Grant et al 6 found positive MRIs in five of 10 ARC patients and in nine of 13 AIDS patients. Eight of these 23 had atrophy, and 10 showed parenchymal lesions. Janssen et al 5 found a lower incidence (1/6) of positive M R I in patients with ARC. It also has been suggested that MRI may be useful to follow the course of ADC. Worsening of the M R I abnormalities has been documented in patients with deterioration in the neuropsychometric testing results. In patients treated with A Z T (Burroughs Wellcome, Research Triangle Park, NC), M R I abnormalities have been noted to resolve. 3~ Although MRI shows greater sensitivity for ADC than CT, autopsy comparisons have shown that significant amounts of pathology are missed on both modalities. In the series of Post et al, 35
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Fig 1. 1231MPcerebral perfusion SPECT was performed in this 47-year-old man with AIDS and Kaposi's sarcoma and complaint of memory loss. A CT performed after the intravenous administration of a double dose of iodinated contrast material showed only mild ventricular atrophy. (A) A transaxial slice through the basal ganglia from the SPECT study demonstrates asymmetry of uptake in the region of the lentiform nuclei. The cortical uptake is fairly uniform. (B) On the sagittal slice, the cerebral uptake is noted to be comparable in intensity to the cerebellar uptake.
deep gray matter lesions and posterior fossa lesions that are commonly found at pathological examination in ADC were not demonstrated by MRI. In general, the areas of white matter abnorrn~lities depicted by MRI correspond to areas of demyelination and may not correspond to the cellular infiltrates (multinucleated macrophages) that are found in the brain in ADC.
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i
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Fig 2. This 47-year-old man w h o w a s HIV seropositive complained of a m e m o r y deficit and increased emotional lability. MRI scan w a s remarkable for sulcal atrophy. (A) A transaxial siice f r o m t h e 1231MPbrain SPECT at t h e level of t h e basal ganglia shows asymmetrical uptake in t h e subcortical gray m a t t e r structures. (B) A transaxial slice at t h e level of the centrum semiovale shows cortical defects. (C) The sagittal slice demonstrates cerebral uptake comparable in intensity to t h a t of t h e cerebellum.
FUNCTIONAL
NEUROIMAGING
Functional neuroimaging, either positron emission tomography (PET) or single-photon emission computed tomographh (SPECT), should have the potential for detecting brain abnormalities before the structural damage occurs. Abnormalities in brain glucose metabolism as well as abnormalities in cerebral perfusion have been demonstrated in HIV-seropositive patients.4147 The abnormalities described on lSfluorodeoxyglucose PET studies by Rottenberg et a141reflect the distribution of pathological changes in the brain at autopsy and the subcortical nature of the clinical presentation. Rottenberg's group per-
formed 13 studies on 12 patients with ADC: six when they were mildly demented, two when moderately demented, and five when severely demented. Increased glucose metabolism was found in regions of the basal ganglia and thalamus in the less severely affected subjects. The basal ganglia and thalamic metabolic rates for glucose normalized by a global scaling factor were the best predictor of results of the grooved pegboard neuropsychometric test. Decreased glucose metabolic rates in cerebral cortical regions correlate with abnormalities in verbal fluency and trailmaking B. This was observed in more severe dementia. Despite the known involvement
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of white matter with ADC, metabolic rates in white matter were not correlated with severity of dementia. Cerebral perfusion SPECT imaging using either 123I-iodoamphetamine (IMP) or 99mTc-(hexamethylpropylene amine oxime (HMPAO) 42-45 has demonstrated cortical defects in the brains of patients with ADC. Pohl et a142 demonstrated multiple cortical lesions in six of 12 patients and single cortical defects in six of 12. In those patients with single cortical defects, clinical presentation (focal neurological signs) correlated with the location of the defects. Clinical progression of dementia corresponded with progression of abnormality on scan in three patients studied at multiple sessions. This group also studied four patients with both 123IMP and 99mTc-HMPAO. In two patients there was close correspondence in the abnormal findings; in the other two, the 99mTc-HMPAO study demonstrated more abnormalities. LaFrance et a143'44have shown cerebral perfusion SPECT abnormalities in HIV-seropositive subjects in the absence of clinical evidence of dementia. Cortical asymmetries (parietal) were present not only in five of seven demented subjects but in five of six cognitively normal HIVseropositive subjects. 43 These investigators have also described significant semiquantitative decreases in the subcortical gray matter structures in five of seven demented subjects and in one of six nondemented, seropositive subjects. 44 Our own experience with ADC suggests that there is a progression of abnormalities on SPECT. We studied 30 HIV-seropositive subjects with SPECT after the administration of 123IMP. All subjects were male homosexuals. Their clinical presentation was varied. Nine denied symptoms. One subject complained of headache but was without signs of dementia or neurological abnormalities. Five complained of memory problems, but had no gross abnormalities on a routine examination. The remainder had abnormal neuropsychiatric examinations. Focal signs were present in five. SPECT studies on these subjects were compared with eight age-matched normal controls. Qualitative findings on the scans were scored as absent, present, or questionable by two nuclear medicine physicians who were blinded to the diagnosis and clinical presentation of the
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Fig 3. A 34-year-old man who was HIV seropositive complained of severe frontal and right-sided headaches. He has also experienced visual hallucinations. MRI showed ventricular dilatation. (A) The transaxial slice from the SPECT scan shows mild asymmetry in the subcortical gray matter structures and cortical defects. (B) The sagittal slice demonstrates the decreased ratio of intensity of cerebral to carebellar uptake.
individual subjects. The scores for the two readers were then averaged. Ratios of average count density for frontal, parietal, temporal, occipital, caudate, thalamus, and lentiform nucleus compared with cerebellum
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Table 1. HIV-Seropositive Subjects Versus HIV-Seronegative Controls: Ratios of Average Regional Count Densities Controls (mean • SD)
HIV Seropositive (mean r SD)
P
Right frontal/cerebellum Left frontal/cerebellum Right temporal/cerebellum
0.937 -+ 0.08 0.949 • 0.09 0.963 + 0.08
0.839 + 0.13 0.859 -+ O. 13 0.868 • 0.11
.O49 .075 .024
Left temporal/cerebellum Right thalamus/cerebellum
0.961 -+ O. 13 1.106 • O. 10
0.879 _+ 0.10 0.967 _+ 0.14
.054 .012
Left thalamus/cerebellum Right caudate/cerebellum Left caudats/cerebellum
1.089 • O.09 1.153 • O. 18 1.107 + O. 16
0.991 • 0.15 1.022 _+ 0.16 0.974 _+ O. 15
.092 .050 .034
Right lentiform/cerebellum Left lentiform/cerebellum Right cerebellum/whole brain
1.176 ,+ O. 15 1.127 + O. 11 0.993 • 0.05
1.079 -+ 0.15 1.006 + 0.15 1.085 -+ O. 11
.109 .035 .023
Left cerebellum/whole brain Right frontal/whole brain Left frontal/whole brain Right thalamus/whole brain Left thalmus/whole brain
1.238 0.949 1.140 1.120 1.302
1.307 0.907 1.092 1.049 1.257
.469 .034 .455 .030 .529
-+ 0.23 + 0.03 -+ O. 19 ,+ 0.04 • 0.18
or average whole brain count density were calculated. These semiquantitative results of the SPECT studies were examined for HIV seropositives compared with normal controls. Qualitatively, the scans on the HIV-seropositive subjects were characterized by asymmetry in the subcortical structures and cortical deficits. One HIV-seropositive subject had a normal scan, 18 had abnormal-appearing distribution of activity in the subcortical gray matter structures, 25 had cortical deficits, and four had decreased cerebral/cerebeUar ratios. Of the 25 with cortical deficits, 18 also had subcortical asymmetry. Three of four subjects with a qualitatively de-
-+ 0.24 + 0.05 _+ O. 15 _+ 0.09 • O. 18
creased cerebral/cerebellar ratio also showed cortical deficits and subcortical asymmetries. This suggests a progression of ADC on SPECT from subcortical asymmetry to cortical abnormality, to more globally affected cerebral perfusion (Figs 1 to 3). Ratios of regional count density to either cerebellar or whole brain count density for agematched HIV-seronegative controls were compared with the HIV-seropositive subjects using an unpaired two-tailed t test. Significantly decreased frontal, temporal, caudate, thalamic, and lentiform to cerebellum ratios as well as significantly increased cerebellar/whole brain
Table 2. HIV-Seropositive Subjects by MRI and/or CT Findings Versus HIV-Seronegative Controls: Ratios of Average Regional Count Densities Controls (mean • SD) Right frontal/cerebellum Left frontal/cerebellum Right parietal/cerebellum Left parietal/cerebellum Right temporal/cerebellum
Atrophy (mean • SD)
VVhite Matter Changes (mean • SD)
P .016 .O19 .019 .O84 .O08 .033 .002 .043 .008 .006 ,118 .013 .026 .593 .009 .021
+ 0.07 -+ 0.09 + 0.09 _+ 0.09 _+ 0.08 • 0.12
O.841 0.854 0.904 0.929 0.841 0.845
• 0.12 + O. 13 + O. 12
Left temporal~cerebellum
0.959 0.976 1.022 1.034 0.978 0.985
_+ 0.06 + 0.08
0.776 -+ O. 12 0.790 + 0.08 0.838 + O. 10 0.864 • 0.08 0.834 • 0.14 0.873 • O. 11
Right thalamus/cerebellum Left thalamus/cerebellum Right caudate/cerebellum Left caudate/cerebellum Right lentiform/cerebellum Left lentiform/cerebellum Right thalamus/whole brain Left thalamus/whole brain Right cerebellum/whole brain Left cerebellum/whole brain
1.141 1.118 1.189 1,136 1.205 1.149 1.127 1.107 0.969 1.O 17
+ O. 10 • 0.09 • 0.15 • O. 14 _+ O. 12 • 0.09 + 0.04 _+ O.O8 • 0.06 -+ O.O7
0.954 0.973 1.006 0,942 1.060 1.010 1.O47 1.O65 1.076 1.33
+ O. 11 _+ O. 16 -+ 0.11 • O. 10 -+ O, 17 • 0.12 • 0.09 _+ O. 12 + O. 11 _+ 0.09
0.885 0.923 0.960 0.929 1.078 0.941 1.OO8 1.053 1.139 1.166
+ O. 16
• O. 14 • O. 15 • 0.08 • O. 13 • O. 10 • 0,13 • 0.08 • 0.08 ,+ 0.08 ,+ O. 14
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ratios were noted in the HIV-seropositive group. When using whole brain count density as the denominator, only the frontal and thalamic regions showed a significant decrease suggesting that these were areas of more pronounced abnormality (Table 1). A subset of this group who underwent CT (5 of 10) and/or MRI (7 of 10) were examined across groups categorized by structural neuroimaging findings (atrophy or atrophy with white matter changes). Results in these groups were compared with age-matched normal controls. Semiquantitative analysis showed significantly decreased frontal/whole brain rations in HIV-seropositive subjects with atrophy, compared with normals. Deficits were also found in the caudate and thalamus in this group and in the group with white matter abnormalities. The group with white matter disease also demonstrated significantly elevated cerebellum/whole brain ratios (Table 2). This could be explained either by globally diminished cerebral uptake or by elevated cerebellar uptake. Elevated cerebellar glucose metabolism has been described in patients with Alzheimer's disease and periventricular white matter lesions. 48 This might be a related phenomenon. These findings are in concert with the work described by LaFrance et a144and by Rottenberg et al.41 The recurring finding of subcortical abnormalities parallels the distribution of macrophage and monocyte infiltrates that are prominent in basal ganglia in patients with HIV encephalitis, u The cortical deficits on scan are more difficult to explain as direct results of HIV involvement of the cortical gray matter because cortical gray matter is relatively spared in HIV encephalitis. However, these cortical deficits might be due to interruption of signal from the white matter disease commonly noted both at histopathologic examination and on MRI of the brain. In the clinical approach to ADC, opportunistic infections must be differentiated from the direct sequelae of HIV brain infection. This must be considered in the evaluation of the functional images as well. Toxoplasmosis and lymphoma, not surprisingly, will present as fairly welldemarcated focal defects on cerebral perfusion SPECT when the lesions involve the gray matter
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Fig 4. A 51-year-old man with AIDS presented with the acute onset of seizures. (A) A C T scan performed after a double dose of intravenous contrast demonstrates an enhancing, space-occupying lesion in the right posterior parietal/occipital region of the brain. (B) ASPECT study performed on the patient showed a focal defect corresponding to the mass. After appropriate therapy for toxoplasmosis, a follow-up CT scan showed partial resolution of the abscess.
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cortex and are large enough to be easily resolved by SPECT 49 (Fig 4). When the lesions are smaller, their appearance on SPECT is less clear-cut. Similarly, lesions of progressive multifocal leukoencephalopathy (PML) often involve the white matter. Because this is an area of relatively less blood flow compared with gray matter, the deficits may be quite subtle on SPECT. For this reason, SPECT will not replace double-dose contrast CT and/or MRI in the evaluation of the HIV-seropositive patient with psychiatric or neurological problems. On the other hand, experience with SPECT suggests that it may be more sensitive than MRI in detecting focal brain abnormalities due to HIV infection in symptomatic patients (Fig 5). 49-5~ Although the sensitivity of functional neuroimaging for brain abnormalities in ADC, even preclinical ADC, may exceed other modalities, the specificity has not been established. This is in part due to the high frequency of CNS opportunistic infections and neoplasms in this population. However, the patterns of subcortical abnormalities followed by cortical deficits and then by global brain deficits may suggest the diagnosis of
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ADC. Further study of carefully screened and followed patients will be necessary before this can be determined. RESPONSE TO THERAPY
More recently, serial]Sfluorodeoxyglucose PET scans have been evaluated in HIV-seropositive subjects with signs and symptoms of dementia and who are undergoing AZT therapy. Brunetti et a146reported two patients whose baseline focal cortical defects resolved after AZT therapy. Two additional patients studied by this group showed an increase in global brain glucose metabolism after therapy. There was concomitant clinical improvement in three patients and one patient remained stable. Although CT did show reversal of white matter lucencies in one patient, CT and MRI were unchanged in two of the patients studied. Response to anti-HIV therapy on MRI has been reported occasionally by others. 6 However, the work of Brunetti et al~s suggests that functional neuroimaging may reflect a response to therapy more consistently. In their study, follow-up scans were performed after 10 to 12 weeks of therapy. If a response to therapy can be
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Fig 5. In June 1988, a 46-year-old man w i t h AIDS presented w i t h focal left upper e x t r e m i t y seizures. A C T scan at t h a t time was negative. MRI done at t h a t time was unremarkable. (A) A S P E C T scan performed after t h e administration of I ~ I M P showed a focal defect in t h e right frontal cortex (arrow), The seizures persisted, and in November 1988, (B) a repeat CT scan showed an area of decreased intensity in a corresponding location. Brain biopsy at that time showed gliosis and multinucleated giant cells consistent with HIV encephalitis.
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d e m o n s t r a t e d within a short period of time, functional n e u r o i m a g i n g m a y offer a m o r e specific, noninvasive m e a n s of diagnosing H I V enc e p h a l o p a t h y when o t h e r studies a r e inconclusive. SUMMARY F u n c t i o n a l S P E C T n e u r o i m a g i n g m a y have a role to play in the diagnosis of A D C because of its sensitivity to a l t e r a t i o n s in b r a i n function c o m p a r e d with s t r u c t u r a l modalities. M a n y of the observations a b o u t A D C m a d e by investigators in the field point to a significant p r o b l e m in the deep g r a y m a t t e r structures. Glucose m e t a bolic a b n o r m a l i t i e s in basal g a n g l i a have been d e m o n s t r a t e d on P E T . T h e r e is a p r e d o m i n a n c e of subcortical p a t h o l o g y identified on histopathologic e x a m i n a t i o n in A D C . Clinically, the presentation of A D C has been t e r m e d a " s u b c o r t i c a l d e m e n t i a " . 2 In addition, B r e i t b a r t et a151 have r e p o r t e d t h a t patients with A D C a r e e x t r e m e l y susceptible to the side effects of neuroleptics, like haloperidol, which localize in d o p a m i n e receptors in the basal ganglia. A b n o r m a l i t i e s det e c t a b l e on S P E C T , ie, t h e a s y m m e t r y seen
qualitatively, and the deficits m e a s u r e d on semiq u a n t i t a t i v e analysis, seem to reflect p a t h o l o g y in the d e e p g r a y m a t t e r . T h e a b i l i t y o f c e r e b r a l perfusion S P E C T to d e t e c t a b n o r m a l i t i e s in the subcortical g r a y m a t t e r offers the potential for m a k i n g a specific diagnosis of A D C . Because a b n o r m a l i t i e s in the b a s a l g a n g l i a have not been a p r o m i n e n t f e a t u r e of either M R I or C T studies in patients with A D C , S P E C T m a y be a useful a d j u n c t to the evaluation of the H I V - s e r o p o s i t i v e subject with n e u r o p s y c h i a t r i c s y m p t o m s once opportunistic infections a n d space-occupying lesions have been excluded. Because functional n e u r o i m a g i n g , both P E T 46 and S P E C T , 42 can be used to d e t e c t progression a n d / o r response to t h e r a p y , we will be able to b e t t e r diagnose a n d follow these patients as the t h e r a p e u t i c a p p r o a c h to A I D S d e m e n t i a complex improves.
ACKNOWLEDGMENT We would like to thank Linda Melnikoff and Catherine Tosado for their dedicated efforts in gathering case material, and Evelyn Millan and Giovanni Lopez for their technical assistance.
REFERENCES 1. Snider WD, Simpson DM, Nielson S, et al: Neurological complications of the acquired immune deficiency syndrome: Analysis of 50 patients. Ann Neurol 14:403-418, 1983 2. Navia BA, Jordan BD, Price RW: The AIDS dementia complex: I. Clinical features. Ann Neurol 19:517-524, 1986 3. Navia BA, Petito CK, Gold JWM, et al: Cerebral toxoplasmosis complicating the acquired immune deficiency syndrome: Clinical and neuropathological findings in 27 patients. Ann Neurol 19:224-238,1986 4. Krupp LB, Lipton RB, Swerdlow ML, et al: Progressive multifocal leukoenceophalopat!ay: Clinical and radiographic features. Ann Neurol 17:344-349, 1985 5. Janssen RS, Saykim A J, Kaplan JE, et al: Neurological complications of lymphadenopathy syndrome associated with immnnodeficiency virus infection. Ann Neurol 23:49-55, 1988 6. Grant I, Atkinson JH, Hesseling JR, et al: Evidence for early central nervous system involvement in the acquired immnnodeficiencysyndrome (AIDS) and other human immunodeficiencyvirus (HIV) infections. Studies with neuropsychlogic testing and magnetic resonance imaging. Ann Intern Med 107:828-836, 1987 7. Navia BA, Price RW: The acquired immunodeficiency syndrome dementia complex as the presenting or sole manifestation of human immunodeficiency virus infection. Arch Neuro144:65-69, 1987 8. Epstein LG, Sharer LR, Joshi VJ, et al: Progressive
encephalopathy in children with acquired immune deficiency syndrome. Ann Neurol 17:488-496, 1985 9. Lantos PL, McLaughlin JE, Scholtz CL, et al: Neuropathology of the brain in HIV infection. Lancet 1:309-311, 1989 10. Budka H, Costanzi G, Cristina S, et al: HIV encephalopathy and lymphadenopathy: Cells associated with viral antigens. Apmis 8:33-39, 1989 (suppl) 11. Vazeux R, Brousse N, Jarry A, et al: AIDS subacute encephalitis. Identification of HIV-infeeted cells. Am J Pathol 126:403-410, 1987 12. Nielsen SL, Petito CK, Urmacher CD, et al: Subacute encephalitis in acquired immune deficiency syndrome: A postmortem study. Am J Clin Pathol 82:678-682, 1984 13. Budka H, Costanzi G, Cristina S, et al: Brain pathology induced by infection with the human immunodeficiency virus (HIV). A histological, immunocytochemical, and electron microscopical study of 100 autopsy cases. Acta Neuropatho175:185-198, 1987 14. Ho DD, Rota TR, Schooley RT, et al: Isolation of HTLV-III from cerebrospinal fluid and neural tissues of patients with neurologic syndromes related to the acquired immnnodeficiency syndrome. N Engl J Med 313:1493-1497, 1985 15. Levy RM, Bredesen DE, Rosenblum ML: Neurological manifestations of the acquired immunodeficiency syndrome (AIDS): Experience at UCSF and review of the literature. J Neurosurg 62:475-495, 1985
AIDS DEMENTIA COMPLEX
16. Cooper DA, Gold J, Maclean P, et al: Acute AIDS retrovirus infection: Definition of a clinical illness associated with seroconversion. Lancet 1:71-73, 1985 17. Hollander HR, Levy JA: Neurologic abnormalities and recovery of human immunodeficiency virus from cerebrospinal fluid. Ann Intern Med 106:692-695, 1987 18. Johnson RT, McArthur JC, Narayan O: The neuroNology of human immunodeficiency virus infections. FASEB J 2:2970-2981, 1988 19. Petito CK, Navia BA, Cho ES, et al: Vacuolar myelopathy pathologically resembling subacute combined degeneration in patients with the acquired immunodeficiency syndrome. N Engl J Med 312:874-879, 1985 20. Navia BA, Cho ES, Petito CW, et al: The AIDS Dementia Complex: II. Neuropathology. Ann Neuro119:525535, 1986 21. Pumarola ST, Navia BA, Cordon Cardo C, et al: HIV antigen in the brains of patients with the AIDS dementia complex, Ann Neurol 21:490-496, 1987 22. De la Monte SM, Moore T, Hedley-Whyte ET: Vacuolar encephalopathy of AIDS. N Engl J Med 315:15491550, 1986 23. Chrysikopouios HS, Press GA, Grafe MR, et al: Encephalitis caused by human immunodeficiency virus: CT and MR imaging manifestation with clinical and pathological correlation. Radiology 175:185-191, 1990 24. Koenig S, Gendelman HE, Orenstein JM, et al: Detection of AIDS virus in macrophages in brain tissue from AIDS patients with eneephalopathy. Science 233:1089-1093, 1986 25. Wiley CA, Nelson JA: Role of human immunodeficiency virus and cytomegalovirus in AIDS encephalitis. Am J Patho1133:73-81, 1988 26. Wiley CA, Schrier RD, Nelson JA, et al: Cellular localization of human immunodeficiency virus infection within the brains of acquired immune deficiency patients. Proc Natl Acad Sci USA 83:7089-7093, 1986 27. Gabuzda DH, Ho DD, de la Monte SM, et al: Immunohistochemieal identification of HTLV-III antigen in brains of patients with AIDS. Ann Nearol 20:289-295, 1986 28. Ho DD, Bredesen DE, Vinters HV, et al: The acquired immunodeficiency syndrome (AIDS) dementia complex. Ann Intern Med 111:400-410, 1989 29. Kermani E J, Bored JC, Brown PH, et al: New psychopathologic findings in AIDS: Case report. J Clin Psychiatry 46:240-241, 1985 30. Grant I, Atkinson JH, Hesselink JR, et al: Human immunodeficiency virus-associated neurobehavioural disorder. J R Coil Physicians Lond 22:149-157, 1988 31. Perry SW, Jacobsen P: Neuropsychiatric manifestations of AIDS-spectrum disorders. Hosp Community Psychiatry 37:135-142, 1986 32. Elovaara I, Iivanainen M, Sirkka-Liisa V, et al: CSF protein and cellular profiles in various stages of HIV infection related neurological manifestations. J Neurol Sci 78:331342, 1987 33. Resnick L, diMarzo-Verenese F, Sehupbach J, et z.l: ~ t r a b!ocd-~rain-b~,rrier sy~:thesi~ cf HTLV-I~H specific IgC in patients ;d~h nemologic symp~::ms associated wid,, A~DS or .A_[DS-rei~tsd ccmp]ex N E!!gl J Me~~ 313:'_'a9~-1504, IC85
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34. Epstein LG, Goudsmit J, Paul DA, et al: Expression of human immunodeficiency virus in cerebrospinal fluid of children with progressive encephalopathy. Ann Neurol 21:397401, 1987 35. Post MJD, Tate LG, Quencer RM, et al: CT, MR and pathology in HIV encephalitis and meningitis. A JR 151:373380, 1988 36. Olsen WL, Longo FM, Mills CM, et al: White matter disease in AIDS: Findings of MR imaging. Radiology 169: 445-448, 1988 37. Jarvik JG, Hesselink JR, Kennedy C, et al: Acquired immunodeficiency syndrome. Magnetic resonance patterns of brain involvement with pathologic correlation. Arch Neurol 45:731-736, 1988 38. Ramsey RG, Geremia GK: CNS complications of AIDS: CT and MR findings. A JR 151:449-454, 1988 39. Ekholm S, Simon JH: Immunohistochemicai staining of cells in the brain of a patient with acquired immune deficiency syndrome (AIDS) with a monoclonal antibody to visna virus. Acta Radiol 73:406-408, 1987 40. Yang NC, Leichner PK, Pearlson GD, et al: MRI brain volumetrics for AIDS patients. Abstr Proc NY Acad Neurol, 1988 41. Rottenberg DA, Moeller JR, Strother SC, et al: The metabolic pathology of the AIDS Dementia Complex. Ann Neuroi 22:700-706, 1987 42. Pohl P, Vogl G, Fill H: Single-photon emission computed tomography in AIDS dementia complex. J Nucl Med 29:1382-1386, 1988 43. LaFrance ND, Pearlson GD, Schaerf FW: 1-123 IMP-SPECT in HIV-related dementia. Adv Funct Neuroimag 1:9-15, 1988 44. LaFrance ND, Pearlson G, Schaerf F, et al: SPECT imaging with I-123 isopropyl amphetamine in asymptomatie HIV seropositive persons. J Nucl Med 29:742, 1988 (abstr) 45. Costa DC, Ell P J, Burns A, et al: CBF tomograms with [99mTc-HM-PAO in patients with dementia (Alzheimer type and HIV) and Parkinson's disease--Initial results. J Cereb Blood Flow Metab 8:S109-115, 1988 (suppl) 46. Brunetti A, Berg G, DiChiro G, et al: Reversal of brain metabolic abnormalities following treatment of AIDS dementia complex with Y-azido-2'3'-dideoxthymidine(AZT, zidovuidine): A PET-FDG study. J Nucl Med 30:581-590, 1989 47. Deisenhammer E, Reisecker F, Leblhuber F, et al: Single-photon emission-computed tomography in the differential diagnosis of dementia. Dtsch Med Wochenschr 114: 1639-1644, 1989 48. Klinger A, de Leon M J, George AE, et al: Elevated eerebellar glucose metabolism in microvascular white matter disease: Normal aging and Alzheimer's disease. J Cereb Blood Flow 8:433-435, 1987 49. Kramer EL, Sanger J J: Central nervous system complications of the acquired immunodeficiency syndrome on I-123 Iodoamphetamine Brain SPECT. Adv Funct Neuroimaging 1:15-19, 1989 50. Smith GS, Kramer EL, Sanger J J, et al: Iodoamphetamine brai~ ~PFCT and M R ! / C T correlates of the AIDS ~t~meatia con'p,~cx. T~adic~cgy '-69:~355, 19~!; (sup!:l) 5i. Sreitbax W, ";.2areola KF. Cail P: :~ i[~S a~d neure!.'~tic ma!ig~t:~nt syndrome. :.a~_cet 2: ] 4~'~-!,'~S9, ] 9 ~
WIDE SPECTRUM of central nervous system (CNS) complications is found in the patient with human immunodeficiency virus (HIV) infection. Opportunistic infections and neoplasms, particularly CNS lymphoma, constitute a significant problem in these immunocompromised patients, but it also has become clear that the HIV virus itself is responsible for a syndrome of dementia. This dementia is accompanied by cognitive and motor abnormalities, and is observed in a large number of HIVseropositive individuals with or without other complications of HIV infection. This has been termed HIV encephalopathy, HIV subacute encephalitis, ] or acquired immunodeficiency syndrome (AIDS) dementia complex (ADC). 2 Although clinically there is a characteristic presentation, this presentation may overlap with other CNS complications of AIDS. Neuroimaging modalities such as computed tomography (CT) or magnetic resonance imaging (MRI) may be suggestive, but inconclusive and/or unrevealing, particularly early in the disease. On the other hand, functional neuroimaging modalities, both positron emission tomography (PET) and singlephoton emission computed tomography (SPECT), hold the potential for detecting HIV encephalitis in its early stages, because ADC causes functional abnormalities before gross anatomical changes are detectable with noninvasive means.
case w h i t e m a t t e r abnormalities, but imagingpathological correlation suggests t h a t these modalities are relatively insensitive t o the presence of HIV brain i n f e c t i o n . Functional n e u r o i m a g i n g , b o t h lefluorodeoxyglucose positron emission t o m o g r a p h y (PET) for evaluation of glucose metabolism and !z31 iodoamphetamine or m"Tc-HMPAO single-photon emission computed t o m o g r a p h y (SPECT) for evaluation of cerebral perfusion, can demonstrate abnormalities in t h e subcortical gray m a t t e r structures and the cerebral c o r t e x in patients w i t h ADC. These abnormalities may be observed early in the course of ADC even w h e n MRI is negative and the patient is relatively asymptomatic. Also, PET and SPECT may be useful to f o l l o w progression of t h e dementia or response t o therapy. 9 1990 b y W.B. Saunders Company.
A
INCIDENCE OF NEUROPSYCHIATRIC COMPLICATIONS
Neurological complications may occur in 30% l of patients with AIDS. Toxoplasmosis is a common cause of brain abscess in these patients and has been found in 10% to 13% 1'3 of patients with CNS complications. Progressive multifocal leukoencephalopathy caused by the Papova virus has been found in 2% to 6% T M of AIDS patients with CNS disease. Cryptococcus neoformans may cause meningitis. Other infections, including Mycobacterium avium intracellulare, herpes encephalitis (zoster or simplex), and Candida albicans I may be encountered. Primary CNS lymphoma occurs in about 6% ] of patients. Somewhat more common is involvement from a systemic neoplasm, again usually lymphoma. Peripheral neuropathies consistent with a demyelinating process also have been reported in 16% of one series of patients with AIDS-related neurological abnormalities ] and in 38% in an-
From the Division of Nuclear Medicine, Department of Radiology, N Y U Medical Center/Bellevue Hospital Center, New York, NY. Address reprint requests to Elissa Lipcon Kramer, MD, Division of Nuclear Medicine H W 215, NYU Medical Center, 560 First Ave, New York, N Y 10016. 9 1990 by W.B. Saunders Company. 0001-2998/90/2004-0006505.00/0
Seminars in Nuclear Medicine, Vol XX, No 4 (October), 1990: pp 353-363
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other series of patients with HIV-related lymphadenopathy syndrome: The ADC, which is believed secondary to direct infection of the brain by the HIV, comprises a larger percentage of CNS complications than opportunistic infections and neoplasms in AIDS patients) In one series of patients with a full-blown AIDS picture, ADC occurred in 11% 1 and constituted 36% (18 of 50) of the neurological complications. Navia et al 2 found clinical evidence of ADC in 65% of a series of 70 AIDS patients assessed clinically. Grant et al 6 found neuropsychometric impairment in 87% of AIDS patients. Approximately half of the patients with lymphadenopathy syndrome studied have shown neuropsychometric evidence of A D C : '6 Furthermore, ADC may occur even in the absence of evidence of immunodeficiency and opportunistic infections. 7 An increased incidence (44%) of neuropsychometric impairment has been found in subjects who are HIV seropositive but without any other markers of immune deficiency.6 In children, HIV encephalopathy presents as a slowing of milestone achievement and deterioration in cognitive function. The infection has been estimated to occur in 75% of AIDS-infected children: Autopsy data suggest a higher incidence of HIV brain involvement. At autopsy, the presence of HIV-infected cells in the brain has been identified in 23% to 61% 9"13 of AIDS patients with neurological abnormalities. Others have found virus present in cerebrospinal fluid (CSF), brain, or spinal cord in 73% of autopsied AIDS patients with neurological manifestations) 4 There are a variety of presentations of primary HIV viral infection of the brain for which there is both clinical and pathological evidence. The dementia complex, as described previously, has been observed in HIV-seropositive patients at all stages of HIV infection. In the early phases of HIV infection, probably at the time of seroconversion, a transient acute meningitis may occur in 5%-10%) '15'16 This may be associated with a flu-like syndrome (fever, myalgias, rash). Although other viruses may cause aseptic meningitis in the AIDS patient, HIV seems to be the most frequent infectious agent. 17A more chronic, indolent form of meningitis manifesting only w i t h headache and CSF pleocytosis has been described) 8 Chronic pleocytosis in patients with
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long-standing seropositivity has also been noted. 18 Vacuolar myelopathy, which causes progressive spastic paraparesis with gait ataxia, leg weakness, and incontinence, has also been described. 19 The myelopathy occurs in association with dementia. 2~ Primarily, the pathology affects the lateral and posterior columns of the spinal cord. At pathological examination, vascular infarcts are also observed. Leptomeningeal thickening may be present consistent with a meningitis. 9 However, most common is the subacute encephalopathy that is associated with ADC. Grossly, the brains of patients with ADC are atrophic, weighing less than brains of nondemented HIVseropositive individuals. However, Navia et al 2~ did not find a correlation between brain weight and severity of dementia in their study. The histological hallmark of ADC is multinucleated giant cells of monocytic origin.I~176These are usually seen in a perivascular distribution, but may also be parenchymal. Reactive astrocytosis is also a part of the histological presentation. 2~ This primarily involves the white matter and subcortical gray matter. 9'11'2~ Cerebellar and pontine involvement also has been described by several authors. 2~ Only infrequently is a predominant involvement of cortical gray matter noted. The involvement of the white matter is manifest by vacuolization, pallor, and areas of demyelinization.22 Microglial nodules occur frequently. These contain microglia, astrocytes, and macrophages. Navia et al 2~ found these to be associated with cytomegalovirus (CMV) inclusions, and Vazeux et al ll have not found a high concentration of HIV-infected cells in these microglial nodules, suggesting that nodules may be more associated with CMV infections than HIV. Very recently, Chrysikopoulos et a123 have described microglial nodules in HIV encephalitis without direct association with CMV. HIV has been found to be concentrated in more loosely scattered monocytes, microglial cells, macrophages, or endothelial cells, m21'24"26 Although it is known that the HIV virus is trophic for CD4 + cells, HIV has been most often localized to C D 4 - microglia) 1 It has been proposed that monocytes serve as a reservoir of the virus and serve as the m , : a n ~ of retrovirus entrance h~Lc:the br4i~7~.~7 [~ecau~e oi" ~b~f~?rcq;.~ent associa~.k,n n.,~g,:dbetwe~r, t.:.,.:~'~-,r., ~ a~d x~:P'~ ,; i:t 1-1~e ....
AIDS DEMENTIA COMPLEX
brain, it has been suggested that the immune response to an opportunistic infection (like CMV) may underly or increase the initial entrance of the already infected monocytes into the brain. Another explanation for the presence of viralladen macrophages in the brain has been the transformation of infected microglia into macrophages with multinucleated cell formation.H The affect on the brain may be due to virusactivation of monocytes or macrophages with subsequent production or release of monokines, for example, tumor necrosis factor, which may have toxic effects on the surrounding tissue. 28 A third possibility proposed is that HIV infection occurs by infection of the endothelial cells with breakdown in the blood-brain barrier, 26 permitting entrance of toxic substances. Less likely is the possibility of direct neuronal infection by HIV, because viral antigen is so rarely identified in neural cells) s CLINICAL MANIFESTATIONS
ADC, which has been termed a subcortical dementia, is characterized by progressive cognitive impairment with behavioral and motor abnormalities.2 The neuropsychiatric manifestations vary greatly. Patients may present with frank delirium, 14delusional states, 29 or a picture easily confused with depressionJ 2 The early manifestations of loss of cognitive function include forgetfulness, inattentiveness, slowed mentation, and confusion.2 On mental status testing, both verbal and motor responses may be slowed. Neuropsychometric testing reported by Grant et al 3~found abnormalities most frequently in tests of problem solving, speeded information processing, and memory, particularly in new information retrieval. Others have found abnormalities in language, verbal cognitive skills, motor speed, and rapid visual scanning) Patients are frequently unable to draw a clock. 3~The behavioral manifestations are marked most commonly by apathy and social withdrawal. These may be difficult to distinguish from depression in these patients. Dysphoria and organic psychoses also have been noted in early ADC. 2 The most common motoric findings are leg weakness, loss of balance, and loss of fine motor control, with handwriting difficulty a frequent complaint.2 On physical examination, gait ataxia is commonly found as well as leg weakness and hyperreflexia.2 Tremor
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on sustension and abnormalities in smooth eye movement and saccadic eye movement may be noted. As the encephalopathy progresses, the cognitive abnormalities become all-encompassing. Patients become withdrawn from their surroundings, with psychomotor slowing a prominent feature. Although they may seem lethargic, patients with advanced ADC generally may be easily roused. Motor abnormalities typically progress with increasing leg weakness that may lead to paraplegia and incontinence. Myoclonus and seizures may be more prevalent. In the very end-stage of encephalopathy, the patients may be unresponsive and mute. LABORATORY
Examination of CSF in patients who are HIV seropositive frequently shows anti-HIV antibodies. 1'2'32It has been suggested that the ratio of serum antibodies to CSF antibodies increases with more advanced manifestations of HIV infection (ie, AIDS v AIDS-related complex [ARC]), but the presence or increase in anti-HIV antibodies is not specific for dementia.32 Commonly, protein levels are elevated (in 67% of patients in one series). 28 A mononuclear pleocytosis may be identified in 25% of patientsJ '2'7'2s The presence of virus in the CSF also is not specific for HIV encephalitis,33'34 However, the presence of HIV- 1 core antigen has been correlated with the presence of dementia.34 Electroencephalography usually shows nonspecific, generalized slowing, 7'8 but this is not usually helpful in distinguishing AIDS dementia complex from other causes of dementia. NEUROIMAGING
Structural neuroimaging plays an important role in the evaluation of the HIV-seropositive patient with psychiatric and/or neurological complaints. In HIV encephalitis/ADC, CT may show only atrophy. Post et a135 found cortical atrophy on CT in 20 of 21 patients with neurological symptoms and AIDS, and ventricular enlargement due to atrophy in 13 of 21 subjects. Snider et al I found cortical atrophy in 80% of their series of AIDS patients with neurological problems. CT may also show low-density parenchymal lesions without any mass effect. Presumably, some of this may be on the basis of
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demyelination. 35 CT has also demonstrated cortical gray matter low-density lesions. 35 Even in the absence of neurological deficits, atrophy may be detected on CT. Navia et al 2 reported on 38 AIDS patients. All of these studies showed cortical atrophy and ventricular dilatation. Three of these patients were without clinical evidence of dementia at the time of the CT. In addition to atrophy, M R I has been successful in demonstrating parenchymal changes, particularly in the white matter. 23 Although several patterns of abnormal signal have been identified on brain MRI in patients with AIDS, the patterns on T-2-weighted images most commonly associated with ADC are multiple, small, highsignal-intensity lesions in a bilateral and subcortical distribution, or more patchy, confluent, high-signal intensity involving the white matter of the brain. 6'23'36"39 Others have described increased signal in the periventricular white matter that becomes more diffuse and widespread with progression of dementia .39Quantification of white matter in the brains of AIDS patients with dementia has shown decreased volumes of white m a t t e r compared with at-risk, noninfected subjects. 4~ It is now generally accepted that MRI is more sensitive to brain parenchymal changes due to HIV infection than CT. 2'14'35'38Four of five AIDS patients with positive MRI had negative CTs 35 and Levy et al ~4 have found that 29% to 35% of patients with normal CTs have abnormal M R I studies. MRI abnormalities due to HIV may precede AIDS. Grant et al 6 found positive MRIs in five of 10 ARC patients and in nine of 13 AIDS patients. Eight of these 23 had atrophy, and 10 showed parenchymal lesions. Janssen et al 5 found a lower incidence (1/6) of positive M R I in patients with ARC. It also has been suggested that MRI may be useful to follow the course of ADC. Worsening of the M R I abnormalities has been documented in patients with deterioration in the neuropsychometric testing results. In patients treated with A Z T (Burroughs Wellcome, Research Triangle Park, NC), M R I abnormalities have been noted to resolve. 3~ Although MRI shows greater sensitivity for ADC than CT, autopsy comparisons have shown that significant amounts of pathology are missed on both modalities. In the series of Post et al, 35
KRAMER AND SANGER
Fig 1. 1231MPcerebral perfusion SPECT was performed in this 47-year-old man with AIDS and Kaposi's sarcoma and complaint of memory loss. A CT performed after the intravenous administration of a double dose of iodinated contrast material showed only mild ventricular atrophy. (A) A transaxial slice through the basal ganglia from the SPECT study demonstrates asymmetry of uptake in the region of the lentiform nuclei. The cortical uptake is fairly uniform. (B) On the sagittal slice, the cerebral uptake is noted to be comparable in intensity to the cerebellar uptake.
deep gray matter lesions and posterior fossa lesions that are commonly found at pathological examination in ADC were not demonstrated by MRI. In general, the areas of white matter abnorrn~lities depicted by MRI correspond to areas of demyelination and may not correspond to the cellular infiltrates (multinucleated macrophages) that are found in the brain in ADC.
AIDS DEMENTIA COMPLEX
i
9
357
if: 84~!~!i
Fig 2. This 47-year-old man w h o w a s HIV seropositive complained of a m e m o r y deficit and increased emotional lability. MRI scan w a s remarkable for sulcal atrophy. (A) A transaxial siice f r o m t h e 1231MPbrain SPECT at t h e level of t h e basal ganglia shows asymmetrical uptake in t h e subcortical gray m a t t e r structures. (B) A transaxial slice at t h e level of the centrum semiovale shows cortical defects. (C) The sagittal slice demonstrates cerebral uptake comparable in intensity to t h a t of t h e cerebellum.
FUNCTIONAL
NEUROIMAGING
Functional neuroimaging, either positron emission tomography (PET) or single-photon emission computed tomographh (SPECT), should have the potential for detecting brain abnormalities before the structural damage occurs. Abnormalities in brain glucose metabolism as well as abnormalities in cerebral perfusion have been demonstrated in HIV-seropositive patients.4147 The abnormalities described on lSfluorodeoxyglucose PET studies by Rottenberg et a141reflect the distribution of pathological changes in the brain at autopsy and the subcortical nature of the clinical presentation. Rottenberg's group per-
formed 13 studies on 12 patients with ADC: six when they were mildly demented, two when moderately demented, and five when severely demented. Increased glucose metabolism was found in regions of the basal ganglia and thalamus in the less severely affected subjects. The basal ganglia and thalamic metabolic rates for glucose normalized by a global scaling factor were the best predictor of results of the grooved pegboard neuropsychometric test. Decreased glucose metabolic rates in cerebral cortical regions correlate with abnormalities in verbal fluency and trailmaking B. This was observed in more severe dementia. Despite the known involvement
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of white matter with ADC, metabolic rates in white matter were not correlated with severity of dementia. Cerebral perfusion SPECT imaging using either 123I-iodoamphetamine (IMP) or 99mTc-(hexamethylpropylene amine oxime (HMPAO) 42-45 has demonstrated cortical defects in the brains of patients with ADC. Pohl et a142 demonstrated multiple cortical lesions in six of 12 patients and single cortical defects in six of 12. In those patients with single cortical defects, clinical presentation (focal neurological signs) correlated with the location of the defects. Clinical progression of dementia corresponded with progression of abnormality on scan in three patients studied at multiple sessions. This group also studied four patients with both 123IMP and 99mTc-HMPAO. In two patients there was close correspondence in the abnormal findings; in the other two, the 99mTc-HMPAO study demonstrated more abnormalities. LaFrance et a143'44have shown cerebral perfusion SPECT abnormalities in HIV-seropositive subjects in the absence of clinical evidence of dementia. Cortical asymmetries (parietal) were present not only in five of seven demented subjects but in five of six cognitively normal HIVseropositive subjects. 43 These investigators have also described significant semiquantitative decreases in the subcortical gray matter structures in five of seven demented subjects and in one of six nondemented, seropositive subjects. 44 Our own experience with ADC suggests that there is a progression of abnormalities on SPECT. We studied 30 HIV-seropositive subjects with SPECT after the administration of 123IMP. All subjects were male homosexuals. Their clinical presentation was varied. Nine denied symptoms. One subject complained of headache but was without signs of dementia or neurological abnormalities. Five complained of memory problems, but had no gross abnormalities on a routine examination. The remainder had abnormal neuropsychiatric examinations. Focal signs were present in five. SPECT studies on these subjects were compared with eight age-matched normal controls. Qualitative findings on the scans were scored as absent, present, or questionable by two nuclear medicine physicians who were blinded to the diagnosis and clinical presentation of the
KRAMER AND SANGER
Fig 3. A 34-year-old man who was HIV seropositive complained of severe frontal and right-sided headaches. He has also experienced visual hallucinations. MRI showed ventricular dilatation. (A) The transaxial slice from the SPECT scan shows mild asymmetry in the subcortical gray matter structures and cortical defects. (B) The sagittal slice demonstrates the decreased ratio of intensity of cerebral to carebellar uptake.
individual subjects. The scores for the two readers were then averaged. Ratios of average count density for frontal, parietal, temporal, occipital, caudate, thalamus, and lentiform nucleus compared with cerebellum
AIDS DEMENTIA COMPLEX
359
Table 1. HIV-Seropositive Subjects Versus HIV-Seronegative Controls: Ratios of Average Regional Count Densities Controls (mean • SD)
HIV Seropositive (mean r SD)
P
Right frontal/cerebellum Left frontal/cerebellum Right temporal/cerebellum
0.937 -+ 0.08 0.949 • 0.09 0.963 + 0.08
0.839 + 0.13 0.859 -+ O. 13 0.868 • 0.11
.O49 .075 .024
Left temporal/cerebellum Right thalamus/cerebellum
0.961 -+ O. 13 1.106 • O. 10
0.879 _+ 0.10 0.967 _+ 0.14
.054 .012
Left thalamus/cerebellum Right caudate/cerebellum Left caudats/cerebellum
1.089 • O.09 1.153 • O. 18 1.107 + O. 16
0.991 • 0.15 1.022 _+ 0.16 0.974 _+ O. 15
.092 .050 .034
Right lentiform/cerebellum Left lentiform/cerebellum Right cerebellum/whole brain
1.176 ,+ O. 15 1.127 + O. 11 0.993 • 0.05
1.079 -+ 0.15 1.006 + 0.15 1.085 -+ O. 11
.109 .035 .023
Left cerebellum/whole brain Right frontal/whole brain Left frontal/whole brain Right thalamus/whole brain Left thalmus/whole brain
1.238 0.949 1.140 1.120 1.302
1.307 0.907 1.092 1.049 1.257
.469 .034 .455 .030 .529
-+ 0.23 + 0.03 -+ O. 19 ,+ 0.04 • 0.18
or average whole brain count density were calculated. These semiquantitative results of the SPECT studies were examined for HIV seropositives compared with normal controls. Qualitatively, the scans on the HIV-seropositive subjects were characterized by asymmetry in the subcortical structures and cortical deficits. One HIV-seropositive subject had a normal scan, 18 had abnormal-appearing distribution of activity in the subcortical gray matter structures, 25 had cortical deficits, and four had decreased cerebral/cerebeUar ratios. Of the 25 with cortical deficits, 18 also had subcortical asymmetry. Three of four subjects with a qualitatively de-
-+ 0.24 + 0.05 _+ O. 15 _+ 0.09 • O. 18
creased cerebral/cerebellar ratio also showed cortical deficits and subcortical asymmetries. This suggests a progression of ADC on SPECT from subcortical asymmetry to cortical abnormality, to more globally affected cerebral perfusion (Figs 1 to 3). Ratios of regional count density to either cerebellar or whole brain count density for agematched HIV-seronegative controls were compared with the HIV-seropositive subjects using an unpaired two-tailed t test. Significantly decreased frontal, temporal, caudate, thalamic, and lentiform to cerebellum ratios as well as significantly increased cerebellar/whole brain
Table 2. HIV-Seropositive Subjects by MRI and/or CT Findings Versus HIV-Seronegative Controls: Ratios of Average Regional Count Densities Controls (mean • SD) Right frontal/cerebellum Left frontal/cerebellum Right parietal/cerebellum Left parietal/cerebellum Right temporal/cerebellum
Atrophy (mean • SD)
VVhite Matter Changes (mean • SD)
P .016 .O19 .019 .O84 .O08 .033 .002 .043 .008 .006 ,118 .013 .026 .593 .009 .021
+ 0.07 -+ 0.09 + 0.09 _+ 0.09 _+ 0.08 • 0.12
O.841 0.854 0.904 0.929 0.841 0.845
• 0.12 + O. 13 + O. 12
Left temporal~cerebellum
0.959 0.976 1.022 1.034 0.978 0.985
_+ 0.06 + 0.08
0.776 -+ O. 12 0.790 + 0.08 0.838 + O. 10 0.864 • 0.08 0.834 • 0.14 0.873 • O. 11
Right thalamus/cerebellum Left thalamus/cerebellum Right caudate/cerebellum Left caudate/cerebellum Right lentiform/cerebellum Left lentiform/cerebellum Right thalamus/whole brain Left thalamus/whole brain Right cerebellum/whole brain Left cerebellum/whole brain
1.141 1.118 1.189 1,136 1.205 1.149 1.127 1.107 0.969 1.O 17
+ O. 10 • 0.09 • 0.15 • O. 14 _+ O. 12 • 0.09 + 0.04 _+ O.O8 • 0.06 -+ O.O7
0.954 0.973 1.006 0,942 1.060 1.010 1.O47 1.O65 1.076 1.33
+ O. 11 _+ O. 16 -+ 0.11 • O. 10 -+ O, 17 • 0.12 • 0.09 _+ O. 12 + O. 11 _+ 0.09
0.885 0.923 0.960 0.929 1.078 0.941 1.OO8 1.053 1.139 1.166
+ O. 16
• O. 14 • O. 15 • 0.08 • O. 13 • O. 10 • 0,13 • 0.08 • 0.08 ,+ 0.08 ,+ O. 14
360
ratios were noted in the HIV-seropositive group. When using whole brain count density as the denominator, only the frontal and thalamic regions showed a significant decrease suggesting that these were areas of more pronounced abnormality (Table 1). A subset of this group who underwent CT (5 of 10) and/or MRI (7 of 10) were examined across groups categorized by structural neuroimaging findings (atrophy or atrophy with white matter changes). Results in these groups were compared with age-matched normal controls. Semiquantitative analysis showed significantly decreased frontal/whole brain rations in HIV-seropositive subjects with atrophy, compared with normals. Deficits were also found in the caudate and thalamus in this group and in the group with white matter abnormalities. The group with white matter disease also demonstrated significantly elevated cerebellum/whole brain ratios (Table 2). This could be explained either by globally diminished cerebral uptake or by elevated cerebellar uptake. Elevated cerebellar glucose metabolism has been described in patients with Alzheimer's disease and periventricular white matter lesions. 48 This might be a related phenomenon. These findings are in concert with the work described by LaFrance et a144and by Rottenberg et al.41 The recurring finding of subcortical abnormalities parallels the distribution of macrophage and monocyte infiltrates that are prominent in basal ganglia in patients with HIV encephalitis, u The cortical deficits on scan are more difficult to explain as direct results of HIV involvement of the cortical gray matter because cortical gray matter is relatively spared in HIV encephalitis. However, these cortical deficits might be due to interruption of signal from the white matter disease commonly noted both at histopathologic examination and on MRI of the brain. In the clinical approach to ADC, opportunistic infections must be differentiated from the direct sequelae of HIV brain infection. This must be considered in the evaluation of the functional images as well. Toxoplasmosis and lymphoma, not surprisingly, will present as fairly welldemarcated focal defects on cerebral perfusion SPECT when the lesions involve the gray matter
KRAMER AND SANGER
Fig 4. A 51-year-old man with AIDS presented with the acute onset of seizures. (A) A C T scan performed after a double dose of intravenous contrast demonstrates an enhancing, space-occupying lesion in the right posterior parietal/occipital region of the brain. (B) ASPECT study performed on the patient showed a focal defect corresponding to the mass. After appropriate therapy for toxoplasmosis, a follow-up CT scan showed partial resolution of the abscess.
AIDS DEMENTIA COMPLEX
361
cortex and are large enough to be easily resolved by SPECT 49 (Fig 4). When the lesions are smaller, their appearance on SPECT is less clear-cut. Similarly, lesions of progressive multifocal leukoencephalopathy (PML) often involve the white matter. Because this is an area of relatively less blood flow compared with gray matter, the deficits may be quite subtle on SPECT. For this reason, SPECT will not replace double-dose contrast CT and/or MRI in the evaluation of the HIV-seropositive patient with psychiatric or neurological problems. On the other hand, experience with SPECT suggests that it may be more sensitive than MRI in detecting focal brain abnormalities due to HIV infection in symptomatic patients (Fig 5). 49-5~ Although the sensitivity of functional neuroimaging for brain abnormalities in ADC, even preclinical ADC, may exceed other modalities, the specificity has not been established. This is in part due to the high frequency of CNS opportunistic infections and neoplasms in this population. However, the patterns of subcortical abnormalities followed by cortical deficits and then by global brain deficits may suggest the diagnosis of
~ !~!~!~i
ADC. Further study of carefully screened and followed patients will be necessary before this can be determined. RESPONSE TO THERAPY
More recently, serial]Sfluorodeoxyglucose PET scans have been evaluated in HIV-seropositive subjects with signs and symptoms of dementia and who are undergoing AZT therapy. Brunetti et a146reported two patients whose baseline focal cortical defects resolved after AZT therapy. Two additional patients studied by this group showed an increase in global brain glucose metabolism after therapy. There was concomitant clinical improvement in three patients and one patient remained stable. Although CT did show reversal of white matter lucencies in one patient, CT and MRI were unchanged in two of the patients studied. Response to anti-HIV therapy on MRI has been reported occasionally by others. 6 However, the work of Brunetti et al~s suggests that functional neuroimaging may reflect a response to therapy more consistently. In their study, follow-up scans were performed after 10 to 12 weeks of therapy. If a response to therapy can be
84
Fig 5. In June 1988, a 46-year-old man w i t h AIDS presented w i t h focal left upper e x t r e m i t y seizures. A C T scan at t h a t time was negative. MRI done at t h a t time was unremarkable. (A) A S P E C T scan performed after t h e administration of I ~ I M P showed a focal defect in t h e right frontal cortex (arrow), The seizures persisted, and in November 1988, (B) a repeat CT scan showed an area of decreased intensity in a corresponding location. Brain biopsy at that time showed gliosis and multinucleated giant cells consistent with HIV encephalitis.
362
KRAMER AND SANGER
d e m o n s t r a t e d within a short period of time, functional n e u r o i m a g i n g m a y offer a m o r e specific, noninvasive m e a n s of diagnosing H I V enc e p h a l o p a t h y when o t h e r studies a r e inconclusive. SUMMARY F u n c t i o n a l S P E C T n e u r o i m a g i n g m a y have a role to play in the diagnosis of A D C because of its sensitivity to a l t e r a t i o n s in b r a i n function c o m p a r e d with s t r u c t u r a l modalities. M a n y of the observations a b o u t A D C m a d e by investigators in the field point to a significant p r o b l e m in the deep g r a y m a t t e r structures. Glucose m e t a bolic a b n o r m a l i t i e s in basal g a n g l i a have been d e m o n s t r a t e d on P E T . T h e r e is a p r e d o m i n a n c e of subcortical p a t h o l o g y identified on histopathologic e x a m i n a t i o n in A D C . Clinically, the presentation of A D C has been t e r m e d a " s u b c o r t i c a l d e m e n t i a " . 2 In addition, B r e i t b a r t et a151 have r e p o r t e d t h a t patients with A D C a r e e x t r e m e l y susceptible to the side effects of neuroleptics, like haloperidol, which localize in d o p a m i n e receptors in the basal ganglia. A b n o r m a l i t i e s det e c t a b l e on S P E C T , ie, t h e a s y m m e t r y seen
qualitatively, and the deficits m e a s u r e d on semiq u a n t i t a t i v e analysis, seem to reflect p a t h o l o g y in the d e e p g r a y m a t t e r . T h e a b i l i t y o f c e r e b r a l perfusion S P E C T to d e t e c t a b n o r m a l i t i e s in the subcortical g r a y m a t t e r offers the potential for m a k i n g a specific diagnosis of A D C . Because a b n o r m a l i t i e s in the b a s a l g a n g l i a have not been a p r o m i n e n t f e a t u r e of either M R I or C T studies in patients with A D C , S P E C T m a y be a useful a d j u n c t to the evaluation of the H I V - s e r o p o s i t i v e subject with n e u r o p s y c h i a t r i c s y m p t o m s once opportunistic infections a n d space-occupying lesions have been excluded. Because functional n e u r o i m a g i n g , both P E T 46 and S P E C T , 42 can be used to d e t e c t progression a n d / o r response to t h e r a p y , we will be able to b e t t e r diagnose a n d follow these patients as the t h e r a p e u t i c a p p r o a c h to A I D S d e m e n t i a complex improves.
ACKNOWLEDGMENT We would like to thank Linda Melnikoff and Catherine Tosado for their dedicated efforts in gathering case material, and Evelyn Millan and Giovanni Lopez for their technical assistance.
REFERENCES 1. Snider WD, Simpson DM, Nielson S, et al: Neurological complications of the acquired immune deficiency syndrome: Analysis of 50 patients. Ann Neurol 14:403-418, 1983 2. Navia BA, Jordan BD, Price RW: The AIDS dementia complex: I. Clinical features. Ann Neurol 19:517-524, 1986 3. Navia BA, Petito CK, Gold JWM, et al: Cerebral toxoplasmosis complicating the acquired immune deficiency syndrome: Clinical and neuropathological findings in 27 patients. Ann Neurol 19:224-238,1986 4. Krupp LB, Lipton RB, Swerdlow ML, et al: Progressive multifocal leukoenceophalopat!ay: Clinical and radiographic features. Ann Neurol 17:344-349, 1985 5. Janssen RS, Saykim A J, Kaplan JE, et al: Neurological complications of lymphadenopathy syndrome associated with immnnodeficiency virus infection. Ann Neurol 23:49-55, 1988 6. Grant I, Atkinson JH, Hesseling JR, et al: Evidence for early central nervous system involvement in the acquired immnnodeficiencysyndrome (AIDS) and other human immunodeficiencyvirus (HIV) infections. Studies with neuropsychlogic testing and magnetic resonance imaging. Ann Intern Med 107:828-836, 1987 7. Navia BA, Price RW: The acquired immunodeficiency syndrome dementia complex as the presenting or sole manifestation of human immunodeficiency virus infection. Arch Neuro144:65-69, 1987 8. Epstein LG, Sharer LR, Joshi VJ, et al: Progressive
encephalopathy in children with acquired immune deficiency syndrome. Ann Neurol 17:488-496, 1985 9. Lantos PL, McLaughlin JE, Scholtz CL, et al: Neuropathology of the brain in HIV infection. Lancet 1:309-311, 1989 10. Budka H, Costanzi G, Cristina S, et al: HIV encephalopathy and lymphadenopathy: Cells associated with viral antigens. Apmis 8:33-39, 1989 (suppl) 11. Vazeux R, Brousse N, Jarry A, et al: AIDS subacute encephalitis. Identification of HIV-infeeted cells. Am J Pathol 126:403-410, 1987 12. Nielsen SL, Petito CK, Urmacher CD, et al: Subacute encephalitis in acquired immune deficiency syndrome: A postmortem study. Am J Clin Pathol 82:678-682, 1984 13. Budka H, Costanzi G, Cristina S, et al: Brain pathology induced by infection with the human immunodeficiency virus (HIV). A histological, immunocytochemical, and electron microscopical study of 100 autopsy cases. Acta Neuropatho175:185-198, 1987 14. Ho DD, Rota TR, Schooley RT, et al: Isolation of HTLV-III from cerebrospinal fluid and neural tissues of patients with neurologic syndromes related to the acquired immnnodeficiency syndrome. N Engl J Med 313:1493-1497, 1985 15. Levy RM, Bredesen DE, Rosenblum ML: Neurological manifestations of the acquired immunodeficiency syndrome (AIDS): Experience at UCSF and review of the literature. J Neurosurg 62:475-495, 1985
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16. Cooper DA, Gold J, Maclean P, et al: Acute AIDS retrovirus infection: Definition of a clinical illness associated with seroconversion. Lancet 1:71-73, 1985 17. Hollander HR, Levy JA: Neurologic abnormalities and recovery of human immunodeficiency virus from cerebrospinal fluid. Ann Intern Med 106:692-695, 1987 18. Johnson RT, McArthur JC, Narayan O: The neuroNology of human immunodeficiency virus infections. FASEB J 2:2970-2981, 1988 19. Petito CK, Navia BA, Cho ES, et al: Vacuolar myelopathy pathologically resembling subacute combined degeneration in patients with the acquired immunodeficiency syndrome. N Engl J Med 312:874-879, 1985 20. Navia BA, Cho ES, Petito CW, et al: The AIDS Dementia Complex: II. Neuropathology. Ann Neuro119:525535, 1986 21. Pumarola ST, Navia BA, Cordon Cardo C, et al: HIV antigen in the brains of patients with the AIDS dementia complex, Ann Neurol 21:490-496, 1987 22. De la Monte SM, Moore T, Hedley-Whyte ET: Vacuolar encephalopathy of AIDS. N Engl J Med 315:15491550, 1986 23. Chrysikopouios HS, Press GA, Grafe MR, et al: Encephalitis caused by human immunodeficiency virus: CT and MR imaging manifestation with clinical and pathological correlation. Radiology 175:185-191, 1990 24. Koenig S, Gendelman HE, Orenstein JM, et al: Detection of AIDS virus in macrophages in brain tissue from AIDS patients with eneephalopathy. Science 233:1089-1093, 1986 25. Wiley CA, Nelson JA: Role of human immunodeficiency virus and cytomegalovirus in AIDS encephalitis. Am J Patho1133:73-81, 1988 26. Wiley CA, Schrier RD, Nelson JA, et al: Cellular localization of human immunodeficiency virus infection within the brains of acquired immune deficiency patients. Proc Natl Acad Sci USA 83:7089-7093, 1986 27. Gabuzda DH, Ho DD, de la Monte SM, et al: Immunohistochemieal identification of HTLV-III antigen in brains of patients with AIDS. Ann Nearol 20:289-295, 1986 28. Ho DD, Bredesen DE, Vinters HV, et al: The acquired immunodeficiency syndrome (AIDS) dementia complex. Ann Intern Med 111:400-410, 1989 29. Kermani E J, Bored JC, Brown PH, et al: New psychopathologic findings in AIDS: Case report. J Clin Psychiatry 46:240-241, 1985 30. Grant I, Atkinson JH, Hesselink JR, et al: Human immunodeficiency virus-associated neurobehavioural disorder. J R Coil Physicians Lond 22:149-157, 1988 31. Perry SW, Jacobsen P: Neuropsychiatric manifestations of AIDS-spectrum disorders. Hosp Community Psychiatry 37:135-142, 1986 32. Elovaara I, Iivanainen M, Sirkka-Liisa V, et al: CSF protein and cellular profiles in various stages of HIV infection related neurological manifestations. J Neurol Sci 78:331342, 1987 33. Resnick L, diMarzo-Verenese F, Sehupbach J, et z.l: ~ t r a b!ocd-~rain-b~,rrier sy~:thesi~ cf HTLV-I~H specific IgC in patients ;d~h nemologic symp~::ms associated wid,, A~DS or .A_[DS-rei~tsd ccmp]ex N E!!gl J Me~~ 313:'_'a9~-1504, IC85
363
34. Epstein LG, Goudsmit J, Paul DA, et al: Expression of human immunodeficiency virus in cerebrospinal fluid of children with progressive encephalopathy. Ann Neurol 21:397401, 1987 35. Post MJD, Tate LG, Quencer RM, et al: CT, MR and pathology in HIV encephalitis and meningitis. A JR 151:373380, 1988 36. Olsen WL, Longo FM, Mills CM, et al: White matter disease in AIDS: Findings of MR imaging. Radiology 169: 445-448, 1988 37. Jarvik JG, Hesselink JR, Kennedy C, et al: Acquired immunodeficiency syndrome. Magnetic resonance patterns of brain involvement with pathologic correlation. Arch Neurol 45:731-736, 1988 38. Ramsey RG, Geremia GK: CNS complications of AIDS: CT and MR findings. A JR 151:449-454, 1988 39. Ekholm S, Simon JH: Immunohistochemicai staining of cells in the brain of a patient with acquired immune deficiency syndrome (AIDS) with a monoclonal antibody to visna virus. Acta Radiol 73:406-408, 1987 40. Yang NC, Leichner PK, Pearlson GD, et al: MRI brain volumetrics for AIDS patients. Abstr Proc NY Acad Neurol, 1988 41. Rottenberg DA, Moeller JR, Strother SC, et al: The metabolic pathology of the AIDS Dementia Complex. Ann Neuroi 22:700-706, 1987 42. Pohl P, Vogl G, Fill H: Single-photon emission computed tomography in AIDS dementia complex. J Nucl Med 29:1382-1386, 1988 43. LaFrance ND, Pearlson GD, Schaerf FW: 1-123 IMP-SPECT in HIV-related dementia. Adv Funct Neuroimag 1:9-15, 1988 44. LaFrance ND, Pearlson G, Schaerf F, et al: SPECT imaging with I-123 isopropyl amphetamine in asymptomatie HIV seropositive persons. J Nucl Med 29:742, 1988 (abstr) 45. Costa DC, Ell P J, Burns A, et al: CBF tomograms with [99mTc-HM-PAO in patients with dementia (Alzheimer type and HIV) and Parkinson's disease--Initial results. J Cereb Blood Flow Metab 8:S109-115, 1988 (suppl) 46. Brunetti A, Berg G, DiChiro G, et al: Reversal of brain metabolic abnormalities following treatment of AIDS dementia complex with Y-azido-2'3'-dideoxthymidine(AZT, zidovuidine): A PET-FDG study. J Nucl Med 30:581-590, 1989 47. Deisenhammer E, Reisecker F, Leblhuber F, et al: Single-photon emission-computed tomography in the differential diagnosis of dementia. Dtsch Med Wochenschr 114: 1639-1644, 1989 48. Klinger A, de Leon M J, George AE, et al: Elevated eerebellar glucose metabolism in microvascular white matter disease: Normal aging and Alzheimer's disease. J Cereb Blood Flow 8:433-435, 1987 49. Kramer EL, Sanger J J: Central nervous system complications of the acquired immunodeficiency syndrome on I-123 Iodoamphetamine Brain SPECT. Adv Funct Neuroimaging 1:15-19, 1989 50. Smith GS, Kramer EL, Sanger J J, et al: Iodoamphetamine brai~ ~PFCT and M R ! / C T correlates of the AIDS ~t~meatia con'p,~cx. T~adic~cgy '-69:~355, 19~!; (sup!:l) 5i. Sreitbax W, ";.2areola KF. Cail P: :~ i[~S a~d neure!.'~tic ma!ig~t:~nt syndrome. :.a~_cet 2: ] 4~'~-!,'~S9, ] 9 ~