The neuropathology of AIDS: a review

Advances in Neuroimmunology Vol. 3, pp. 1 15, 1993

Printed in Great Britain. All rights reserved

0960-34281/93 $24.00 © 1993 Pergamon Press Ltd

The neuropathology of AIDS: a review Chandrakant

Rao, 1 Archinto

P. A n z i l a n d J o a n n a H o l l e n b e r g

Sher ~

Kings County Hospital Center and State University of New York Health Science Center at Brooklyn, Brooklyn, NY, U S A

Introduction

The acquired immunodeficiency syndrome (AIDS) is a fatal disease caused by human immunodeficiency virus, HIV-1 (formerly referred to as HTLV-III or LAV). HIV-1, an enveloped R N A virus belongs to the lentivirus subfamily and is a new addition to the previously known subfamily members (causing neurological diseases) such as visna, caprine arthritis-encephalitis virus, equine infectious anemia virus and simian T-cell lymphotropic virus-3 (Johnson and McArthur, 1987). The first decade of AIDS has stimulated publication of numerous case reports, review articles (Andcrs el al., 1986; Petito et al, 1986; Gray et al., 1988; Lang et al., 1989; Kure et al., 1991; Budka, 1991; Burns et al., 1991; Sharer, 1992) and monographs (Roscnblum et al., 1988; Lechtenberg and Sher, 1988; Nash and Said, 1992) describing the wide spectrum of neuropathology of AIDS. Although considerable advances have been made in the areas of morphological interpretation and nomenclature, many pathogenetic mechanisms especially in relation to the primary or putatively primary HIV CNS pathology remain enigmatic. The mechanism for HIV entry into the CNS is still debated, though the 'Trojan horse hypothesis', that is to say, HIV being carried passively into the CNS by infected lymphomonocytes across the blood-brain barrier, possibly damaged by circulating cytokines, i Corresponding author. Deceased.

is the favored one (Ho et al., 1987; Dal Canto, 1989; Budka, 1991). Another suggested mechanism is the spread of HIV to endothelial cells and thence into the CNS (Dal Canto, 1989; Rhodes and Ward, 1991). Central nervous system involvement in AIDS, is seen in up to 80% of cases at postmortem (De Girolami and Smith, 1992), becoming a contributing factor to the AIDS mortality in a considerable percentage of cases. Neurological presentation as the initial or sole manifestation of AIDS is seen in 5-10% of cases (Levy et al., 1985; Rhodes, 1987). AIDS associated pathology confined to the CNS is well documented thus qualifying many of the lesions as index or marker diseases for the diagnosis of AIDS (CDC, 1987). CNS pathology is seen at any one level or at multiple levels of the nervous system. At the current stage of our understanding, the neuropathological processes can be grouped as follows (see Table 1): (1) Primary HIV infection. (2) HIV associated pathology with unsettled etiopathogenesis. (3) Opportunistic infections. (4) Neoplasms. (5) Miscellaneous lesions such as nutritional, metabolic, etc. Multiple coexisting intracranial and or intraspinal pathologies from within the same group or from a combination of the above groups are also common in these patients.

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Table 1.

Advances in N e u r o i m m u n o l o g y CNS pathology in AIDS

(1) Primary H I V infection HIV encephalitis/myelitis (encephalomyelitis) (2) HIV-associated pathology with lesions of unsettled etiopathogenesis Nonspecific leukoencephalopathy Vacuolar myelopathy Vacuolar leukoencephalopathy Diffuse poliodystrophy Multiple sclerosis-like demyelinating lesions Focal pontine leukoencephalopathy Cerebral arteriopathy/arteritis Lymphocytic meningitis

(3) Opportunistic infections of the CNS Viral Cytomegalovirus JC virus (PML) Other such as Herpes simplex 1 and 2, Herpes zoster, HTLV-I Fungal

Cryptococcus Candida Other such as Aspergillus, Histoplasma, Phycomyces, Coccidioides, Blastomyces, Acremonium, Cladosporium Algae Prototheca Parasitic Protozoa - - Toxoplasma, Acanthamoeba, Leptomyxid amoeba Trypanosoma cruzi Metazoa - - Strongyloides Bacterial Pyogenic - - E. coli, Listeria, Staph., Sabnonella Mycobacterial - - Mycobacterium tuberculosis M. avium-intracellulare (MAI) Spirochetal - - Treponema pallidum Filamentous - - Nocardia Miscellaneous - - Whipple's disease (4) Neoplasms Primary CNS lymphoma Secondary CNS lymphoma Other: Intravascular lymphoma, lymphomatoid granulomatosis, metastatic (multicentric?) Kaposi's sarcoma, primary glial neoplasms, metastatic squamous cell carcinoma of anal canal

(5) Miscellaneous Effects of nutritional, electrolyte, metabolic or systemic disturbances Wernicke's encephalopathy, central pontine myelinolysis, hepatic encephalopathy, hypoxic encephalopathy, embolic infarctions from NBTE, hemorrhages due to coagulopathy

Neuropathology of AIDS

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Neuromuscular pathology and ophthalmic pathology are also an important part of the neurological involvement of AIDS. CNS pathology in pediatric population has noticeable differences from that of adults and thus will be considered separately. CNS pathology in AIDS Primary H I V infection

H I V encephalitis/myelitis (encephalomyelitis): (formerly referred to as HIVencephalopathy). Clinical features: AIDS dementia complex (ADC) is often but not always the clinical counterpart of HIV encephalitis. A D C is characterized by gradual onset of cognitive changes beginning with impaired concentration and memory, progressing to intellectual deterioration, behavioral and motor changes and finally global cognitive dysfunction. Tremors, weakness of legs, ataxia, myoclonus and incontinence are seen in a varying proportion of ADC cases (Price et al., 1988). Pathology: Cerebral atrophy, reduction of white matter volume and ventricular dilatation of varying degrees may be seen but are not a constant finding. Sharer and coworkers' suggestion (1985) that the multinucleated giant cells (MGC) in the microglial nodules might be related to HIV, led to the recognition of said cells as histological markers of HIV encephalitis. Ultrastructural (Epstein et al., 1985), immunocytochemical and in situ hybridization (Wiley et al., 1986) studies have demonstrated either viral particles or viral antigens in these cells. Thus the microglial nodules with MGC and varying number of inflammatory cells became the sine qua non criterion for the diagnosis of HIV encephalitis (Fig. 1). These nodules are widely scattered preferring the cerebral white matter and deep gray over other areas. MGC, believed to be formed by fusion of macrophages or resident microglia, dis-

Histopathology of HIV encephalitis: A microglial nodule with many multinucleated giant cells.

Fig. 1.

play rather hyperchromatic nuclei arranged peripherally in a ring fashion or clustered centrally. When haphazard crowding of the nuclei in a cell with scanty cytoplasm is seen, the word giant cell seems a misnomer. Microglial nodules alone without MGC can be regarded as specific only by proving the presence of HIV antigens or nucleic acids in the tissue, in the absence of which they must be considered nonspecific for diagnostic purposes. Presence of MGC, often in a perivascular location, without microglial nodules in the setting of white matter pathology such as myelin pallor, astrocytosis and perivascular macrophages, is held to be indicative of HIV encephalitis or 'HIV leukoencephalopathy' (Budka et al., 1991). HIV encephalitis is seen in 30% of cases at autopsy (Kure et al., 1991). Although HIV encephalitis appears to be the common denominator in clinically diagnosed cases of ADC, the pathological substrate of dementia in AIDS is not really understood. Absence of histological evidence of HIV encephalitis in clinically well documented cases of A D C (Rosenblum, 1990), absence of a close correlation between severity of pathological changes and neurological im-

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pairment (Navia et al.; 1986) and demonstration of HIV in brains with few neuropathological changes (Shaw et al., 1985) led to various alternate speculations regarding the pathogenesis of ADC. It has been aptly suggested that the pathogenetic mechanisms might be multifactorial incriminating not only the HIV specific pathology but also the HIV-associated nonspecific pathology (Budka, 1991). The role of a direct cytopathic effect of HIV on glia and neurons has been considered, though to date there is no compelling evidence of significant infection of these cells by the HIV. Thus far microglia-macrophages - - MGC are the only cells in the CNS satisfactorily proven to be infected by HIV to any substantial degree. Other suggested mechanisms include gp 120 induced neuronotoxicity or receptor blocking activity, neurotoxic 'microgliamacrophage factors' with associated microvascular injury (Budka, 1991; Lipton, 1991) and other yet unrecognized, possibly opportunistic pathogens (Sharer, 1992). Wiley (1992) recently demonstrated direct correlation between the CNS viral burden (as measured by the presence of the HIV antigen in the tissue) and neuropathology of HIV encephalitis including atrophy and neocortical neuronal loss in the brains of adults. Significant dendritic pathology such as shortening of dendrites, pruning of spines and vacuolation of processes has been demonstrated by Golgi studies (Masliah et al., 1992) as was loss of pre- and postsynaptic elements by immunomicroscopy (Wiley et al., 1991). These findings bring us closer to the understanding of AIDS dementia. Neurons and neuronal circuitry, while not infected, appear to be damaged indirectly by the HIV (Wiley, 1992). H I V associated pathology of unsettled etiopathogenesis Nonspecific leukoencephalopathy. Myelin pallor, astrocytosis and perivascular macrophages

in the white matter unassociated with MGC is not an infrequent observation in AIDS brains. These changes along with cerebral vasculitis and lymphocytic meningitis were shown in HIV seropositive, non-AIDS, non-ARC cases with negative HIV immunocytochemistry (Gray et al., 1992). In the absence of demonstrable HIV in the affected tissue these changes remain nonspecific for diagnostic purposes. Vacuolar myelopathy (VM). First described by Goldstick et al. (1985) then Petito et al. (1985), VM is reported in 2-55% of AIDS cases in autopsy (Budka, 1991). Clinical features: Patients present with progressive spastic, ataxic paraparesis with urinary incontinence and variable loss of position and vibratory sensation. Pathology: Grossly the spinal cord may appear unremarkable on cross sections or may rarely reveal discolored sunken posterior and lateral columns. Microscopically, numerous vacuoles with many macrophages, some of them located within the vacuoles in the lateral and posterior and occasionally anterior columns of thoracic and cervical spinal cord segments characterize this entity (Fig. 2). Myelin stains but first and foremost ultrastructural studies reveal the vacuoles to be intramyelinic. Pathogenesis: Identical pathology of similar distribution is seen in subacute combined degeneration (SACD) of spinal cord due to Vitamin Bl2 deficiency and also in non-AIDS, immunosuppressed patients with malignancies (Kamin and Petito, 1991). Demonstration of MGC and productive HIV infection within the lesions of VM by light and electron microscopical immunocytochemistry was considered as adequate proof that VM is HIV induced (Maier et al., 1989). However, it might be suggested that these findings merely represent coexistence of HIV myelitis and VM. On the other hand, Vitamin B~2 deficiency is common in AIDS patients (Herbert 1990; Herbert et al., 1990).

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Fig. 2. Vacuolar myelopathy: (a) Low power view of a corticospinal tract, thoracic segment, showing vacuolation. (b) Close-up view showing many vacuoles some with macrophages within them.

Thus, the exact etiopathogenesis of VM is still debated - - HIV infection, Bl2 deficiency, toxic injury and opportunistic infections contending for the etiological role.

Vacuolar leukoencephalopathy. Similar vacuoles as described in VM have been seen in the cerebral white matter. Diffuse poliodystrophy. Here the brain may be atrophic. Histologically, diffuse reactive astrocytosis, diffuse microgliosis and a suggestion of neuronal loss are seen in the cerebral gray matter (Budka, 1991). Considering the variety of metabolic insults in AIDS patients, the specificity of these findings and the very existence of this entity are in question. Multiple sclerosis (MS)-like demyelinating lesions. Ten cases of this distinct white matter disease are reported in the literature (Berger et al., 1989; Gray et al., 1991: Berger et al., 1992). Clinically, a MS-like illness may pre-

cede, accompany or follow the recognition of HIV infection. An alternatively relapsing and remitting course was observed in eight of the ten patients. Histological examination of the lesions in six cases, three obtained by biopsy and three by autopsy, revealed primary demyelination with relative axonal preservation, foamy macrophages and perivascular lymphocytes. No evidence of ,Jpportunistic infections and especially of progressive multifocal leukoencephalopathy (PML) was present in spite of a directed search for it. In one of these cases presence of HIV within a demyelinated lesion was documented by electron microscopy and in situ hybridization (Berger et al., 1992). We have seen three such biopsy cases, presenting as mass lesions, a presentation also documented in MS proper (Hunter et al., 1987, Giang et al., 1992). One of our cases also had a relapsing and remitting course and responded to steroid therapy. Attempts to demonstrate the HIV by electron microscopy and immunocytochemistry were unsuccessful.

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Advances in Neuroimmunology

The etiopathogenesis of this entity needs further elucidation as even the authors who successfully demonstrated HIV within the lesion suggested the possibilities of a casual association between HIV and MS, the ability of HIV to unmask a propensity to develop MS, or an independent capability of HIV to cause primary demyelination with a MS-like illness (Berger et al., 1992).

Focal pontine leukoencephalopathy (FPL). Multifocal areas of vacuolation, axonal injury with swelling and prominent punctate or 'nemaline' (linear) calcifications within the pons (FPL) and/or occasionally in the cerebral hemispheres have been described in AIDS patients and also in cancer patients who received chemo- or radiotherapy (Vinters et al., 1989a). The clinical correlates, if any, and etiology of these lesions remain unidentified. We have observed MGC within FPL lesions in one of our cases with HIV encephalitis but this observation may again only mean random coexistence of two pathologies, as pointed out in VM. Cerebral arteriopathy/arteritis. Several reports have emphasized the cerebrovascular pathology pointing out that AIDS patients, despite their young age appear to be fifteen to thirty times at higher risk for cerebral infarction than age-matched control subjects (Engstrom et al., 1989; Kieburtz et al., 1992). Cerebral infarction can also occur as the initial manifestation of AIDS. Two identifiable etiologies for cerebral infarctions in AIDS are emboli from nonbacterial thrombotic endocarditis (NBTE) and arteriopathy/arteritis associated with opportunistic infections such as cryptococcosis, herpes zoster, tuberculosis, etc. Apart from these, there still remains a poorly understood third group with arteriopathy of large, medium and small vessels causing macroand/or microinfarctions. Stroke is also documented in pediatric AIDS and in one such case an aneurysmal arteriopathy of the cir-

cle of Willis with marked intimal proliferation, attenuation of media and disruption of elastica was demonstrated (Park et al., 1990). Many mononuclear cells throughout the intima stained positively for gp 41, while the arteries were negative for herpes zoster antigen by immunocytochemistry. However, the presence of intracellular acid-fast bacilli in a subendothelial focus clouds the univocal interpretation of the remarkable findings in this case. Thus, whether the vascular pathology in AIDS is due to a direct HIV effect or whether it is cytokine-elastase mediated, remains speculative. A case of primary or isolated CNS granulomatous angiitis, in whom HIV was isolated from the CSF, is on record (Yanker et al., 1986).

Lymphocytic meningitis. An acute, self limiting aseptic meningitis with fever, headache, meningismus and CSF pleocytosis occurring at the time of seroconversion is clinically well known. The relation of rarely observed lymphocytic meningitis at autopsy to this clinical syndrome and to HIV infection is difficult to evaluate. As pointed out earlier, lymphocytic meningitis and cerebral vasculitis was demonstrated in HIV seropositive, non-AIDS cases (Gray et al., 1992). Opportunistic infections This ever expanding group includes common, rare and esoteric diseases. Defective cell-mediated immunity due to the cytopathic effect of HIV on the circulating T lymphocytes explains the wide array of these infections in AIDS.

Viral Cytomegalovirus (CMV). CMV is the most common opportunistic CNS viral infection in AIDS and is seen in 10-26% of AIDS autopsies (Kure et al., 1991). The clinical features being nonspecific, CNS infection

Neuropathology of AIDS by CMV is either missed or confused with ADC. Pathologically, CNS involvement by CMV is seen in various forms. The two most common being nodular encephalitis with formation of microglial nodules containing cytomegalic cells with intranuclear and/or intracytoplasmic inclusions in the center of several of them; the other form being a necrotizing ependymitis-encephalitis with CMV inclusions along the shores bathed by the CSF circulation. The latter form can be grossly identified or at least suspected. CMV-bearing cells are characterized firstly by cytomegaly and secondly by the Cowdry type A owl eye intranuclear inclusions with or without intracytoplasmic inclusions. CMV inclusions can be seen in astrocytes, ependymal cells, neurons and endothelial cells, however identification of the nature of the inclusion bearing cell is difficult except for the endothelial cells that can be identified by their location. Meningoradiculitis, radiculomyelitis, focal necrosis and demyelination are also seen due to CMV infection (Morgello et al., 1987; Vinters et al., 1989b). Progressive multifocal leukoencephalopathy (PML). This demyelinating disease, due to a species from the polyoma group of the Papova viruses namely the JC virus, is seen in 2-7% of AIDS patients at autopsy (Kure et al., 1991). More importantly it is the third most common cause of focal CNS lesions (20%) seen by neuro-imagining studies (Ciricillo and Rosenblum, 1990). The very multifocal nature of the disease explains the varied clinical presentations ranging from focal signs such as hemiparesis, hemianopsia and ataxia to diffuse behavioral changes. The lesions involve predominantly cerebral and some times cerebellar white matter, though the gray matter is by no means completely spared. It starts as small multifocal areas of pallor but at the time of autopsy, especially in AIDS patients, it is often seen as large confluent areas of granular softening with a melted cheese appearance involv-

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Fig. 3. Progressive multifocal leukoencephalopathy (PML): Section of a brain in semihorizontal, CT scan plane showing an extensive granular to flocculent softening of the occipital lobe white matter and splenium of the corpus callosum.

ing almost the entire cerebral white matter (Fig. 3). Histologically, it is characterized by demyelination with associated macrophages, enlarged oligodendroglial cells with basophilic, eosinophilic, or purplish ground glassappearing intranuclear inclusions, located at the periphery of the lesion in denser concentration. Reactive astrocytosis with many astrocytes revealing bizarre, neoplastic looking nuclei, bespeaking an oncogenic effect of the virus, complete the classical histological appearance. Axonal preservation seen in smaller lesions is inconsistently demonstrated in the large confluent lesions. The extent and severity of the lesions as well as the number of the oligodendroglial inclusions is greater in AIDS patients than in non-AIDS patients. Uncommon viral infections. Herpes simplex (HSV) and herpes zoster (HZV) encephalitis are uncommon and seen in 1.6% and 0.6% of AIDS autopsy series, respectively (Kure et al., 1991). The pathological changes in HSV encephalitis are similar to those de-

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scribed in non-AIDS patients except for a more diffuse distribution. Multifocal areas of demyelination, leukoencephalitis, arteriopathy with thrombosis and infarction (Morgello et al., 1988; Frank et al., 1989), HZV encephalitis involving the visual centers with transsynaptic spread along the visual pathways (Rostad et al., 1989) are all reported in HZV infection of the CNS in AIDS. Intranucelar inclusions with immunocytochemical demonstration of HZV have been reported in some cases, HTLV-1 myelopathy in an AIDS patient has been recorded only recently (Rosenblum et al., 1992).

Fungal Cryptococcosis. Cryptococcal meningitis or meningoencephalitis is seen in up to 12.5% of cases in autopsy cases (Kure et al., 1991). Paucity of inflammatory infiltrates even in the presence of a large number of organisms (hence the term cryptococcosis) is generally the rule and it is reflected in the gross appearance of the brain where no change other than a gray gelatinous or soapy appearance of the meninges may be appreciated. However, the cross sections often reveal diagnostic 'soap bubble cysts' in the basal ganglia, substantia nigra and superficial cortex. The soap bubble cysts are dilated Virchow-Robin perivascular spaces filled with cryptococcal organisms and mucoid material. Confluence of such areas gives rise to a large gelatinous lesion that can be visualized on neuro imaging studies. Rare pathological reactions include cryptococcomas, granulomatous meningitis and abscess formation. Candidiasis. CNS candidiasis is seen in 1-2% of cases at postmortem, a surprisingly low incidence in view of the common occurrence of oral candidiasis in AIDS patients. The lesions may take the form of microabscesses or abscesses and sometimes they may be seen as contrast enhancing lesions radiologically indistinguishable from

other mass lesions in the CNS of AIDS patients. Other fungal infections, for instance aspergillosis, are uncommon but well documented. Protozoan Toxoplasmosis. CNS toxoplasmosis is seen in 5-26% of AIDS autopsy cases (Kure et al., 1991). It is the commonest cause of focal lesions in AIDS patients accounting for 50% of such lesions (Ciricillo and Rosenblum, 1990). Clinical symptomatology ranges from focal to diffuse findings including hemiparesis, hemianopsia, ataxia, seizures, headache, confusion and coma. Movement disorders are described due to toxoplasma lesions in the basal ganglia (Nath and Jankovic, 1989). We have seen a case of disabling bilateral ballismus due to the involvement of subthalamic nuclei by toxoplasma lesions. Toxoplasma lesions tend to be multiple, involving preferentially the gray-white matter junction, the basal ganglia and the cerebellum. They appear as ring enhancing lesions in a CT scan after contrast medium injection (Farkash et al., 1986; Navia et al., 1986).

Fig. 4. Cerebral toxoplasmosis: Coronal section of a brain showing a necrotic lesion in the basal ganglia with hyperemic rim and central hemorrhage.

Neuropathology of AIDS Grossly, the lesions are characterized by a gray-yellow necrotic area with a hyperemic rim (Fig. 4). Histologically, a central core of coagulative necrosis surrounded by macrophages, hypertrophied arteries with concentric arrays of reticulum fibers, inflammatory cells and reactive astrocytosis are seen. Encysted bradyzoites and free tachyzoites are seen at the interface between necrotic and viable tissues. Prior antitoxoplasma treatment makes finding an organism within an otherwise typical lesion extremely difficult. Although immunoperoxidase stains do decorate the bradyzoites and tachyzoites quite well, in the absence of a histologically recognizable cyst these stains are not very helpful in the identification of tachyzoites due to nonspecific staining of punctate calcium. Old toxoplasma lesions often appear as cystic infarcts. An encephalitic form of CNS toxoplasmosis with scattered microglial nodules and encysted or free toxoplasma organisms in the center instead of a mass lesion, has also been seen in AIDS patients. Amoebiasis. Acanthamoeba involving the CNS has been reported in a few AIDS patients. Pathologically, it is characterized by an acute necrotizing encephalitis. We have reported a case of granulomatous meningoencephalitis which we initially identified as being due to acanthamoeba but was later proven by immunofluorescent studies to be due to a leptomyxid ameba, thus emphasizing the limitations of light microscopic identification of these pathogens (Anzil et al., 1991).

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and increasing numbers of cases with CNS involvement are being reported (Bishburg et al., 1986, Berenguer et al., 1992). However, pathologically documented cases are still few. We have recently reported 6 cases of pathologically confirmed CNS tuberculosis due to mycobacterium tuberculosis in AIDS: 2 with brain abscesses, 2 with suppurative leptomeningitis and 2 with mononuclear leptomeningitis with karyorrhexis and cytolysis. Remarkably none of the cases had epithelioid granulomas, although such cases have also been reported. Apparently in AIDS patients it is important to prepare stains and cultures of acid-fast bacilli either at the clinical stage or at autopsy even when a suppurative CSF cytology or an exudative brain tissue histology is seen in AIDS patients (Anzil et al., 1992). Mycobacterium avium intracellulare infection of the CNS thus far appears to be an incidental finding coexisting with other pathogens or present at sites lacking or without the blood-brain barrier (Vinters et al., 1989a). Pathologically documented cases of neurosyphilis are rare in AIDS. A notable exception, however, is that of a severe encephalitis teeming with treponemal organisms (quaternary neurosyphilis) (Morgello and Laufer, 1989). No cardial abscesses in the CNS are documented (Seymour et al., 1992). A case of CNS Whipple's disease presenting with mild dementia, supranuclear ophthalmoparesis and oculomasticatory myorrhythmia has been reported (Jankovic, 1986). Neoplasms

Bacterial. Pyogenic meningitis and abscesses are rare in AIDS patients although they have been documented. Even in children with AIDS who have a high incidence of extracranial pyogenic infections, CNS involvement by these agents is only rarely seen.

It is evident that infection due to mycobacterium tuberculosis in AIDS is on the rise

Primary central nervous system lymphoma. Incidence of primary central nervous system lymphoma has been noted to be increasing in both AIDS and non-AIDS populations. It is the second (30%) commonest cause of CNS mass lesion in AIDS (Ciricillo and Rosenblum, 1990) and is seen in 3-8% of postmortems (Kure et al., 1991). Eighty-

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Advances in Neuroimmunology

five percent of CNS lymphomas in AIDS at autopsy were multifocal, occurring with relatively equal frequency in cerebral hemispheres, basal ganglia, diencephalon and brainstem (Morgello et al., 1990). Thus location, uni- or multifocal appearance and radiological patterns cannot clearly distinguish lymphoma from toxoplasma lesions. When the lymphoma is necrotic this difficulty sometimes extends to the interpretation of the gross appearance of the lesion. Primary CNS lymphoma in AIDS is seen either as a diffusely infiltrating or a circumscribed lesion often with necrosis (Fig. 5). Microscopically, diffuse infiltration, necrosis, characteristic perivascular infiltration with increased reticulin rings are usual features. They are most commonly either large cell or mixed large and small cell or small noncleaved cell type lymphomas by the Working Formulation (So et al., 1986; Morgello et al., 1990). In all cases in which an elaborate immunocytochemical study was carried out with an extensive panel of antibodies, the neoplasms were of B cell origin (Morgello et al., 1990, So

Fig. 5. Primary CNS lymphoma: Section of a brain in semihorizontal, CT scan plane showing a necrotic expansile tumor mass in the basal ganglia.

et al., 1986). Interestingly, the majority of

the CNS lymphomas in AIDS patients (9 of 15) were accompanied by polyclonal mixed infiltrates of T and B lymphocytes (Morgello et al., 1990). The Epstein-Barr virus (EBV) genome has been detected on several occasions in the nuclei of lymphoma cells of HIV patients by in situ hybridization (Ioachim et al., 1991). This finding coupled with a number of karyologic and other similarities between AIDS-associated lymphoma and endemic EBV-induced Burkitt's lymphoma suggest the possible direct etiological role of EBV in lymphoma in AIDS (Ioachim et al., 1991; Knowles et al., 1988). Other neoplasms: rare cases of intravascular lymphoma (Dozic et al., 1990), lymphomatoid granulomatosis (Anders et al., 1989) and intracerebral Hodgkin's disease (Hair et al., 1991) have been reported in HIV positive patients. Secondary CNS lymphoma is seen in 1-5% of AIDS autopsy cases. However, CNS lymphoma in AIDS is twice more likely to be primary than secondary (Kure et al. , 1991). Metastatic Kaposi's sarcoma is also documented in the CNS and its coverings in AIDS patients (Gorin et al., 1985). We have examined the CNS metastasis of a squamous cell carcinoma of anal canal origin from a HIV positive homosexual patient. The lesion, radiographically, was indistinguishable from a lymphoma. Four cases of cerebral astrocytoma are reported in the literature (Kasantikul et al., 1992) and we have seen a case of glioblastoma multiforme in an AIDS patient. These cases might very well represent a fortuitous association. N e u r o m u s c u l a r disorders. Various neuromuscular disorders are described in AIDS patients (Table 2). Peripheral neuropathies are common clinically and pathologically (Mah et al., 1988) as are pathological changes in the skeletal muscle (Wrzolek et al., 1990). The etiological role of HIV and

Neuropathology of AIDS

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Advances in Neuroimmunology

immune mediated mechanisms are still debated in these various forms of neuropathies and myopathies (Dalakas and Illa, 1991). An ALS-like clinical presentation with loss of m o t o r neurons and astrocytosis in cervical and lumbar anterior horns at autopsy was also reported (Sher et al., 1988). Zudovidine ( A Z T ) , a D N A chain terminator that inhibits the mitochondrial-~-DNA polymerase, is toxic to muscle mitochondria and thus explains the muscle pathology of A Z T myopathy (Pezeshkpour et al., 1991). O p h t h a l m i c p a t h o l o g y . The most common ophthalmologic findings in AIDS patients are cotton wool spots occurring in 50-90% of patients. This ophthalmoscopic finding represents, pathologically, foci of cytoid bodies (swollen axons) in the nerve cell layer of the retina. The pathogenesis of these bodies is not understood. Microcirculatory disturbances due to viral infection of the vessels or immune mediated mechanisms have been incriminated (De Girolami et al., 1992). CMV retinitis is common in AIDS patients. In addition, parasitic (toxoplasma, pneumocystis), fungal (cryptococcal) and bacterial (mycobacterium tuberculosis, syphilis) infections have all been documented in the eye of AIDS patients as are Kaposi's sarcoma and malignant lymphoma (De Girolami et al., 1992; Palestine and De Smet, 1991). Pediatric A I D S . Commonest neuropathological abnormalities in pediatric brains are micrencephaly and basal ganglia mineralization. H I V encephalitis is also seen in 30% of brains examined. Opportunistic CNS infections other than CMV are extremely uncommon. Myelin pallor is often noted in the cerebral white matter. Spinal cord pathology, seen clinically as spastic paraparesis (Belman, 1990) and pathologically as corticospinal tract involvement is frequent (about 65% autopsied cases). It consists of diminished axons and myelin or poor myelination with preservation of axons

(Dickson et al., 1989). Vacuolar myelopathy is uncommon in children and we have seen two cases of VM in children in addition to the few reported cases (Sharer and Cho, 1989). References Anders, K. H., Guerra, W. F., Tomiyasu, U., et al. (1986). The neuropathology of AIDS: UCLA experience and review. Am. J. Pathol. 124:537-538. Anders, K. H., Latta, H., Chang, B. S., et al. (1989). Lymphomatoid granulomatosis and malignant lymphoma of the central nervous system in the acquired immunodeficiency syndrome. Human Pathol. 20:326-334. Anzil, A. P., Rao, C., Wrzolek, M. A., et al. (1991). Amebic meningoencephalitis in a patient with AIDS caused by a newly recognized opportunistic pathogen Leptomyxid Ameba. Arch. Pathol. Lab. Med. 115:21-25. Anzil, A. P., Rao, C., Seymour, A. W., et al. (1992). CNS tuberculosis in AIDS: A synopsis of six cases with emphasis on morphology. J. Neuropathol. Exp. Neurol. 51:375 (abstract). Belman, A. L. (1990). AIDS and pediatric neurology. Neurol.Clin. 8:571-603. Berenguer, J., Moreno, S., Laguna, F., et al. (1992). Tuberculous meningitis in patients infected with human immunodeficiency virus. N. Eng. J. Med. 326:668-672. Berger, J. R., Sheremata, W. A., Resnick, L., et al. (1989). Multiple sclerosis like illness occurring with HIV infection. Neurology 39:324-329. Berger, J. R., Tornatore, C., Major, E. O., et al. (1992). Relapsing and remitting HIV associated leukoencephalomyelopathy. Ann. Neurol. 31:34-38. Bishburg, E., Sunderam, G., Reichman, L. B., et al. (1986). CNS tuberculosis with the AIDS and its related complex. Ann. Intern. Med. 105:210-220. Budka, H. (1991). Neuropathology of HIV infection. Brain Pathol. 1:163-175. Budka, H., Wiley, C. A., Kleihues, P., et al. (1991). HIV-associated disease of the nervous system: Review of nomenclature and proposal for neuropathology based terminology. Brain Pathol. 1:143-152.

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