Neurosurg. Rev. 13 (1990) 189--194
Spinal cord lesions in the Acquired Immune Deficiency Syndrome (AIDS) Franfoise Gray1,2, Romain Gherardi~'2, Pierre Trotot3, Gilles Fenelon 4, and Jacques Poirier 1,2 ~Department of Pathology (Neuropathology) Henri Mondor Hospital, Cr6teil, France, 2Department of Medical Neurosciences, Faculty of Medicine, University of Paris-Val de Marne, Cr6teil, France, 3Radiology Service, Pasteur Institute Hospital, Paris, France, and 4Neurological Clinic, Tenon Hospital, Paris, France
Abstract Spinal cord involvement in AIDS is not uncommon. Different types of lesions corresponding to varying pathogenetic mechanisms have been reported. Vacuolar myelopathy is the most frequently found. The symptoms and pathological changes resemble those of subacute combined degeneration; however, cobalamine or folate levels have always been found normal. Its frequent association with the multi-nucleated giant cells characteristic of HIV encephalitis makes it likely that the virus plays a role in its pathogenesis. Cytomegalovirus may be responsible for acute myeloradiculitis involving the spinal roots of the cauda equina and inferior part of the spinal cord. In cases of Herpes simplex virus myelitis has been reported; they are usually associated with cytomegalovirus infection and are due to herpes simplex virus type II. Secondary spread from systemic lymphomas may involve the subarachnoid space of the cord and the spinal roots. Compression of the spinal cord by epidural lymphomatous masses has also been described. Spinal infarcts may be secondary to acute or chronic vasculitis or to less specific vascular processes such as disseminated intravascular coagulation.
Keywords: Acquired Immune Deficiency Syndrome (AIDS),, cytomegalovirus, Human Immunodeficiency Virus (HIV), myelopathy, spinal cord, vacuolar myelopathy.
1 Introduction Acquired immune deficiency syndrome is due to an infection by the human immunodeficiency virus (HIV) which has a particular tropism for the membrane antigen CD4 [8]. This receptor is contained 9 1990by Walter de Gmyter & Co. Berlin 9New York
in T-helper lymphocytes which are destroyed. This causes loss of cell-mediated immunity and favors the occurence of opportunistic infections and nonHodgkin lymphomas. A direct infection of the CNS by the virus has also been proved, and it has been demonstrated that mononuclear-macrophages, which also contain the receptor, represent, in the CNS, the main cells capable of synthesizing viral ribonucleic acid and may, therefore, be both the main reservoir and the vehicle of spread for the virus [21]. Neurological complications are frequent; it has been reported that 40% to 50% of AIDS patients have neurological symptom and that 75% to 100% of AIDS patients show morphological abnormalities of the nervous system [1, 13, 14, 16, 23, 26, 34]. These varying types of neurological complications correspond to different pathogenetic mechanisms which are not yet perfectly understood [11]. Some are opportunistic infections and lymphomas secondary to T-helper depletion. Some have been related to a direct infection of the nervous system by HIV, probably through mononuclear-macrophages. Still others may be secondary to vascular alterations or visceral organ impairement, correspond to terminal events, or represent coincidental occurence [13]. Spinal cord changes, although far less frequent than brain lesions, are not uncommon in AIDS [33]. In our series of 40 AIDS patients, collected in the Department of Neuropathology of Henri Mondor Hospital between 1982 and 1987, 32 had neurological symptoms. Clinical signs of spinal cord involvement were found in three of these
190 patients, and pathological spinal changes were found in four of the six cases whose spinal cord was examined [14]. Almost all the diffuse or multifocal pathological processes involving the central nervous system and/or the leptomeninges may also affect the spinal cord; but some of them involve it predominantly, causing specific myelopathic diseases. These latter may be classified as follows: vacuolar myelopathy and other changes predominantly involving the long tracts possibly related to direct HIV infection; opportunistic myelitis or myeloradiculitis mainly due to viruses of the herpes group; secondary spread from systemic lymphomas and miscellaneous less specific lesions.
Gray et al., Spinal cord lesions in AIDS or folate deficiency were never found [25]. Its frequent association with MGC encephalitis makes it likely that HIV is involved in its pathogenesis as has been demonstrated for HTLV 1 in tropical spastic paraparesis [36]. This hypothesis is supported by the frequent association of vacuolar myelopathy with HIV encephalitis and the constatallation, in one instance, of multinucleated giant cells characteristic of HIV infection [6, 12, 31], closely adjacent to the vacuolar spinal changes (Figure lb) [14, 15]. In the other hand, although vacuolar myelopathy is seldom found in infants and young children despite severe infection of the CNS [32], it has
2 Vacuolar myelopathy Vacuolar myelopathy is probably the most common of the myelopathies associated with HIV infection. Its incidence varies from 0% to 29% of the pathological series [1, 3, 14, 16, 25, 26, 27, 29, 34]. These vacuolar, non-inflammatory lesions are symmetrical, more severe in the lateral and posterior columns of the thoracic cord, and not confined to specific anatomical tracts (Figure la). Ultrastructurally, the vacuoles consist of intramyelin swelling with splitting of the lamellae and presence of lipid-laden macrophages. Axons are normal in mildly affected areas, but may be disrupted in areas with severe vacuolation with consequent Wallerian degeneration. This disease manifests clinically by spastic paraparesis and ataxia; urinary incontinence is possible; dementia is observed in about 60% of the affected individuals [23]. Precise correlations of spinal cord abnormalities with myelopathic symptoms may be difficult because of coexisting peripheral neuropathies and brain lesions. However, it appears that spinal symptoms are constant only in severe lesions and that the severity of pathological lesions correlates not only with symptoms of spinal cord disease but also with dementia [25, 27]. CSF examination is not contributive. Radiological examination is usually of only little help to evidence spinal cord lesions. In contrast magnetic resonance imaging or computed tomography of the brain frequently demonstrates associated HIV encephalitis. The pathogenesis of vacuolar myelopathy remains controversial; although the changes resemble those of subacute combined degeneration, cobalamine
Figure 1. Vacuolar myelopathy, a) Horizontal section of the thoracic cord, Loyez stain, • 10. b) Posterior column of the thoracic cord: multi-nucleated giant cell (arrow) near vacuolar lesions, hematoxyline and eosin, • 250. Neurosurg. Rev. 13 (1990)
Gray et al., Spinal cord lesions in AIDS been observed in non-AIDS immuno-comproraised patients. This suggests that mecanisms other than direct HIV infection may produce vacuolar myelopathy [19, 27]. Other pathological processes predominantly involving the long tracts have been described. Wallarian degeneration of the corticospinal tracts secondary to necrotic lesions containing multinucleated giant cells of the internal capsules was observed by RHODES [29] in one case. A discrete gracile tract degeneration was found in four AIDS patients who had prominent acral paresthesiae, suggesting a sensory neuropathy. A direct HIV
]91 infection and damage to the lumbar dorsal root ganglia was hypothesized [28]. Involvement of the spinal cord is not uncommon in infants and young children who usually have severe HIV infection of the CNS. In a series of 15 cases reported by KIM et al. [20], 14 had some degree of spasticity and ten showed corticospinal tract changes. These consisted either of proportional loss of both myelin and axons or disproportional loss of myelin over axons.
3 Opportunistic infections of the spinal cord Disseminated opportunistic infections of the central nervous system and/or leptomeninges may also involve the spinal cord. However, in rare instances, such infections may be responsible for more characteristic spinal diseases.
Figure 2. Acute CMV myeloradiculitis, a) Inflammatory lesions with typical intranuclear inclusion body (arrow) in a spinal root of the cauda equina, hematoxylin and eosin, x 400. b) Necrotic and inflammatory lesions with typical intranuclear inclusion body in the inferior part of the cord, hematoxylin and eosin, x 400. e) Spinal root of the cauda equina, typical intranuclear inclusion body in possible Schwann cells, hematoxylin and eosin, x 400. Neurosurg. Rev. 13 (1990)
192
Gray et al., Spinal cord lesions in AIDS
One case of acute tabes dorsalis has been reported by RHODES [29]. Seven cases of acute CMV myeloradiculitis [2, 4, 9, 18, 22, 24, 33], also referred to as progressive inflammatory polyradiculoneuropathy presenting as cauda equina syndromes [7], have been reported. The clinical features in these cases are remarkably similar and include: pain at onset, rapid progression to flaccid paraplegia, absence of major sensory deficit, early and severe global sphincter dysfunction, and acute aggravatire course leading to death in a few weeks. Usually, this complication appears late in the course of the disease, subsequent to multiple opportunistic infections; but in two instances, it was the initial manifestation of AIDS [22, 24]. Meningitis with pleocytosis of polymorphonuclear predominance and increased protein level is a constant finding. Viral test for CMV are usually of only little help, as are radiological investigations. Neuropathological findings include inflammatory necrotic lesions, in the spinal roots of the cauda equina and inferior part of the spinal cord (Figure 2a). Typical intranuclear "owl eye" inclusion bodies were observed in the inflammatory lesions (Figure 2b), in the leptomeninges and in possible Schwann cells (Figure 2c). Associated CMV encephalitis, with infection of ependymal cells, some of which protruded into the ventricular lumen was
found by MAHIEUX et al. [22] and EIDELBERGet al. [9] who proposed that such "infected ependymal cells may detach, travel along CSF pathways and implant caudally". This hypothesis could account for the lumbosacral predilection and intrathecal localization of the inflammatory lesions. In two cases, Herpes simplex virus myelitis was associated with CMV spinal infection [5, 35]. In both cases it was due to HSV type II. Herpes zoster virus typically causes ganglioradiculitis; however, it has caused myelitis in rare instances [231. 4 Lymphomatous tumors
Lymphomas are not uncommon in AIDS. They are predominantly extra-nodal and highly malignant [37]; some of them have been related to Epstein Barr virus infection [30]. In the spinal cord, secondary spread from systemic lymphomas [34] may involve the subarachnoidal space of the cord and the spinal roots (Figure 3a and b) with cauda equina syndrome or polyradiculoneuropathy predominant. Lymphomatous cells may be found at CSF examination. Compression of the spinal cord by epidural lymphomatous masses has also been reported occasionally. Paraspinal location of non-Hodgkin lyre-
a
Figure 3. Lymphomatous infiltration into spinal roots, hematoxylin and eosin, • 100 (a), • 400 (b). Neurosurg. Rev. 13 (1990)
Gray et al., Spinal cord lesions in AIDS p h o m a was found in five of 90 A I D S cases by ZIEGLER et al. [37], and two cases of spinal cord compression by immunoblastic sarcoma or plasm o c y t o m a were reported by SNIDER et al. [34].
5 Miscellaneous Ischemic lesions of the spinal cord have been found by RHODES in three of 99 pathological cases in which the cord was examined [29]. These may have been due to the acute vasculitis usually associated with bacterial, mycotic, or parasitic leptomeningitis. In rare instances, chronic vasculitis could be related to HIV, CMV, and/or HSV infection. Less specific vascular lesions may also cause spinal infarcts. One of our cases with dis-
193 seminated intravascular coagulation developed rapidly progressive paraplegia. Neuropathological examination showed a recent infarct o f the thoracic cord. Microthrombi were present in and near the ischemic lesions; small haernorrhages and limited infarcts with similar vascular changes were also disseminated in the brain; no inclusion bodies or multinucleated giant cells were found. Only one case of rapidly progressive amyotrophic lateral Sclerosis concommitant with H I V seroconversion was described by HOFFMANNet al. [17] and one case of glioblastoma of the spinal cord was recorded by GASTAUT [10]. In these cases, a coincidental occurence cannot be excluded. Acknowledgements: This study was supported in part by a grant to Dr. GRAYfrom ARSIDA.
References [1] ANDERSKH, WF GUERRA, U TOMIYASU,MA VERITY, HV VINTERS: The Neuropathology of AIDS. UCLA experience and review. Am J Pathol 124 (1986) 537- 558 [2] BEHAR R, C WILEY, JA Mr CUTCHAN: Cytomegalovirus polyradiculoneuropathy in acquired immune deficiency syndrome. Neurology 37 (1987) 557- 561 [3] BERGERJR, L RESNICK:HTLV-III/LAV related neurological disease. In: BRODERS (ed): AIDS Modern Concept and Therapeutic Challenges. Marcel Dinker, Inc, New York-Basel 1987 [4] BISHOPRICG, J BRUNER, J BUTLER:Guillain-Barr6 syndrome with cytomegalovirus infection of peripheral nerves. Arch Pathol Lab Med 109 (1985) 1106--1108 [5] BRITTONCB, R MESA-TEJADA,CM FENOOLIO,AP HAYS, GO GARV~Y,JR MILLER:A new complication of AIDS: Thoracic myelitis caused by herpes simplex virus. Neurology 35 (1985) 1071 -1074 [6] BUDKAH: Multinucleated Giant Cells in Brain: A Hallmark of the Acquired Immune Deficiency Syndrome (AIDS). Acta Neuropathol (Berl) 69 (1986) 253-258 [7] DALAKASMC, GH PEZESHKPOUR:Neuromuscular diseases associated with Human Immunodeficiency Virus infection. Ann Neuro123 (suppl) (1988) $ 3 8 $48 [8] DALGLEISHAG, PCL BEVERLY,PR CLAPHAM,DH CRAWEORD,MF GREAWS,RA WEISS:The CD4 (T4) antigen is an essential component of the receptor for the AIDS retrovirus. Nature 312 (1984) 763 [9] EIDELBEROD, A SOTREL, H VOGEL, P WALKER, J KLEEF1ELD, c a CRUMPACKER:Progressive polyradiculopathy in acquired immune deficiency syndrome. Neurology 36 (1986) 912-916 Neurosurg. Rev. 13 (1990)
[10] GASTAUTJL: Atteintes m6dullaires et p6riph6riques. In: Trotot P (ed) Imagerie du SIDA et des retrovirus. Vigot, Paris (in press) [11] GENDELMANHE, JM LEONARD,FJ DUTKO, S KOENIG, .IS KHILLAN,MS MELTZER:Immunopathogenesis of Human lmmunodeficiency Virus infection in the Central Nervous System. Ann Neurol 23 (suppl) (1988) $78-$81 [12] GRAY F, R GHERARDI,M BAUDRIMONT,PH GAULARD,CH MEYRIGNAC,C VEDRENNE,J POIRIER:Leucoencephalopathy with multinucleated giant cells containing HIV-like particles and multiple opportunistic cerebral infections in one patient with AIDS. Acta Neuropathol (Berl) 73 (/987) 99-104 [13] GRAY F, R GHERARDI, F SCARAVILLI:The neuropathology of the acquired immune deficiency syndrome (AIDS) A review. Brain 111 (1988) 2 4 5 266 [14] GRAYF, R GHERARDI,C KEOHANE,M FAVOLINI,A SOBEL, J PommR: Pathology of the Central nervous system in 40 cases of Acquired Immune deficiency syndrome (AIDS) Neuropathology Applied Neurobiology 14 (1988) 365- 380. [15] F GRAY, G FI~NELON,R GHERARDI, M. FAVOLINI, M. GOULON, A GUILLARD, J. POIRIER:Etude neuropathologique de 15 cas d'enc6phalite ~ cellules g4antes multinuc166es au cours du syndrome d'immunod6ficience acquise (SIDA). Annales de Pathologie 8 (1988) 281-289 [16] HENIND, C DUYCKAERTS,MP CHAUNU,R VAZEUX, W ROZENBAUM, JJ HAUW: Etude neuropathologique du syndrome d'immuno-d6pression acquise. Apropos de 30 observations, Rev Neurol (Paris) 143 (1987) 631-642 [17] HOFEMANPM, BW FESTOFF, LT GIRON, LC HOLLENBECK, RM GARRUTO, FW RUSCETTI: Isolation
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Gray et al., Spinal cord lesions in AIDS of LAV/HTLV-III from a patient with amyotrophic lateral sclerosis. New Engl J Med 313 (1985) 3 2 4 325 JEANTILS V, M-O LEMAYTRE, J ROBERT, Y GAUDOUEN, A KRIVITZKY,G DELZANT: Subacute polyneuropathy with encephalopathy in AIDS with human cytomegalovirus pathogenicity. Lancet II (1986) 1039 KAMIN SS, CK PETITO: Vacuolar Myeolopathy in immunocompromised non AIDS patients. (Abstract) J Neuropathol Exp Neurol (1988) KIM TS, A BELMAN, DW DICKSON: Spinal cord pathology in pediatric AIDS. (Abstract) J Neuropathol Exp Neurol (1988) KOENIG S, HE GENDELMAN,JM ORENTSTEIN,MC DAL CANTO,GH PEZESHKPOUR,M YUNGBLUTH,F JANOTTA,A AKSAMIT,MA MARTIN,AS FAUCI:Detection of AIDS Virus in Macrophages in Brain Tissue from AIDS Patients with Encephalopathy. Science 233 (1986) 1089-1093 MAHrmUXF, F GRAY,G FI~NELON,R GttERARDI,D ADAMS, A GUILLARD, J POIRIER: Acute Myeloradiculifis due to cytomegalovirus as the initial manifestation of AIDS. J Neurol Neurosurg Psychiat 52 (1989) 270-274. MCARTHUR JC: Neurologic manifestations of AIDS. Medicine 66 (1987) 407-437 MOSKOWITZLB, JB GREGORIOS,GT HENSLEY, JR BERGER: Cytomegalovirus-induced demyelination associated with acquired immune deficiency syndrome. Arch Pathol Lab Med 108 (1984) 873-877 PETITOCK, BA NAVIA, E-S CHO, BD JORDAN, DC GEORGE, RW PRICE: Vacuolar myelopathy pathologically resembling subacute combined degeneration in patients with the acquired immunodeficiency syndrome. New Engl J Med 312 (1985) 874-879 PETITO CK, E-S CHO, W LEMANN,BA NAVIA, RW PRICE: Neuropathology of acquired immunodeficiency syndrome (AIDS): An autopsy review. J Neuropathol Exp Neurol 45 (1986) 635-646 PETITOCK: Review of Central nervous System Pathology in Human Immunodeficiency Virus Infection. Ann Neurol 23 (suppl) (1988) $54-$57 RANCE NE, JC McARTHUR, DR CORNBLATH,DL LANDSTROM, JW GRIFFIN,DL PRICE: Gracile tract degeneration in patients with sensory neuropathy and AIDS. Neurology 38 (1988) 265-271
[29] RHODESRH: Histopathology of the Central nervous system in the Acquired Immunodeficiency Syndrome. Human Pathol 18 (1987) 636-643 [30] ROSENBERG NL, FH HOCHBERG, G MILLER, BK KLEINSCHMIDT-DEMASTERS:Primary central nervous system lymphoma related to Epstein-Barr virus in a patient with Acquired Immune Deficiency Syndrome. Ann Neurol 20 (1986) 98-102 [31] SHARERLR, E-S CHO, LG EPSTEIN: Multinucleated giant cells and HTLV-III in AIDS encephalopathy. Hum Pathol 16 (1985) 760 [32] SHARER LR, LG EPSTEIN, E-S CHO, CK PETITO: HTLV-III and vacuolar myelopathy. (Letter) New Engl J Med 315 (1986) 6 2 - 6 3 [33] SINGH BM, S LEVINE, RL YARRISH, MJ HYLAND, D JEANTY, GP WORMSER:Spinal cord syndrome in the acquired immune deficiency syndrome. Acta Neurol Scan 73 (1986) 590-598 [34] SNIDERWD, DM SIMPSON,S NIELSEN,JWM GOLD, CE METROKA, JB POSNER: Neurological complications of acquired immune deficiency syndrome: Analysis of 50 patients. Ann Neuro114 (1983) 403 418 [35] TUCKER T, RD DIX, C KATZEN, RL DAVIS, JW SCHMIDLEY: Cytomegalovirus and Herpes simplex virus ascending myelitis in a patient with acquired immune deficiency syndrome. Ann Neurol 18 (1985) 74--79 [36] VERNANT JC, L MAVRS, O GOUT, G BUISSON, Y PLUMELLE, C NEISSON-VERNANT, N MONPLAISIR, GC ROMAN: HTLV-I associated tropical paraparesis in Martinique: a reappraisal. Ann Neurol 23 (suppl) (1988) S133-S135 [37] ZIEGLERJL, JA BECKSTEAD,PA VOLDERBINGet al: Non-Hodgkin's lymphomas in 90 homosexual men. Relation to Generalized Lymphadenopathy and The Acquired Immunodeficiency Syndrome. N Engl J Med 311 (1984) 565-579 Dr. Frangoise Gray D6partement de Pathologie (Neuropathologie) H6pital Henri Mondor Cr6teil Cedex France
Neurosurg. Rev. 13 (1990)
Spinal cord lesions in the Acquired Immune Deficiency Syndrome (AIDS) Franfoise Gray1,2, Romain Gherardi~'2, Pierre Trotot3, Gilles Fenelon 4, and Jacques Poirier 1,2 ~Department of Pathology (Neuropathology) Henri Mondor Hospital, Cr6teil, France, 2Department of Medical Neurosciences, Faculty of Medicine, University of Paris-Val de Marne, Cr6teil, France, 3Radiology Service, Pasteur Institute Hospital, Paris, France, and 4Neurological Clinic, Tenon Hospital, Paris, France
Abstract Spinal cord involvement in AIDS is not uncommon. Different types of lesions corresponding to varying pathogenetic mechanisms have been reported. Vacuolar myelopathy is the most frequently found. The symptoms and pathological changes resemble those of subacute combined degeneration; however, cobalamine or folate levels have always been found normal. Its frequent association with the multi-nucleated giant cells characteristic of HIV encephalitis makes it likely that the virus plays a role in its pathogenesis. Cytomegalovirus may be responsible for acute myeloradiculitis involving the spinal roots of the cauda equina and inferior part of the spinal cord. In cases of Herpes simplex virus myelitis has been reported; they are usually associated with cytomegalovirus infection and are due to herpes simplex virus type II. Secondary spread from systemic lymphomas may involve the subarachnoid space of the cord and the spinal roots. Compression of the spinal cord by epidural lymphomatous masses has also been described. Spinal infarcts may be secondary to acute or chronic vasculitis or to less specific vascular processes such as disseminated intravascular coagulation.
Keywords: Acquired Immune Deficiency Syndrome (AIDS),, cytomegalovirus, Human Immunodeficiency Virus (HIV), myelopathy, spinal cord, vacuolar myelopathy.
1 Introduction Acquired immune deficiency syndrome is due to an infection by the human immunodeficiency virus (HIV) which has a particular tropism for the membrane antigen CD4 [8]. This receptor is contained 9 1990by Walter de Gmyter & Co. Berlin 9New York
in T-helper lymphocytes which are destroyed. This causes loss of cell-mediated immunity and favors the occurence of opportunistic infections and nonHodgkin lymphomas. A direct infection of the CNS by the virus has also been proved, and it has been demonstrated that mononuclear-macrophages, which also contain the receptor, represent, in the CNS, the main cells capable of synthesizing viral ribonucleic acid and may, therefore, be both the main reservoir and the vehicle of spread for the virus [21]. Neurological complications are frequent; it has been reported that 40% to 50% of AIDS patients have neurological symptom and that 75% to 100% of AIDS patients show morphological abnormalities of the nervous system [1, 13, 14, 16, 23, 26, 34]. These varying types of neurological complications correspond to different pathogenetic mechanisms which are not yet perfectly understood [11]. Some are opportunistic infections and lymphomas secondary to T-helper depletion. Some have been related to a direct infection of the nervous system by HIV, probably through mononuclear-macrophages. Still others may be secondary to vascular alterations or visceral organ impairement, correspond to terminal events, or represent coincidental occurence [13]. Spinal cord changes, although far less frequent than brain lesions, are not uncommon in AIDS [33]. In our series of 40 AIDS patients, collected in the Department of Neuropathology of Henri Mondor Hospital between 1982 and 1987, 32 had neurological symptoms. Clinical signs of spinal cord involvement were found in three of these
190 patients, and pathological spinal changes were found in four of the six cases whose spinal cord was examined [14]. Almost all the diffuse or multifocal pathological processes involving the central nervous system and/or the leptomeninges may also affect the spinal cord; but some of them involve it predominantly, causing specific myelopathic diseases. These latter may be classified as follows: vacuolar myelopathy and other changes predominantly involving the long tracts possibly related to direct HIV infection; opportunistic myelitis or myeloradiculitis mainly due to viruses of the herpes group; secondary spread from systemic lymphomas and miscellaneous less specific lesions.
Gray et al., Spinal cord lesions in AIDS or folate deficiency were never found [25]. Its frequent association with MGC encephalitis makes it likely that HIV is involved in its pathogenesis as has been demonstrated for HTLV 1 in tropical spastic paraparesis [36]. This hypothesis is supported by the frequent association of vacuolar myelopathy with HIV encephalitis and the constatallation, in one instance, of multinucleated giant cells characteristic of HIV infection [6, 12, 31], closely adjacent to the vacuolar spinal changes (Figure lb) [14, 15]. In the other hand, although vacuolar myelopathy is seldom found in infants and young children despite severe infection of the CNS [32], it has
2 Vacuolar myelopathy Vacuolar myelopathy is probably the most common of the myelopathies associated with HIV infection. Its incidence varies from 0% to 29% of the pathological series [1, 3, 14, 16, 25, 26, 27, 29, 34]. These vacuolar, non-inflammatory lesions are symmetrical, more severe in the lateral and posterior columns of the thoracic cord, and not confined to specific anatomical tracts (Figure la). Ultrastructurally, the vacuoles consist of intramyelin swelling with splitting of the lamellae and presence of lipid-laden macrophages. Axons are normal in mildly affected areas, but may be disrupted in areas with severe vacuolation with consequent Wallerian degeneration. This disease manifests clinically by spastic paraparesis and ataxia; urinary incontinence is possible; dementia is observed in about 60% of the affected individuals [23]. Precise correlations of spinal cord abnormalities with myelopathic symptoms may be difficult because of coexisting peripheral neuropathies and brain lesions. However, it appears that spinal symptoms are constant only in severe lesions and that the severity of pathological lesions correlates not only with symptoms of spinal cord disease but also with dementia [25, 27]. CSF examination is not contributive. Radiological examination is usually of only little help to evidence spinal cord lesions. In contrast magnetic resonance imaging or computed tomography of the brain frequently demonstrates associated HIV encephalitis. The pathogenesis of vacuolar myelopathy remains controversial; although the changes resemble those of subacute combined degeneration, cobalamine
Figure 1. Vacuolar myelopathy, a) Horizontal section of the thoracic cord, Loyez stain, • 10. b) Posterior column of the thoracic cord: multi-nucleated giant cell (arrow) near vacuolar lesions, hematoxyline and eosin, • 250. Neurosurg. Rev. 13 (1990)
Gray et al., Spinal cord lesions in AIDS been observed in non-AIDS immuno-comproraised patients. This suggests that mecanisms other than direct HIV infection may produce vacuolar myelopathy [19, 27]. Other pathological processes predominantly involving the long tracts have been described. Wallarian degeneration of the corticospinal tracts secondary to necrotic lesions containing multinucleated giant cells of the internal capsules was observed by RHODES [29] in one case. A discrete gracile tract degeneration was found in four AIDS patients who had prominent acral paresthesiae, suggesting a sensory neuropathy. A direct HIV
]91 infection and damage to the lumbar dorsal root ganglia was hypothesized [28]. Involvement of the spinal cord is not uncommon in infants and young children who usually have severe HIV infection of the CNS. In a series of 15 cases reported by KIM et al. [20], 14 had some degree of spasticity and ten showed corticospinal tract changes. These consisted either of proportional loss of both myelin and axons or disproportional loss of myelin over axons.
3 Opportunistic infections of the spinal cord Disseminated opportunistic infections of the central nervous system and/or leptomeninges may also involve the spinal cord. However, in rare instances, such infections may be responsible for more characteristic spinal diseases.
Figure 2. Acute CMV myeloradiculitis, a) Inflammatory lesions with typical intranuclear inclusion body (arrow) in a spinal root of the cauda equina, hematoxylin and eosin, x 400. b) Necrotic and inflammatory lesions with typical intranuclear inclusion body in the inferior part of the cord, hematoxylin and eosin, x 400. e) Spinal root of the cauda equina, typical intranuclear inclusion body in possible Schwann cells, hematoxylin and eosin, x 400. Neurosurg. Rev. 13 (1990)
192
Gray et al., Spinal cord lesions in AIDS
One case of acute tabes dorsalis has been reported by RHODES [29]. Seven cases of acute CMV myeloradiculitis [2, 4, 9, 18, 22, 24, 33], also referred to as progressive inflammatory polyradiculoneuropathy presenting as cauda equina syndromes [7], have been reported. The clinical features in these cases are remarkably similar and include: pain at onset, rapid progression to flaccid paraplegia, absence of major sensory deficit, early and severe global sphincter dysfunction, and acute aggravatire course leading to death in a few weeks. Usually, this complication appears late in the course of the disease, subsequent to multiple opportunistic infections; but in two instances, it was the initial manifestation of AIDS [22, 24]. Meningitis with pleocytosis of polymorphonuclear predominance and increased protein level is a constant finding. Viral test for CMV are usually of only little help, as are radiological investigations. Neuropathological findings include inflammatory necrotic lesions, in the spinal roots of the cauda equina and inferior part of the spinal cord (Figure 2a). Typical intranuclear "owl eye" inclusion bodies were observed in the inflammatory lesions (Figure 2b), in the leptomeninges and in possible Schwann cells (Figure 2c). Associated CMV encephalitis, with infection of ependymal cells, some of which protruded into the ventricular lumen was
found by MAHIEUX et al. [22] and EIDELBERGet al. [9] who proposed that such "infected ependymal cells may detach, travel along CSF pathways and implant caudally". This hypothesis could account for the lumbosacral predilection and intrathecal localization of the inflammatory lesions. In two cases, Herpes simplex virus myelitis was associated with CMV spinal infection [5, 35]. In both cases it was due to HSV type II. Herpes zoster virus typically causes ganglioradiculitis; however, it has caused myelitis in rare instances [231. 4 Lymphomatous tumors
Lymphomas are not uncommon in AIDS. They are predominantly extra-nodal and highly malignant [37]; some of them have been related to Epstein Barr virus infection [30]. In the spinal cord, secondary spread from systemic lymphomas [34] may involve the subarachnoidal space of the cord and the spinal roots (Figure 3a and b) with cauda equina syndrome or polyradiculoneuropathy predominant. Lymphomatous cells may be found at CSF examination. Compression of the spinal cord by epidural lymphomatous masses has also been reported occasionally. Paraspinal location of non-Hodgkin lyre-
a
Figure 3. Lymphomatous infiltration into spinal roots, hematoxylin and eosin, • 100 (a), • 400 (b). Neurosurg. Rev. 13 (1990)
Gray et al., Spinal cord lesions in AIDS p h o m a was found in five of 90 A I D S cases by ZIEGLER et al. [37], and two cases of spinal cord compression by immunoblastic sarcoma or plasm o c y t o m a were reported by SNIDER et al. [34].
5 Miscellaneous Ischemic lesions of the spinal cord have been found by RHODES in three of 99 pathological cases in which the cord was examined [29]. These may have been due to the acute vasculitis usually associated with bacterial, mycotic, or parasitic leptomeningitis. In rare instances, chronic vasculitis could be related to HIV, CMV, and/or HSV infection. Less specific vascular lesions may also cause spinal infarcts. One of our cases with dis-
193 seminated intravascular coagulation developed rapidly progressive paraplegia. Neuropathological examination showed a recent infarct o f the thoracic cord. Microthrombi were present in and near the ischemic lesions; small haernorrhages and limited infarcts with similar vascular changes were also disseminated in the brain; no inclusion bodies or multinucleated giant cells were found. Only one case of rapidly progressive amyotrophic lateral Sclerosis concommitant with H I V seroconversion was described by HOFFMANNet al. [17] and one case of glioblastoma of the spinal cord was recorded by GASTAUT [10]. In these cases, a coincidental occurence cannot be excluded. Acknowledgements: This study was supported in part by a grant to Dr. GRAYfrom ARSIDA.
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