patients with PML presented with new-onset seizures of various types, generalized or partial. None of them met the criteria of the AIDS dementia complex or had ...
AIDS-Associated Progressive Multifocal Leukoencephalopathy Revealed by New-Onset Seizures Antoine Moulignier, MD, Jacqueline Mikol, MD, Gilles Pialoux, MD, Gilles Fknelon, MD, PhD, Paris, France, Francoise Gray, MD, PhD, Garches, France, Jean Baptiste Thiebaut, MD, Paris, France
PURPOSE: To describe the clinical features of new-onset seizures in HlV-l-infected persons with progressive multiiocal leukoencephalopathy (PML), and to discuss potential mechanisms. PATIENTS AND METHODS: Forty-nine consecutive HN-l-infected patients with PML attended our institutions between January 1988 and September 1993. We retrospectively analyzed cases with seizures as the presenting symptom of PML. RESULTS: Twenty percent of the HIV-l-infected patients with PML presented with new-onset seizures of various types, generalized or partial. None of them met the criteria of the AIDS dementia complex or had a concomitant opportunistic infection. Their mean CD4 cell count was c80/mm3. Brain magnetic resonance imaging showed areas of increased signal intensity on T,weighted images in 9 cases, and atrophy in only 1 case. Lesions most often involved subcortical white matter in parieto-occipital or frontal lobes, but 2 patients had posterior fossa lesions. Image-guided stereotactic brain biopsies in 8 cases and postmortem examination in 2 confirmed the diagnosis of PML. Typical histological lesions were observed in all cases, and positive immunolabelling of oligodendroglial nuclei was obtained in all cases with the polyclonal antibody directed against late SV40 antigens. Putative causative factors for the seizures include demyelinated lesions adjacent to the cerebral cortex acting as irritative foci, axonal conduction abnormalities, or disturbances of the neuron-glia balance. CONCLUSION: These cases ihtrate that PML should be considered as a possible cause of new-onset seizures in patients with HN-1 infection.
From the Service de Neurologie (AM,GF), Hopital Tenon, Paris; Hopital de l’lnstitut Pasteur fAM,GP), Paris; Service d’Anatomopathologie (JM), Hopital Lariboisiere, Paris; Neuropathologie (FG), Hbpital Raymond Poincare, Garches; Service de Neurochirurgie (JET), Hopital Henry Dunant, Paris, France. Requests for reprints should be addressed to Dr. Antoine Moulignrer, Hopital Tenon, Service de Neurologie, 4, rue de la Chine, F-75020 Paris, France. Manuscript submitted April 20, 1994 and accepted in rewed form November 11, 1994.
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P
regressive multifocal leukoencephalopathy (PML) is a demyelinating disease of the central nervous system (CNS) resulting from infection of glial cells by a polyomavirus of the Papowaviridae family. Most cases involve JC virus (JCV), l but BK (BKV) and SV40 viruses have also been implicated.13 PML occurs almost exclusively in patients with conditions leading to a defect in cell-mediated immunity, and HIV infection is now the most frequent cause.’ An incidence of 3% to 7% in AIDS patients has been estimated from clinical and pathological series, and a large epidemiological study conducted between 1981 and 1988 reported a similar rate that remained stable throughout those years4 PML is usually fatal within 6 months, and currently causes 2% to 4% of deaths in AIDS patients’s4 The clinical course of PML is protean, but it usually starts with insidious-onset neurological signs that develop progressively, giving rise to evidence of a hemispheric lesion-ie, weakness of a limb or one side of the body, homonymous hemianopia, or alteration of mental functions.1’5 New-onset seizures, that imply cerebral cortical dysfunction, are very rare and, furthermore, they are unexpected in a disease of the white matter.5-6 We report 10 cases of PML in the course of HIV infection in which partial or generalized seizures were the neurologic presenting signs. We also discuss the possible causal mechanisms.
PATIENTS AND METHODS Patients Prom January 1988 to September 1993,49 patients with AIDS-associated PML (22 pathologically proven) attended Hopi&l Tenon and Hop&al de l’Institut Pasteur. The diagnosis of AIDS was based on the standard Centers for Disease Control (CDC) epidemiological surveillance definition. Patients developing neurologic signs or symptoms were seen by a neurologist (AM or GF) and underwent magnetic resonance imaging @RI) of the brain. All failed empiric antibiotic therapy for toxoplasmosis, consisting of sulfadiazine and pyrimethamine given for a minimum of 3 weeks. Sixteen were referred for stereotactic brain biopsy. Ten (20%) of the 49 patients presented with newonset seizures as the first manifestation of PML, which was proven either by stereotactic brain biopsy
SEIZURES
(n = 8) or postmortem examination (n = 2). Only 3 of the remaining patients (8?@ developed generalized tonic-clonic seizures in the late stage of the disease. The patients who had seizures as the presenting symptom were 9 men and 1 woman, aged 26 to 40 years (mean 32.2). Their risk factors for HIV infection and clinical characteristics are summarized in the Table. Based upon clinical and electroencephalographic (EEG) findings, their seizures were of various types: generalized tonic-clonic; simple partial, complex partial; and status epilepticus. In 9 of them, MRI of the brain showed high-intensity lesions on T,weighted spin-echo images, principally in the cerebral white matter, with no mass effect, contrast enhancement, or cortical atrophy. MRI revealed lesions extending to the cortical gray matter in 2 cases (patients 5 and 9; Figure); principally localized in the midbrain and the right cerebellar hemisphere in 2 other cases (patients 1 and 7); and generalized atrophy alone in 1 case (patient 8). MRI for the other patients showed characteristic areas of increased signal in the white matter in parietooccipital or frontal lobes on T,weighted images. The neurologic examination and brain MRI correlated with the location of onset of partial seizures, as determined by EEG. Lumbar puncture was done in 8 patients and the cerebrospinal fluid (CSF) was normal in all. Cultures of blood and CSF for bacteria, mycobacteria, fungi, and viruses (including cytomegalovirus [CMV] and varicella zoster virus [VZV]) were negative, as were tests for Treponema pcdhdum and cryptococcal antigen, and India ink staining of the CSF. The mean CD4+ cell count was 55.3/mm3 (range 6 to 176). Seven patients were treated with valproate 1,500 mg/d, and 1 with carbamazepine 800 mg/d. Following the diagnosis of PML, 4 of these 8 received antiviral therapy, 3 with zidovudine and 1 with interferon alpha Two patients had recurrent seizures despite therapeutic levels of anticonvulsant medication. Both had lesions extending to the cortical gray matter. Their seizures improved with valproate plus carbamazepine. No difference in the course of the disease was noted between the 10 patients who had seizures as the pre senting symptom and the 3 patients who had seizures as an accrued symptom. The following 2 cases are typical.
Patient 8 A 26-year-old woman infected with HIV-l through blood transfusion in 1985 (CDC stage II) had a history of chronic renal failure for which she underwent unsuccessful kidney transplantation in 1983. She was subsequently dialyzed and had been treated with erythropoietin since 1988. She had generalized seizures in September 1988 and again 4 months later. No concomitant metabolic changes were found. The computed tomography (CT) scan and CSF were nor-
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Figure. Brain MRI (T,-weighted) showing areas of high signal at the white/gray matter junction.
mal and no antiepileptic drugs were prescribed. A fatal status epilepticus occurred 9 months after the first seizures. Serial MRI only showed generalized atrophy until death. Autopsy of the brain confirmed PML.
Patient 9 A 33-year-old homosexual man who had been HIV1-seropositive since July 1986 (CDC stage RI) was admitted in November 1992 for complex partial seizures. He reported experiencing, since September 1992, sudden-onset buzzing or roaring in the ears lasting a few minutes, and unrecognizable human voices resembling reverberated speech. He also stated that old memories or scenes came to mind and recurred with striking clarity. His colleagues had noticed that he was sometimes “absent,” either failing to answer or only giving stereotyped responses. Neurological examination disclosed bradyphrenia and a left inferior quadrantanopia The fundi were normal. MRI of the brain showed several lesions of high intensity in T,-weighted images, with no contrast enhancement, within the white matter, but also at the white&ray junction (Figure). Antitoxoplasma therapy was started, but the patient’s condition worsened. He developed generalized tonic-clonic seizures, left hemihypoesthesia, and frontal lobe syndrome. A stereotactic brain biopsy of the right temporo-parietal lesion was performed. A brief clinical improvement was then noted, but the patient died 8 months later. Autopsy was not performed.
Histopathological
Studies
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TABLE Clinical and Radiological Features of AIDS-Associated PML Patients Patient Risk CDC CD4+(/mm3) Age (~1 / No. Factor Sex SP Stage Diagnosis [CD4/CD8] Type of Seizures 1 (bi) 34/M 24 II SB 106 LO.141 Permanent myoclonic jerks of the right arm 2 II (h) SB 12 [O.lOl Right brachial motor 40/M 3 30/M 3; II SB (h) 6 IO.031 Right adversive, secondarily generalized 4 (hl 33/M 72 II SB 8 fO.021 Status epilepticus 5 (iv) II SB 7 EO.031 Generalized tonic-clonic 33/M 6 27/M :; II SB (hf 167 IO.301 Generalized tonic-clonic 7 (iv) 27/M 29 II A 10 [ndl Right adversive, secondarily generalized 8 26/F 31 (tr) II A 20 [ndl Generalized tonic-clonic 9 33/M 64 III 176 (h) SB LO.31 Complex partial 10 39/M 78 II SB 41 LO.071 Status epilepticus (h) PML = progressive multifocalieukoencephalopathy;Eli = bisexual; h = homosexual; iv = intravenous drug user; tr = blood transfusion; A = autopsy; sd = syndrome.
at -8O”C, or fixed in glutaraldehyde-osmic acid and Epon-embedded. Postmortem specimens were fixed in formalin and embedded in pa&fin, celIoidin, and Epon. In both cases, gross examination of the CNS was performed on coronal sections of the cerebral hemispheres and on sections of the brainstem and cerebellum, perpendicular to their axes, In each case, at least 15 serial blocks from both cerebral hemispheres, cerebellum, brainstem, and focal lesions were embedded in paraffin, and 6 blocks (4 hemispheric slices and 2 from the brainstem and cerebellum> were embedded in celloidin, according to a protocol described elsewhere.7 Immunocytochemistry techniques were done as usual, with the avidin-biotincomplex method and peroxidase revelation with diaminobenzidin as chromogen. The following antibodies were used: polyclonal antiSV40 (I/500, Lee Molecular, San Diego, California); anti-glial fibrillary acid protein (l/1,000, Dako, Glostrup, Denmark); antitoxoplasma (VZOO, Bioquote, Iickley, United Kingdom); and monoclonal anti-CMV early nuclear antigen (kindly provided by Dr. Mazeron). Typical lesions of PML were observed in every case. The demyelination appeared more acute in patients 2 and 4, where many enlarged lipid-laden macrophages were present, some of them cuffed around vessels. In case 8, hemispheric lesions were restricted to a few demyelinated foci in the subcorticaI srcuate fibers of the fifth temporal circumvolution of both sides. Wider typical lesions of PML were noted in the cerebellar white matter. In all cases, intranuclear oligodendroglial inclusions were difficult to demonstrate by light microscopy, but many nuclei were enlarged. Dystrophic and enlarged astrocytes frequently extended into the deep cortex. Positive immunolabeling of oligodendroglial nuclei was obtained in all cases with the rabbit polyclonal antibody directed against late SV40 antigens (this antibody cross-reacts with the corresponding JC pro teins). The number of labeled nuclei varied from pa66
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tient to patient, and was very small in patient 9. Papovavirus virions were easily found at the ultrastructural level in oligodendroglial nuclei. They were also observed in the cytoplasm of astrocytes and macrophages in patient 7. Few isolated multinucleated giant cells were also observed in patients 5 and 7. In patient 7, HIV was identified in macrophages at the ~Itrastructural level, together with cyIindricaI structures (cylindrical confronting cisternae) and tubulo-reticular inclusions in endothelial cells. CMV and toxoplasma were absent.
DISCUSSION Ten patients seen in our institutions from January 1988 to September 1993 had seizures-generalized tonic-clonic, simple partial, complex partial, or status epilepticus-as the first manifestation of AIDSassociated PML. HIV-l infection was known in all cases, and PML was the AIDS-defining illness in 9. PML has been reported as the cause of the initial or the only significant clinical manifestations of AIDS in 0.8% of cases.4 It has been found in l%* to 4%g of cases of new-onset seizures in HIV-infected subjects. Radiological signs in our patients were similar to those previously described in PML.ip5 Infratentorial structure lesions were prominent in 2 cases, a presentation that is unusual but seems to be more frequent in AIDSassociated PML than in non-AIDS PML.‘r6 The immune status of our patients was poor at the onset of PML, and immunosuppression is thought to be a key step in the reactivation of JCV infection.ll10 CT-guided stereotactic brain biopsy was performed in 8 cases in order to rule out a treatable condition such as multifocal VZV leukoencephalitis mimicking PML.‘O The mean time from onset of symptoms to death in our patients was 7.3 months, consistent with the 3 to 9 months previously reported.4l5p10 Patient 2 remained stable for 7 months on zidovudine before he was lost to follow-up. Only patient 9 improved clini-
SEIZURES REVEALING AIDS-RELATED PML/MOULIGNIER
Neurological Signs at Hospitalization Right cerebellar sd and Fisher sd Normal Mild memory impairment Bradyphrenia Right homonymous hemianopia Left hemiparesia Mild memory impairment Normal Left inferior quadrantanopia Left hemiparesia CDC = Centers for Disease Control; SP = length of known seropositivity
tally (for 2 months) before his death, which occurred 8 months after the onset of seizures. Therapy has generally been ineffective, but spontaneous stabilization and prolonged survival have been reported.1~5~10 Our 10 patients with seizures as a first manifestation of PML represented 20% of a total of 49 patients with clinical and radiological AIDS-associated PML (22 pathologically proven) seen in our institutions during the same 5-year period. This frequency is higher than those previously described,1~4~10perhaps because specialists in infectious diseases in our institution send all patients with neurological symptoms to a neurologist who has special experience in HIV-related neurological manifestations. Nevertheless, another study recently reported seizures occurring in one third of HIV-seropositive PML patients, and being the presenting symptom of PML in 20%.5 AIDS-related PML may have a different course than PML in immunosuppressed HIV-seronegative patients. Conceivably, the role of concomitant HIV-l infection has made it difficult to ascribe seizures specifically to PML. New-onset seizures are frequent in all stages of HIV infection8,g and have been described as a marker in 36% of cases of AIDS dementia complex.g In 2 of our cases, a few multinucleated giant cells were seen adjacent to the PML lesions in the absence of other neuropathological lesions of HIV encephalopathy. A nonspecific mechanism of macrophage recruitment and activation by associated JCV infection may lead to dissemination of HIV-infected macrophages in the brain of adult AIDS patients.” Likewise, Budka12 emphasized that lesions caused by opportunistic agents may contain HIV-infected cells without HIV-specific CNS histopathology. Since HIV replication may be triggered when infected monocytes/macrophages are activated,13 and as none of our patients met the criteria of the AIDS dementia complex or had another cerebral opportunistic infection, the presence of a few multinucleated giant cells was probably a response to white matter lesions produced by JCV.
ET AL
Outcome After First Seizure Rapidly progressive and death within 2 months Stability for 7 months then lost to follow-up Progressive dementia and death within 6 months Lost to follow-up Lost to follow-up Lost to follow-up Left hemiparesia: 9 months; dementia and death: 12 months Fatal status epilepticus 9 months after first seizures Improvement for 2 months, death 8 months after onset Still alive 5 months after onset (months before onset); nd = not done; SE! = stereotactic
biopsy;
New-onset seizures have been described in non-AIDS-associated PML,‘O proving that HIV cannot be the sole causal link between PML and seizures. Only 3% of 230 cases of PML reviewed by Brooks and WalkerlO were associated with AIDS, and more than 60% of their patients had immunosuppression due to an underlying lymphoproliferative disease. Seizures occurred at onset in 2% to 6% of patients (2.5% in virologically and pathologically confirmed cases). In our patients 1,2,3,7, and 9, the presence of lateralizing ictal features (in relation with cerebral lesions) prompted us to consider the seizures as the first manifestation of PML. No metabolic or toxic disturbances were found. It is true that patient 8 was treated with erythropoietin, which has been implicated in a few cases of epilepsy associated with hypertensive encephalopathy.14 However, she did not have encephalopathy at the time her first seizures appeared, and she developed further seizures after erythropoietin was stopped. The occurrence of seizures in PML is unexpected because this is a disease of white matter while seizures are, by definition, the clinical manifestation of cortical paroxysmic hyperactivity. The mechanisms that govern seizure activity in PML remain to be explained. Direct or indirect mechanisms can be considered. Papovaviruses target the oligodendrocyte, which is the myelin-producing cell of the CNS.’ Demyelinated lesions could act as irritative foci, since pathological studies have shown that, in extensive forms of the disease, lesions are found adjacent to the cerebral cortex and even extend into the gray matter.5v415 Very extended PML foci seem, indeed, to be more frequent in AIDSassociated PML than in non-AIDS PML, and to involve the gray matter more frequently.6 The greater degree of gray matter involvement in AIDS patient@ may indicate that this disease has a different, possibly more aggressive, course in HIV infection. The particularly severe immunodeficiency in AIDS may be responsible for these peculiarities.5~6 Moreover, in vitro July 1995 The American Journal of Medicine@ Volume 99
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studies have shown that the presence of the HIV-l tat gene may positively affect the JCV lytic cycle by stimulating JCV gene expression.17 It remains to be determined if this mechanism works in viva.” Our patients 5 and 9 had documented involvement of the gray matter. Subtle lesions not visible on MRI or in biopsies of spared cortex cannot be ruled out in the other cases. However, gray matter involvement also occurred in 2 other patients and in 3 of 15 patients from the series of Von Einsiedel et al5 who did not have seizures. The extent of demyelinating lesions on brain MRI was not different in patients who had seizures from those who did not. This suggests that indirect mechanisms may be responsible for the seizures. Different types of abnormal conduction have been demonstrated in demyelinated fibers, as in multiple sclerosis, another white-matter disease, in which seizures can occur in 0.45% to 108% of cases.18 Oligodendrocyte infection by papovaviruses may also lead to a release of factors that are potentially toxic for neurons, or may induce electrolyte changes producing seizures. Astrocytes have been shown to maintain an ionic microenvironment that results in stability of the resting neuronal membrane potential.1g Disturbances of the neuron-glia balance can modify neuron excitability by different mechanisms that interact in the intraextracellular ionic exchanges to cause abnormal neuronal discharge. Many if not all of the reactive astrocytes at the edge of the demyelination foci are monstrous and bizarre, showing changes that might adversely affect glial-neuronal interactions6 In fact, astrocytes can be infected by JCV.5 Moreover, Orenstein and Jannotazo found cytoplasmic collections of papovavirus in astrocytes with atypical nuclear features, an observation not seen in cases of non-AIDS PML. These astrocyte abnormalities may promote seizures by modifying the ionic neuron-glia balance. PML is a common complication of AIDS and today can no longer be regarded as a rare disease. Our study shows that PML may be revealed by seizures of various types and therefore has to be considered in the differential diagnosis in HIV-infected patients who present with new-onset seizures. Prompt recognition of PML is increasingly important, since a potential treatment has recently been reported.21
ACKNOWLEDGMENT The authors thank Prof. B. DuPont (Hopital de I’lnstitut Pasteur) for providing clinical data and Dr. P.M. Trotot (Hopital de I’lnstitut Pasteur) for help in reading the magnetic resonance imaging scans. This study was supported by grants from the Agence Natfonale de Recherche sur le SIDA (AIRS) and is part of the concerted action on the neuropathology of AIDS of the Medical Commission of the European Communities.
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