Human Immunodeficiency Virus-Associated Progressive Multifocal ...

REVIEWS OF INFECTIOUS DISEASES • VOL. 12, NUMBER 3 • MAY-JUNE 1990

© 1990 by The University of Chicago. All rights reserved. 0162-0886/90/1203-0014$02.00

Human Immunodeficiency Virus-Associated Progressive Multifocal Leukoencephalopathy: Apparent Response to 3'-Azido-3'-Deoxythymidine Brian Conway, William C. Halliday, and Robert C. Brunham

From the Departments of Medicine and Medical Microbiology and the Department of Pathology (Neuropathology), University of Manitoba, Winnipeg, Manitoba, Canada

Neurologic disease is clinically apparent in up to 60070 of patients with AIDS [I]. In up to 10070 of patients, neurologic disease is the initial manifestation of AIDS [2, 3]. Cerebral toxoplasmosis is the most commonly identified CNS infection, accounting for more than one-third of cases [2]. Progressive multi focal leukoencephalopathy (PML) may account for up to 4070 of cases [2]. In a recent report, two AIDS patients with neurologic disease improved after treatment with 3'-azido3'-deoxythymidine (AZT) [4]. There has also been a report of AZT therapy resulting in marked improvement in a patient with suspected PML [1]. In this communication, we describe an AIDS patient with biopsy-proved PML whose neurologic disease showed an apparent response to AZT, possibly in a dose-dependent manner.

with left-sided headaches. He had also noticed some abnormalities of vision, speech, and memory and right arm and leg weakness. Infused computed tomography (CT) of the head, done 15 August, showed a white matter lucency without mass effect with slight cortical enhancement in the left frontal and parietal regions. He was admitted to hospital on 19August. Oral temperature was 38.1°C. He was alert, although oriented to person only. A mixed expressive and receptive aphasia was noted, along with right homonymous hemianopsia (later confirmed on formal visual field testing) and right facial, arm, and leg weakness. T cell analysis showed a ratio of CD4 to CD8 cells of 0.12 (168:1,397 cells/mm"). Serum protein electrophoresis showed a polyclonal gammopathy. CSF showed 10 x 106 cells/L (90070 lymphocytes, 10070 neutrophils). The total protein concentration was 0.49 giL, and glucose, 4.8 mmol/L (simultaneous serum glucose, 4.8 mmol/L). Gram stain, fungal stain, and acid-fast stain were all negative. Fungal cultures were also negative. Serum and CSF Venereal Disease Research Laboratories determinations and serology for Toxoplasma gondii were negative. A left posterior parietal brain biopsy, including portions of cerebral cortex, grey-white matter junction, and white matter present in the biopsy, was done on 21 August. Multiple sections were produced, and none revealed any evidence of toxoplasmosis, cytomegalovirus infection, or lymphoma. Multiple samples of cortex and white matter were examined with the electron microscope. An exhaustive search finally revealed an infected oligodendroglial cell the

Case Report This 26-year-oldhomosexual man was known to have been seropositive for human immunodeficiency virus (HIV) since 1984. He presented in August 1987 Received for publication 10 March 1989 and in revised form 11 August 1989. The authors thank Carol Sigurdson for her preparation of the manuscript, Paul Hazelton for his photographic work, and M. McMannis and S. Lehrman (Burroughs-Wellcorne) for helpful comments. Please address requests for reprints to Dr. R. C. Brunham, Department of Medical Microbiology, University of Manitoba, Room 543, Basic Medical Sciences Building, 730 William Avenue, Winnipeg, Manitoba, Canada R3E OW3.

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We present the case of a 26-year-old human immunodeficiency virus-seropositive man who developed progressive multifocalleukoencephalopathy as the initial manifestation of AIDS. He appears to have responded dramatically to therapy with 3'-azido-3'deoxythymidine (AZT). His neurologic status deteriorated shortly after an AZT dose reduction. He has stabilized since resuming his previous AZT dose. Although it remains unclear whether AZT is useful in the treatment of JC virus infection, we think that all AIDS patients with progressive multifocal leukoencephalopathy should be offered treatment with AZT, especially in light of recent reports describing a possible potentiation of human immunodeficiency virus infection of the central nervous system in this setting.

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was unchanged. His granulocytopenia had resolved, and dosage of AZT was increased on 31 May to 200 mg orally every 4 hours. Repeat examination on 10 June showed only a mild right visual field defect and right hand weakness. Discussion

nucleus of which contained virions characteristic of the papovavirus group, by morphology and size (figure 1). This confirmed the diagnosis of PML. No particles characteristic of HIV or herpes group viruses were noted during the electron microscopic study. The patient was offered therapy with AZT. This was begun on 30 September at 200 mg orally every 4 hours. He improved markedly over the next few months. Serial T cell analysis showed little change. CT on 25 January 1988 showed considerable improvement, with only a small area of lucency in the left parietal area. On 19 April the patient was admitted for treatment of bacterial pneumonia, which responded very well to antibiotics. At that time, however, he was found to be granulocytopenic (absolute neutrophil count of 600 cells/mrrr'). Consequently, AZT dosage was reduced to 200 mg orally every 8 hours. On 16 May he presented with acute onset of left-sided headaches along with new right-sided weakness and speech and visual abnormalities. Neurologic examination revealed right inferior quadrantanopsia and worsening right arm and facial weakness. Repeat CT


Figure 1. A hypertrophied oligodendroglial nucleus containing innumerable papovavirus virions; the spherical forms measure 40 nm in diameter (glutaraldehyde fixation, postfixed in osmium tetroxide and stained with lead citrate and uranyl acetate) (nucleus x 18,900;virions [inset] x 135,(00).

PML was first described in 1958as a terminal complication in patients with fatallymphoproliferative disorders [5]. In 1971, a papovavirus was cultured from brain tissue in a patient with PML [6]. This virus, called JC virus, is a new human papovavirus of the polyomavirus subgroup. It is associated with the vast majority of cases of PML [7]. The epidemiologic features of infection remain unclear, but based on seroprevalence data, JC virus infection is common. In one series, 191 (69%) of 277 adults had antibodies against JC virus [8].Nothing is known about the character or the usual course of the primary JC virus infection. It is tempting to conclude that PML represents immune suppression-induced reactivation of latent virus in the brain, but primary infection of immunodeficient hosts has not been excluded . Not surprisingly, many cases of PML have been reported in the setting of HIV infection. The prevalence of JC virus disease in HIV-infected individuals is not known . In an autopsy series of 93 patients, three had evidence of PML [9]. Berger et aI. reviewed 28 cases of patients with AIDS and biopsy-proved PML [10]. The commonest presenting symptom was limb weakness . However, a wide variety of neurologic symptoms was observed. An inverted ratio of CD4 to CD8 cells was found in all cases. Serum protein electrophoresis done in five cases showed a polyclonal gammopathy. CSF analysis was normal in 12 of 22 patients. Positive findings in other cases included elevated protein level (six patients) and mild mononuclear pleocytosis (three patients). CT with and without contrast was performed in all cases. Abnormalities weredetected in 23 patients. Typically,nonenhancing, hypodense white matter lesions without mass effect were seen, predominantly in the parieto-occipital region. Only one lesion was found to be enhancing with double-dose-contrast delayedscanning. Magnetic resonance imaging (MRI) was consistently abnormal (nine of nine patients), and the white matter lesions weremore extensivethan those demonstrated by CT. Electron microscopy of brain biopsy material showed papovavirus-like struc-

HIV and PML Responsive to AZT

time. This may be particularly important in light of recent findings suggesting that J C virus not only causes damage by directly infecting oligodendroglia but may cause additional damage by eliciting the ingress of macrophages latently infected with HIV [9J. Overall, the total number of cases of PML remains small. A concerted, multicenter study will be required to assess the efficacy of any specific form of therapy. A randomized placebo-controlled clinical trial of AZT in patients with AIDS and PML will probably never be done because of ethical considerations in withholding effective treatment from patients with AIDS. The study of PML in non-AIDS patients, along with a careful analysis of ongoing antiviral studies in AIDS patients, may help to detect trends specific for PML. Until then, in light of recent reports of possible potentiation of HIV infection by JC virus infection [9J, it seems prudent to initiate treatment of any AIDS patient having PML with a drug known to cross the blood-brain barrier such as AZT. References I. Fiala M, Cone LA, Cohen N, Patel D, Williams K, Casareale

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D, Shapshak P, Tourtelotte W. Responses of neurologic complications of AIDS to 3'-azido-3'-deoxythymidine and 9-(l,3-dihydroxy-2-propoxymethyl)guanine. I. Clinical features. Rev Infect Dis 1988;10:250-6 Helweg-Larsen S, Jakobsen J, Boesen F, Arlien-Seborg P. Neurological complications and concomitants of AIDS. Acta Neurol Scand 1986;74:467-74 Levy RM, Bredesen DE, Rosenblum ML. Neurological manifestations of the acquired immunodeficiency syndrome (AIDS): experience at UCSF and review of the literature. J Neurosurg 1985;62:475-95 Yarchoan R, Berg G, Brouwers P, Fischl MA, Spitzer AR, Wichman A, Grafman J, Thomas RV, Safai B, Brunetti A, Perno CF, Schmidt PJ, Larson SM, Myers CE, Broder S. Response of human immunodeficiency-virus-associated neurological disease to 3'-azido-3'-deoxythymidine. Lancet 1987;1:132-5 Astrom KE, Mancall EL, Richardson EP Jr. Progressive multifocalleuko-encephalopathy: a hitherto unrecognized complication of chronic lymphatic leukaemia and Hodgkin's disease. Brain 1958;81:93-111 Padgett BL, Walker DL, ZuRhein GM, Eckroade RJ, Dessel BH. Cultivation of papova-like virus from human brain with progressive multi focal leukoencephalopathy. Lancet 1971;1:1257-60 Padgett BL, Walker DL, ZuRhein OM, Hodach AE, Chou SM. JC papovavirus in progressive multifocaI leukoencephalopathy. J Infect Dis 1976;133:686-90 Padgett BL, Walker DL. Prevalence of antibodies in human sera against JC virus, an isolate from a case of progressive multi focal leukoencephalopathy. J Infect Dis 1973;127: 467-70


tures in the nuclei of oligodendrocytes in 11 of 13 cases where this study was performed. The outcome for patients with PML and AIDS is similar to that seen in other immunosuppressive circumstances [11]. Twenty-two of 28 patients died within 18 months, two were lost to follow-up, two were alive at 3 months, and two others improved and remained healthy at 20 and 23 months. Thus, the course of PML can be surprisingly indolent with extended periods of clinical improvement. Our case illustrates many interesting aspects of PML and AIDS. It represented the patient's initial manifestation of AIDS. Clinical and laboratory features were quite characteristic of PML. The presence of fever with PML has been previously reported [12]. The appearance of the CT was quite consistent with the diagnosis, but other reasonable possibilities in this setting included infarction, tumor, or other CNS infections [13]. Nuclear magnetic resonance scanning, unavailable to us, would likely not have provided a more specific diagnosis [13]. Currently, brain biopsy with demonstration of typical pathologic findings of polyomavirus infection by electron microscopy remains the diagnostic procedure of choice. A number of reports have described the concomitant presence of other neuropathogens in this setting, most notably HIV [9, 14]. Although other infections were extensively sought, none was found in this case. The sensitivity of electron microscopy for HIV detection has not been conclusively established. In one study, brain tissues from seven patients with progressive encephalopathy were studied [15]. Five were observed to have replicating HIV virions. AZT was offered to this patient in view of his decreased CD4 cell count. No specific antiviral treatment, including AZT, has been shown to be effective for PML. In a placebo-controlled trial of AZT in the treatment of HIV infection, four of 145 patients developed CNS lesions, compared with nine of 137controls [16J. None of the patients with CNS disease had PML. Long-term follow-up of 229 patients receiving long-term AZT therapy has shown that, despite more than 30 cases of CNS infection, PML has never been reported (Dr. Sandra Lehrman, personal communication). One AIDS patient with presumed PML was treated with AZT, with good results [IJ. Our patient's response was quite dramatic. His later clinical deterioration was temporally related to a reduction in dosage of AZT and seemed to stabilize after the higher dosage was resumed. However, no neurodiagnostic procedure was performed at that

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14. Gray F, Gherardi R, Baudrimont M, Gaulard P, Meyrignac C, Vedrenne C, Poirier J. Leucoencephalopathy with multinucleated giant cells containing human immune deficiency virus-like particles and multiple opportunistic cerebral infections in one patient with AIDS. Acta Neuropathol (Bert) 1987;73:99-104 15. Gyorkey F, Melnick JL, Gyorkey G. Human immunodeficiency virus in brain biopsies of patients with AIDS and progressive encephalopathy. J Infect Dis 1987;155:870-6 16. Fischl MA, Richman DD, Grieco MH, Gottlieb MS, Volberding PA, Laskin OL, Leedom JM, Groopman JE, Mildvan D, Schooley RT, Jackson GG, Durack DT, King D, AZT Collaborative Working Group. The efficacy of azidothymidine (AZT) in the treatment of patients with AIDS and AIDS-related complex: a double-blind, placebo-controlled trial. N Engl J Med 1987;317:185-91


9. Wiley CA, Grafe M, Kennedy C, Nelson JA. Human immunodeficiency virus (HIV) and JC virus in acquired immune deficiency syndrome (AIDS) patients with progressive multifocal leukoencephalopathy. Acta Neuropathol (Berl) 1988;76:338-46 10. Berger JR, Kaszovitz B, Donovan-Post J, Dickinson G. Progressive multi focal leukoencephalopathy associated with human immunodeficiency virus infection. Ann Intern Med 1987;107:78-87 II. Brooks BR, Walker DL. Progressive multifocal leukoencephalopathy. Neurol Clin 1984;2:299-313 12. Bedri J, Weinstein W, DeGregorio P, Verity MA. Progressive multi focal leukoencephalopathy in acquired immunodeficiency syndrome [letter]. N Engl J Med 1983;309: 492-3 13. Ramsey RG, Geremia GK. CNS complications of AIDS: CT and MR findings. AJR 1988;151:449-54

Conway, Halliday. and Brunham