HIV-associated PML presenting as epilepsia partialis continua

Journal of the Neurological Sciences 161 (1998) 180–184

HIV-associated PML presenting as epilepsia partialis continua a

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Sergio Ferrari , Salvatore Monaco *, Michela Morbin , Gianluigi Zanusso , Laura Bertolasi , Roberto Cerini b , Nicolo’ Rizzuto a a

Section of Clinical Neurology, Department of Neurological and Visual Sciences, University of Verona, Verona, Italy b Institute of Radiology, University of Verona, Verona, Italy Received 1 June 1998; received in revised form 24 September 1998; accepted 28 September 1998

Abstract Two patients with human immunodeficiency virus (HIV) type 1 infection presented new-onset epilepsia partialis continua (EPC) as an early manifestation of progressive multifocal leukoencephalopathy (PML). EPC occurred with no other seizures and was associated with negative radiographic and electrophysiological findings for several weeks. PML represents an increasingly recognized cause of new-onset seizures in both seropositive and seronegative patients, with no report of EPC as a presenting complaint.  1998 Elsevier Science B.V. All rights reserved. Keywords: Progressive multifocal leukoencephalopathy; Epilepsia partialis continua; Human immunodeficiency virus infection

1. Introduction The range of HIV-related diseases that may present with new-onset seizures is relatively broad, including tumors, metabolic disorders, toxic disturbances and opportunistic infections [11]. Among the latter, progressive multifocal leukoencephalopathy (PML) represents the cause of newonset seizures in up to 20% of HIV-infected patients [10,13], with no reports of epilepsia partialis continua (EPC) as a presenting complaint. Early recognition of PML as the cause of seizures is important and may provide a better prognosis according to recent reports suggesting the efficacy of multiple antiretroviral therapy [7], splenectomy [18] or both [14] in increasing CD41 levels and inducing disease remission [7,14]. Although HIV-related focal disorders are best diagnosed by using an approach that combines clinical features, neuroimaging studies, and biopsy / molecular techniques [16], evidence has been provided that early and small

*Corresponding author. Tel: 139-45-8074285; fax: 139-45-585933.

cortical lesions induced by PML may be beyond the resolution of computed tomography (CT) [12,15], and can be missed by magnetic resonance imaging (MRI) [17]. In such instances the diagnosis of PML should be entertained on clinical grounds, regardless of negative imaging studies. We describe two HIV-infected patients in whom PML was the underlying cause of new-onset EPC in the absence of MRI and EEG alterations.

2. Case reports

2.1. Patient 1 A 39-year-old man intravenous drug user, known to be HIV-seropositive since 1994, in early April 1995 developed continuous involuntary twitching of the right arm and shoulder, aggravated by action; he was in treatment with didanosine and had no previous neurological disease. During the following 2 weeks the patient complained of progressive weakness of his right arm with hand paresthesias. A partial response to clonazepam administration

0022-510X / 98 / $ – see front matter  1998 Elsevier Science B.V. All rights reserved. PII: S0022-510X( 98 )00281-0

S. Ferrari et al. / Journal of the Neurological Sciences 161 (1998) 180 – 184

was observed. A cranial CT scan, before and after administration of contrast material, and an EEG were negative. In June, brain MRI and EEG were normal. In September, on neurological examination at our Department, jerkings of the right arm, pectoral and trunk muscles, which had been continuous since April, were observed, with weakness, hyperreflexia and positive Hoffmann’s reflex in the affected limb. EEG was normal and cervical spinal cord MRI was negative. The CD41 cell count was 60 per mm 3 . One month later EEG showed spike and slow wave complexes in the left central regions and brain MRI disclosed bilateral frontal white matter changes and a subcortical prerolandic lesion with scalloped lateral margins; these abnormalities were hypointense on T1-weighted images, not enhanced with contrast material, and hyperintense on T2-weighted images (Fig. 1). Analysis of CSF showed normal protein and glucose content and 2 lymphocytes per mm 3 ; polymerase chain reaction (PCR) analysis with primers for JC virus (JCV)DNA identified a 106 bp fragment located in the large T-gene region; bacterial, fungal and viral cultures were sterile. Physiological studies showed that spontaneous jerks of the right arm occurred at irregular intervals with a rate of 1–3 Hz, as short bursts (30–60 ms duration) of EMG activity synchronous in antagonist muscle pairs, time-locked with EEG activity. Cortical somatosensory potentials evoked by median nerve stimulation at the wrist were of normal amplitude and latency bilaterally. Tran-

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scranial magnetic stimulation disclosed absence of the silent period in the right first dorsal interosseous; motor evoked potential (MEP) were normal in latency and amplitude on the left side and absent on right side, with normal bilateral potentials following root stimulation (Fig. 2). The patient was thereafter lost to follow-up and death was reported in February 1996.

2.2. Patient 2 A 36-year-old HIV-seropositive homosexual man, in treatment since 1991 with AZT switched to didanosine in 1993, with no previous history of neurologic disease, was admitted to the hospital December 1995 due to continuous twitching of his left arm associated with distal weakness and motor impairment. The CD41 cell count was 270 per mm 3 . The patient, a ballet dancer, was well until 2 months before when he started to complain of recurrent episodes of uncontrolled jerking of the left hand associated with mild weakness. EEG was normal; ‘back averaging’ was not performed. Brain CT scan obtained before and after the intravenous administration of contrast material was normal. The CSF contained 68 mg / dl protein, normal glucose and no cells; PCR was negative for JCV-DNA and others viral sequences including cytomegalovirus (CMV), herpes simplex virus type 1 and 2, and Epstein-Barr virus (EBV); also the search for toxoplasma gondii sequences was negative. The CSF-Venereal Disease Research Laboratories

Fig. 1. Brain MR images obtained 6 months after the onset of EPC. Axial (A) and coronal (B) T2-weighted images show hyperintense changes in the left precentral gyrus at the grey matter–white matter junction.

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fragment of 238 bp corresponding to gp 220 EBV region) [8]. The patient was treated with intravenous cytarabine (2 mg / kg for 5 days); after two cycles of therapy, despite regression of the left hemiplegia, the patient declined further cytarabine administration and was lost to followup. The patient’s neurological condition progressively worsened with reported left hemiplegia, right hemiparesis, dysarthria and dysphagia. Brain MRI scan disclosed spread of lesions to cerebellum and brainstem; EEGs, at another hospital, were characterized by rhythmical theta and delta slowing in a diffuse distribution, in the absence of focal alterations. He died of pneumonia in February, 16 months after the onset of symptoms.

Fig. 2. Physiological studies in Patient 1 showing potentials of normal latency and amplitude following bilateral cervical magnetic root stimulation (upper traces). Transcranial magnetic stimulation failed to produce MEPs in the right first interosseus (lower traces).

(VDRL) test was nonreactive; bacterial, fungal and herpes cultures were sterile. In January 1996 cranial (Fig. 3) and cervical MRI were unremarkable. During the following weeks the weakness in the left arm worsened and motor involvement of the leg was observed; by March the patient developed a complete left hemiplegia with ensuing abatement of the jerks. A repeat MRI disclosed a right white matter frontal lesion of low signal intensity on T1-weighted images and high signal intensity on T2-weighted and protonic density images extending to the omolateral gray matter of motor and insular areas (Fig. 3). The CD41 cell count was 193 per mm 3 . A repeat EEG was unremarkable. In June, brain MRI disclosed extension of the lesion to involve the lenticular nucleus, thalamus, periventricular white matter, centrum semiovale and cerebral peduncle on the right and posterior portion of the caudate nucleus on the left. The patient underwent CT-guided stereotactic biopsy of the right frontal lesion. Pathological examination revealed demyelination, reactive astrocytes with large atypical nuclei and oligodendrocytes with swollen inclusion-bearing nuclei, consisting of paracristalline inclusions by ultrastructural examination. In situ hybridization, using a commercial byotinilated DNA-probe of 4900 bp, corresponding to the JCV entire genoma (Dish System Kreatech Biotechnology, Amsterdam, The Netherlands), disclosed high hybridization signal in scanty oligodendrocyte nuclei. In addition, PCR analysis of the biopsy specimen confirmed the presence of the JCV-DNA and excluded the presence of Toxoplasma gondii (PCR fragment of 90bp corresponding to 18s ribosomal RNA) and EBV (PCR

3. Discussion The patients here reported presented new-onset EPC as the likely first manifestation of HIV-related PML. EPC occurred in isolation with no other seizures and was characterized by negative radiographic and electrophysiological findings for up to several weeks from the onset. The negativity of earlier MRI scans in our patients confirms previous observations that small PML lesions within cortical areas may not be visible with conventional imaging [17]. Accordingly, neurophysiological evidence for cortical myoclonus was obtained only in Patient 1, at the time of appearance of MRI abnormalities, confirming that the challenge posed by patients with EPC is not linked to clinical detection of attacks, but rather in recording seizure generator [9]. In Patient 2 only MRI scan showed clear-cut evidence for motor cortical involvement; this is at variance with a recent study on EPC, suggesting that imaging is only confirmatory of clinical and electrophysiological findings [6]. The results of MRI and laboratory follow-up in our patients provided consistent clues to suggest that PML was responsible for both early and late neurological findings. The diagnosis of PML was established by CSF PCR results combined with typical MRI pattern in Patient 1 and proved by brain biopsy in the other case with negative PCR. Molecular results were consistent in both cases with assessed evidence showing almost 100% specificity of JCV-DNA detection in CSF [1], as opposed to 50–70% sensitivity of the technique [5], especially in the absence of target cells in the CSF. No evidence for subacute encephalitis secondary to coinfection by fungal, bacterial or viral pathogens was observed during the course of the disease; in addition, clinical and MRI findings were not supportive for a diagnosis of HIV encephalopathy, a major cause of epilep-

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Fig. 3. Brain MR axial images obtained 1 (A, D) and 5 months (B, C, E, F) after the onset of EPC, respectively. T2-weighted images (A, D) of the initial MR were normal. Five months later, T2-weighted (B, E) and proton-density weighted (C, F) images show areas of hyperintensity on the right precentral cortex and insula.

tic attacks in HIV-infected patients [2]. New-onset seizures are not exclusive of HIV-associated PML, as they have been reported also in seronegative PML [4], proving that JCV infection itself may be responsible for direct cortical dysfunction. The occurrence of grey matter lesions in PML is also suggested by symptoms reflecting cortical, basal ganglia

and cerebellar involvement [10,16]. Pathological evidence has been provided that early lesions of PML develop both in cortical and subcortical locations [3] and may remain confined to cerebral, cerebellar cortex and immediate subcortical structures [17]. The spectrum of new-onset seizures secondary to PML ranges from generalized tonic-clonic attacks to single

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partial, EPC representing a hitherto unrecognized presentation of JCV infection. New-onset focal motor seizures [12,13], bilateral myoclonic jerks [12], stimulus-sensitive myoclonic jerks [17], and permanent myoclonic jerks of the arm [13], the latter as likely expression of myoclonia continua in a patient with infratentorial lesions, have been reported in HIVassociated PML. Our study extends this spectrum and suggests that in HIV-infected patients presenting EPC the diagnosis of PML should be entertained regardless of MRI and EEG findings.

References [1] Antinori A, Ammassari A, De Luca A, et al. Diagnosis of AIDSrelated focal brain lesions: A decision-making analysis based on clinical and neuroradiologic characteristics combined with polymerase chain reaction assays in CSF. Neurology 1997;48:687–94. [2] Aronow HA, Feraru ER, Lipton RB. New-onset seizures in AIDS patients: etiology, prognosis and treatment. Neurology 1989;39(1):688. [3] Astrom KA, Stoner GL. Early pathological changes in progressive multifocal leukoencephalopathy: a report of two asymptomatic cases occurring prior to the AIDS epidemic. Acta Neuropathol 1994;88:93–105. [4] Brooks BR, Walker DL. Progressive multifocal leukoencephalopathy. Neurol Clin North Am 1984;2:299–313. [5] Cinque P, Vago L, Dahl H, et al. Polymerase chain reaction on cerebrospinal fluid for diagnosis of virus-associated opportunistic diseases of the central nervous system in HIV-infected patients. AIDS 1996;10:951–8. [6] Cockerell OC, Rothwell J, Thompson PD, Marsden CD, Shorvon SD. Clinical and physiological features of epilepsia partialis continua. Cases ascertained in the UK. Brain 1996;119:393–407.

[7] Domingo P, Guardiola JM, Iranzo A, Margall N. Remission of progressive multifocal leucoencephalopathy after antiretroviral therapy. Lancet 1997;349:1555–6. [8] Eisenstein BI. The polymerase chain reaction. A new method of using molecular genetics for medical diagnosis. New Engl J Med 1990;322:178–83. [9] Fish DR, Marsden CD. Epylepsy masquerading as a movement disorder. In: Marsden CD, Fahn S, editors. Movement disorders 3. Oxford: Butterworth-Heinemann, 1994:346–58. [10] Giesen HJ, Neuen-Jakob E, Dorries K, Jablonowsky H, Roick H, Arendt G. Diagnostic criteria and clinical procedures in HIV-1 associated progressive multifocal leukoencephalopathy. J Neurol Sci 1997;147:63–72. [11] Holtzman DM, Kaku DA, So YT. New-onset seizures associated with human immunodeficiency virus infection: causation and clinical features in 100 cases. Am J Med 1989;87:173–7. [12] Lechtenberg R, Hollenberg Sher J. AIDS in the nervous system. New York: Churchill Livingstone, 1988:83–92. [13] Moulignier A, Mikol J, Pialoux G, Fenelon G, Gray F, Thiebaut JB. AIDS-associated progressive multifocal leukoencephalopathy revealed by new-onset seizures. Am J Med 1995;99:64–8. [14] Power C, Nath A, Aoki FY, Del Bigio M. Remission of progressive multifocal leukoencephalopathy following splenectomy and antiretroviral therapy in a patient with HIV infection. New Engl J Med 1997;336:661–2. [15] Price RW, Navia BA, Infections in AIDS and in other immunosuppressed patients. In: Kennedy PGE, Johnson RT, editors. Infections of the nervous system. London: Butterworths, 1987;248– 73. [16] Price RW. Neurological complications of HIV infection. Lancet 1996;348:445–52. [17] Sweeney BJ, Manji H, Miller RF, Harrison MJG, Gray F, Scaravilli F. Cortical and subcortical JC virus infection: two unusual cases of AIDS associated progressive multifocal leukoencephalopathy. J Neurol Neurosurg Psychiatry 1994;57:994–7. [18] Tunkel AR, Kelsall B, Rein MF, et al. Case report: increase in CD4 lymphocyte count after splenectomy in HIV-infected patients. Am J Med Sci 1993;306:105–10.