Casi clinici A “progressive” visual loss Lorenzo Capaldi, Stefano Ursella, Luca Miele*, Dora Larussa**, Federico Pallavicini**, Giovanni Gasbarrini*, Antonio Grieco*, Nicolò Gentiloni Silveri An unusual cause of acute-onset and progressively worsening visual loss is presented. A 60-yearold woman was referred for left homonymous hemianopsia to our Emergency Medicine Department because of a suspected vascular accident. Ten years earlier she had been diagnosed as having chronic lymphocytic leukemia. Brain computed tomography and magnetic resonance imaging revealed “bilateral foci of white matter abnormalities in the occipital regions, compatible with a diagnosis of progressive multifocal leukoencephalopathy”. Her cerebrospinal fluid was positive for papovavirus JC. Progressive multifocal leukoencephalopathy due to papovavirus JC, a typical complication in AIDS patients, is a rare complication in patients with other immunosuppressive conditions, such as chronic lymphocytic leukemia. (Ann Ital Med Int 2004; 19: 118-121) Key words: AIDS; Cerebrospinal fluid; Chronic lymphocytic leukemia; Papovavirus JC; Progressive multifocal leukoencephalopathy. Introduction maintenance therapy with interferon-α injections 3 times weekly. On examination she was alert and collaborative, was not feverish, was fully conscious, had no dizziness or systemic symptoms and her heart rate and arterial pressure were normal. Physical examination of the heart, thorax and abdomen was unremarkable and the carotid pulses were present with no bruits. No neck stiffness was elicited. The patient was unsteady on her feet but there was no postural drift of the upper and lower limbs; the tendon reflexes were symmetrical and normal and the plantar reflex was flexor bilaterally. The pupils were equal and reactive with no ptosis. The extraocular movements were intact, without nystagmus. The hematocrit was 0.43, the white cell count was 85 u 109/L with 0.82 lymphocytes (CD4 2.75 u 109/L; CD8 3.53 u 109/L; CD4/CD8 ratio 0.78) and 0.11 neutrophils; her hemoglobin level was 143 g/L, the platelet count was 83 u 109/L, the blood glucose was 11 766 mmol/L. The level of total serum IgG was 2.38 g/L (n.v. 8.0-18.0 g/L), IgA < 0.26 g/L (n.v. 0.07-3.0 g/L), and that of IgM was < 0.19 g/L (n.v. 0.05-2.5 g/L). A bone marrow biopsy showed a lymphocytic infiltrate with nodular and trabecular patterns and hypocellularity of myeloid lineage. An accurate visual field examination revealed a left homonymous hemianopsia and a cranial computed tomographic scan without injection of contrast material showed hypodensity of the white matter of the occipital lobes. Fluid-attenuated inversion recovery (FLAIR) and gadolinium-enhanced magnetic resonance imaging (MRI) of the brain showed hypointense signals in T1-weighted and hyperintense signals in T2-weighted images in the white matter of the right and left occipital lobes without any mass effect (Fig. 1). Progressive multifocal leukoencephalopathy (PML) is a demyelinating disease of the central nervous system and is caused by the papovavirus JC1. The main pathologic features include multiple foci of myelin and oligodendroglial cell loss, hyperchromatic enlarged oligodendroglial nuclei, and bizarre astrocytes with enlarged multilobulated nuclei2. The widespread use of immunosuppressive agents in autoimmune diseases and organ transplantation, and, more recently, acquired immunodeficiency syndrome (AIDS) led to an increase in the incidence of PML3,4. In other diseases, PML is still a rare and undiagnosed complication5 even though positive results for JC virus DNA testing of the cerebrospinal fluid (CSF) may yield the diagnosis without brain biopsy6. We report the case of a woman with chronic lymphocytic leukemia (CLL), in whom PML has been diagnosed without brain biopsy. Case report A 60-year-old woman came to the Emergency Department reporting blurred vision and visual field impairment manifesting 1 month earlier. She had a history of CLL lasting 10 years (Rai staging system IV)7 and cyclically treated with chlorambucil and prednisone. At the time of hospitalization she was on Dipartimento di Emergenza e Accettazione (Direttore: Prof. Rodolfo Proietti), *Istituto di Medicina Interna e Geriatria (Direttore: Prof. Giovanni Gasbarrini), **Istituto di Malattie Infettive (Direttore: Prof. Roberto Cauda), Università Cattolica del Sacro Cuore, Policlinico “A. Gemelli” di Roma © 2004 CEPI Srl 118 Lorenzo Capaldi et al. FIGURE 1. Magnetic resonance imaging axial fluid-attenuated inversion recovery image showing bilateral hyperintense signals in the white matter of the occipital lobes with sparing of the gray matter and no mass effect. Lumbar puncture yielded a clear, normal-pressure CSF with glucose and protein levels normal with respect to the plasma values and 3 lymphocytes/mm3. Polymerase chain reaction (PCR) examination of the CSF for the presence of JC virus yielded a positive result. On the basis of the FLAIR-MRI and CSF findings a diagnosis of PML was made. During the following weeks, the patient completely lost her vision and developed left hemiparesis and her conditions progressively worsened. She was finally transferred to the Infectious Disease Department and during the following months she developed tetraparesis, progressive mental impairment and coma. The patient died 8 months after the diagnosis was made. DNA genome12. JC virus infection is ubiquitous and it is thought to be asymptomatic in immunocompetent individuals13,14. It is still being debated whether PML is due to reactivation of a latent childhood JC virus infection of the central nervous system, or to a cerebral primary infection in an immunocompromised host15-19. Several cases have been reported in association with leukemia and lymphomas, cancer chemotherapy and immunosuppressive treatment13,14. A definitive diagnosis of PML requires evaluation of the brain tissue, but recent studies indicate that the presence of JC virus in the CSF may be identified by PCR with a high specificity and sensitivity20. The neuroimaging characteristics of PML are a decreased attenuation on computed tomographic scans and a hyperintense signal on T2-weighted MRI. The lesions most often involve the periventricular and subcortical white matter of the occipitoparietal or frontal lobes. Occasionally, the posterior fossa is involved too. Rarely, the lesions show contrast enhancement or produce a mass effect21,22. In a prospective cohort study of AIDS patients with focal brain lesions, the absence of a mass effect on neuroimaging studies and a positive PCR testing for JC virus in the CSF yielded a 0.99 probability of making a diagnosis of PML6,23. As in our patient, computed tomography of the brain shows hypodense, non-enhancing lesions of the cerebral white matter and the lesion extension is often less than would be expected on the basis of the neurological symptoms. MRI, which proves to be more sensitive, typically shows high intensity abnormalities in the white matter in T2-weighted and fluid-attenuated inversion recovery Discussion CLL is the most prevalent leukemia in western countries8. Symptomatic central nervous system involvement with CLL has been reported to occur in < 1% of cases9 while PML is one of the opportunistic infections of the central nervous system in patients with CLL3,5. PML, first recognized in 1958 in a patient with chronic lymphocytic leukemia10,11, was a relatively rare condition prior to the emergence of AIDS and today it is mandatory to rule out PML in AIDS patients with focal brain symptoms5. In 1971, Padgett et al.10 reported the cultivation of a papova-like virus from human brain cells with PML and that virus was called JC (JC are the initials of the patient from whom the first virus isolates were obtained). JC is a polyomavirus and, as such, is a member of the Papovaviridae family. These are small, non-enveloped viruses with a covalently closed, circular, doubled-stranded 119 Ann Ital Med Int Vol 19, N 2 Aprile-Giugno 2004 images and low intensity abnormalities in T1-weighted images, not enhanced after gadolinium and with no mass effect24. This characteristic helps to differentiate PML from lymphomatous infiltration of the central nervous system25,26. The clinical manifestations of PML include visual deficit, upper motor neuron weakness, and an altered mental state. Language and speech dysfunction, extrapyramidal syndromes, cerebellar disorders, sensory deficits, headaches, and seizures may also occur27,28. Most commonly the patient’s conditions deteriorate rapidly, and death usually occurs within 6 months of the diagnosis5. PML may be distinguished from central nervous system lymphocytic infiltration and from encephalitis caused by others viruses on the basis of the MRI pattern (sparing of the cortical gray matter, no enhancement after gadolinium)24, by the normal or near normal characteristics of the CSF and by evidence of JC virus in the CSF at PCR analysis29. This method can obviate the need of brain biopsy, allowing the detection of the viral sequences in > 85% of cases, with no false positive results30,31. A positive result has to be considered diagnostic only when associated with characteristic findings on clinical and radiographic examinations, while a negative result does not exclude the diagnosis when these findings are present29,30. Unfortunately, no treatment is currently available for this complication. A few reports refer a somewhat delayed progression of the disease after cidofovir therapy32. Physicians must consider carrying out a PCR test for JC virus DNA on the CSF to rule out the diagnosis of PML in patients with CLL or an immunodeficiency state with a history of progressive neurologic deficit and white matter lesions at cerebral computed tomography or MRI scans. In this clinical setting, clinicians need to keep immunodepression-related infectious processes high in the list of probabilities, with PML ranking at the first place. complicanza del paziente affetto da AIDS, ma è presente anche in altre condizioni di immunodepressione come la leucemia linfatica cronica. 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N Engl J Med 1993; 328: 708-16. 32. Bagnato F, Pietropaolo V, Di Taranto C, Lorenzano S, Toni D. Chronic lymphocytic leukemia complicated by progressive multifocal leukoencephalopathy without apparent immunodepression. Eur J Neurol 2001; 8: 367-8. 25. Atlas SW. Intraaxial brain tumors. In: Atlas SW, ed. Magnetic resonance imaging of the brain and spine. New York, NY: Raven Press, 1991: 223-326. Manuscript received on 10.10.2003; accepted on 3.2.2004. Address for correspondence: Dr. Luca Miele, Istituto di Medicina Interna e Geriatria, Università Cattolica del Sacro Cuore, Policlinico “A. Gemelli”, Largo A. Gemelli 8, 00168 Roma. E-mail: [email protected] 121