Progressive multifocal leukoencephalopathy in a 15-year-old boy with scleroderma and secondary amyloidosis.

Abstract

Progressive multifocal leukoencephalopathy (PML) is a rapidly progressive degenerative demyelinating disease that results from infection with JC virus. PML usually occurs in an immunocompromised individual, putatively attributable to reactivation of a latent JC virus. In childhood PML has been reported in individuals with acquired immunodeficiency syndrome (AIDS),1–3 Wiskott–Aldrich syndrome,4 and inherited immunodeficiencies.5,6We report here a 15-year-old boy with generalized morphea, a form of limited cutaneous sclerodema, and secondary amyloidosis who developed PML. The rapid onset of his neurologic manifestations and the initial neuroimaging studies suggested acute disseminated encephalomyelitis (ADEM), and a brain biopsy was needed for the diagnosis of PML.A 15-year-old boy with scleroderma and amyloidosis was admitted for progressive ataxia, dysarthria, and weakness. His medical history was notable for generalized morphea confirmed by a skin biopsy at 3 years of age. He had severe cutaneous involvement and finger and toe contractures attributable to skin and soft tissue involvement. He was treated with prednisone andD-penicillamine for several years. All autoantibodies were negative, and immunologic work-up revealed normal complement and immunoglobulin levels but a low absolute T-cell count of 533 cells/μL. There was no evidence of active arthritis or recurrent infections. Two years before admission, he was diagnosed with secondary amyloidosis with serum amyloid A protein by liver biopsy. A concomitant skin biopsy showed no evidence of amyloid deposition and continued to be consistent with morphea. Proteinuria was noted. Prednisone was stopped, and chlorambucil (4 mg per day) was started. He responded well to the chlorambucil over the next several months with significant regression of amyloidosis-related clinical findings and marked dermatologic improvement. He was maintained on chlorambucil only. However, 2 months before admission the dosage had to be decreased from 4 mg to 3 mg daily because of leukopenia with a white blood cell (WBC) count between 2000 and 4000 cells/μL and an absolute granulocyte count of <1500 cells/μL.Six weeks before admission, he developed progressive ataxia. Previously, he was able to walk independently, but on the day of admission, he was noted to be staggering as he walked and preferred to use a wheelchair. He complained of general weakness and had more coordination problems on his left side. He also had facial weakness, dysarthria, and dysphagia. He was able to tolerate solids, but was unable to drink liquids. He also had difficulty with his concentration and developed emotional lability. There was no history of fever and no previous viral illnesses or recent immunizations.His medical history revealed no evidence of recurrent infections or immunodeficiencies. His only medication was chlorambucil. Family history revealed no autoimmune, neurologic, or immunodeficiency disorders, nor familial amyloidosis or familial Mediterranean fever.On admission, he was an alert and awake adolescent male. His general examination was notable for poor dentition, areas of pigmentary change, subcutaneous atrophy, and contractures of the fingers and toes attributable to morphea. There was no organomegaly. Mental status testing revealed a slow dysarthric speech, but he had good comprehension, expressive speech, attention and remote and recent memory. Pupils were normally reactive and visual acuity and fields were normal to bedside testing. He had difficulty with voluntary upgaze, but the eyes moved with respect to the head when the neck was passively flexed and extended. The left lower part of the face appeared to be weak with voluntary movements. Motor examination showed bilateral mild weakness in the upper and lower extremities (4/5 on the right and 4-/5 on the left). Muscle tone was increased with a clasp-knife like quality. He had mild intention tremor and dysmetria in the left arm. He could only stand for 2 seconds and was unable to walk unassisted. Sensory examination was intact to touch and pin prick. Tendon reflexes were 3–4+ bilaterally with clonus in the ankles. Plantar responses were difficult to assess because of the contractures.Laboratory studies on admission revealed a WBC count of 3200 cells/μL, absolute granulocyte count of 2100 cells/μL, absolute lymphocyte count of 608 cells/μL, and an erythrocyte sedimentation rate of 5 mm/h. Antinuclear antibodies and antineutrophil cytoplasmic antibodies were negative, and complement levels and immunoglobulin levels were normal.Magnetic resonance imaging (MRI) revealed several areas of increased signal intensity on T2-weighted images in both thalami, midbrain, pons, medulla, left cerebellum, and right frontal lobe (Fig 1). These areas showed mild enhancement with gadolinium contrast. These findings were thought to represent ADEM.Lumbar puncture revealed 0 white blood cells/μL and a glucose of 50 mg/dL and protein of 51 mg/dL. Viral titers for Epstein–Barr virus, cytomegalovirus, and herpes simplex revealed evidence of remote infections only. Serologies for toxoplasmosis, Borrelia burgdorferi, mycoplasma, hepatitis B and C, and human immunodeficiency virus (HIV) were negative.Chlorambucil was discontinued, and he was treated with a course of high-dose methylprednisolone, and later with intravenous gamma globulin and plasmapheresis. Cerebral angiogram showed only minimal vascular irregularities in the branches of both middle cerebral arteries. There was no clear evidence of vasculitis.Despite these measures, he continued to deteriorate and developed generalized marked spasticity. Subsequent MRI scans over the ensuing 2 months showed slow progressive enlargement of the previously described lesions. In addition, there were bilateral lesions in the subcortical regions of both frontal lobes with extension to the right centrum semiovale and insular region.A brain biopsy of the right frontal lobe was performed revealing focal thickening of the leptomeninges with minimal inflammation. Occasional scattered and focal perivascular cuffs of lymphocytes were observed in the white matter. Reactive astrocytes and patchy areas of pallor, indicative of demyelination, were also present. Numerous enlarged nuclei with peripheral condensation of chromatin and central “glassy” gray inclusions were identified (Fig 2A), which immunoreacted with antibodies prepared against a similar polyomavirus, SV40 virus (Access Biomedical, Inc, San Diego, CA) (Fig 2B). The histologic and immunohistochemical findings were diagnostic of PML.The patient's corticosteroid therapy was discontinued. After lengthy discussion with the patient's parents regarding the poor prognosis of PML and lack of proven effective therapy, he was placed on cidofovir, an antiviral drug to which JC virus shows susceptibility in vitro.7 He has thus far received a 3-month course of 5 mg/kg of cidofovir given every 2 weeks. His neurologic status is stable with some improvement in motor function. MRI has also shown stabilization of his lesions.He continues to have low total WBC counts of 2600 to 3600 cells/μL and low absolute T-lymphocyte count of <700 cells/μL with a CD4/CD8 ratio of 1.0 at last follow-up, 4 months after discontinuing the chlorambucil and 3 months after discontinuing high-dose corticosteroid pulses. He has shown no sign of renal dysfunction while on cidofovir and his total WBC count is not significantly lower than that before therapy.PML is a rapidly progressive demyelinating disease that results from infection with JC virus. JC virus is a polyomavirus (so named because of the propensity of viruses in this family to induce tumors in rodents). It was first isolated in 1971, when brain tissue from a patient with PML was inoculated into cell culture derived from fetal brain.8 The pathogenesis of infection is unclear, but the virus probably enters the body through the respiratory tract. JC virus appears to target the kidneys as the main site of infection and remains latent for the lifetime of the individual.9Reactivation, leading to PML, occurs in immunocompromised individuals. The virus is likely transported to the central nervous system (CNS) by B lymphocytes.10 Oligodendrogliocytes become infected and undergo cytolytic destruction, resulting in multifocal demyelination of the white matter. Rarely astrocytes also become infected. The observation of JC virus genomic variability in the brains of patients with PML suggests that reactivation and CNS growth could be related to new gene rearrangements.11The source of initial JC infection is presumed to be infected family members with whom the child has close prolonged contact.12Primary JC virus infection is not associated with symptoms. Approximately 50% of all children are seropositive for antibody to JC virus by age 10 to 14 years; the seroprevalence rate in adults approaches 70%.13 Generally, PML occurs in middle to late adulthood.14 Before the mid-1980s, PML was typically seen in individuals with underlying lymphoproliferative disorders, immunosuppressive therapy, autoimmune disease, or in the elderly. It is now estimated that 4% of all patients with AIDS will develop PML.3 PML remains rare in childhood. It has been reported in children with AIDS,1–3 Wiskott–Aldrich syndrome,4 and inherited immunodeficiencies.5,6The onset of PML may be insidious. Presenting signs and symptoms include impaired speech, memory loss, changes in mentation, and visual disturbance. Visual field loss (homonymous hemianopsia) and motor weakness, progressing to hemiparesis, are common findings.9Patients remain afebrile during the course of the illness.This 15-year-old child had a long history of sclerodema and secondary amyloidosis and was treated with chlorambucil for 1½ years. He had mild leukopenia associated with the chlorambucil and long-standing moderately low T-lymphocyte counts. Low T-cell counts and low CD4/CD8 ratios have been found in certain autoimmune diseases.15There had been no previous evidence of significant immune deficiency or recurrent or opportunistic infections in this patient. Consequently, chlorambucil was the most significant factor leading to his compromised immune state. To our knowledge, we believe that this is the first case of PML associated with systemic amyloidosis and the use of chlorambucil.Typically in PML, neuroimaging studies demonstrate abnormalities of the cerebral or cerebellar white matter (hypodense white matter by computerized tomography and high-signal intensities of white matter by T2-weighted MRI). These abnormalities represent demyelinating lesions in the deep white matter. The involvement of the deep gray matter structures, such as in our case, is unusual, but have been described in patients with PML and AIDS.16 The predominantly deep gray matter distribution of the MRI abnormalities was initially more suggestive of ADEM, encephalitis, CNS lymphoma, vasculitis, or other opportunistic infections. More typical white-matter lesions of PML were not seen until later in the course.The lack of significant cerebrospinal fluid (CSF) pleocytosis and elevation in CSF protein made viral encephalitis or meningitis unlikely in this patient. CSF findings in PML are nonspecific and in many cases normal. In a small percentage of cases, a minimal mononuclear pleocytosis or mildly elevated CSF protein can be seen.9The rapid onset of this patient's neurologic symptoms and signs taken together with the neuroimaging studies initially suggested ADEM. The patient was treated with three modalities for possible ADEM, including methylprednisolone, intravenous gamma globulin, and plasmapheresis. Despite these measures, the patient continued to deteriorate clinically. The lack of clinical improvement with these measures and the progression of lesions on serial MRI scans made ADEM an improbable diagnosis. A brain biopsy was, therefore, pursued.Definitive diagnosis of PML was made by brain biopsy. The histologic findings were very characteristic of PML. The immunocytochemical staining with antibodies directed against SV40 (which cross-reacts with JC virus antigens) provided further evidence of PML. We have used this antibody for diagnostic purposes for the past 8 years. It has yielded positive results in more than a dozen cases of PML. In addition, we have tested the antisera against several cases of other viral infections of the brain, such as cytomegalovirus and herpes simplex virus, and have found no cross-reactivity.Short of a brain biopsy, a probable diagnosis can be made when a typical clinical syndrome is accompanied by characteristic MRI changes and a positive JC virus polymerase chain reaction (PCR) from CSF. The sensitivity of JC virus PCR from CSF in diagnosis of PML ranges from 70% to 90% depending on the methodology used.17,18PML is almost always fatal, with death occurring 3 to 9 months after onset of symptoms. There are case reports of spontaneous improvement in symptoms after withdrawal of immunosuppression or with institution of antiretroviral therapy in patients with HIV infection.19No specific therapy exists for PML other than withdrawal of immunosuppressive therapy. Proposed treatment regimens have been based on anecdotal reports and small case series. Cytarabine and αinterferon have been suggested as drugs with potential efficacy.20,21 A recently published multicenter trial of cytarabine in HIV-infected patients with PML showed no difference in survival among patients receiving therapy compared with those who did not.22Cidofovir therapy was instituted in this patient based on results of reports of in vitro susceptibility of JC virus to various antiviral compounds.7 Cidofovir may be associated with significant toxicity to the kidneys and may cause bone marrow suppression. After the institution of therapy, this patient's neurologic status stopped deteriorating and even improved slightly. Neuroimaging studies also showed stabilization of his lesions. However, it is premature to attribute his neurologic improvement to cidofovir treatment. It is entirely possible that the cessation of immunosuppressants, such as corticosteroid and chlorambucil, led to this early response. A longer follow-up period is needed to assess the efficacy of cidofovir in this patient. Recent clinical trials serve as a reminder that efficacy of any drug regimen cannot be based on anecdotal case reports, and further research into effective therapy for PML is much needed.22Although PML is rarely described in children, this case report underscores the importance of considering the diagnosis in any child with underlying chronic disease associated with immunosuppression or in a child on immunosuppressive therapy who presents with progressive degenerative demyelinating disease. Until the pathogenesis of PML is better understood and effective therapy is determined, the prognosis for this devastating disease remains poor.We thank Dr Dikran Horoupian for his review and helpful comments regarding this manuscript.