June 19, 2007
Progressive Multifocal Leukoencephalopathy: a Case Study
By McCalmont, Vicki Bennett, Kristi
Progressive multifocal leukoencephalopathy is a rare, highly fatal demyelinating brain infection caused by the JC virus. This infection is associated with immunosuppressive agents and is emerging in the transplant population. There has never been a documented case of progressive multifocal leukoencephalopathy in a transplant recipient receiving sirolimus. We present a study, in which the JC virus was found in a 68-year-old man who had received a postorthotopic heart transplant 3 years earlier and who was receiving sirolimus and prednisone for immunosuppression. We review the clinical presentation, diagnosis, current treatment options, and the outcomes of progressive multifocal leukoencephalopathy in transplant recipients. (Progress in Transplantation. 2007; 17:157- 160) CASE StudyA 65-year-old white man received an orthotopic heart transplant for idiopathic cardiomyopathy. Triple immunosuppression with cyclosporine, mycophenolate mofetil (MMF), and prednisone was used after transplantation. Six months later, the patient was changed to a renal-sparing protocol of sirolimus, MMF, and prednisone. At 1 year after transplantation, the MMF was discontinued because of persistent neutropenia. For the next 2 years the patient received low-dose sirolimus and prednisone without any rejection episodes. Sirolimus levels were routinely checked and ranged from 3.9 to 8.7 ng/mL.
Three years after transplantation, the patient called the police to report an intruder in his home. Police responded to this call and upon arrival found a confused man having visual and auditory hallucinations. Paramedics were called and the patient was taken to the emergency department for evaluation. The patient had an altered level of consciousness with visual and auditory hallucinations. His family reported a recent cough, weakness, ataxia, frequent falls, and intermittent unintentional "tremors." They also reported concerns that the patient was intermittently confused and had experienced auditory and visual hallucinations for several weeks. They attributed these findings to his recent changes in pain medication. His medical history included hypertension, renal insufficiency, painful peripheral neuropathy requiring narcotics, deep vein thrombosis, multiple previous admissions for pneumonia, and recent cataract surgery without vision improvement 2 months earlier. Immunosuppression consisted of sirolimus and prednisone.
Initial physical examination was significant for diminished breath sounds with coarse crackles to the left base. Diagnostic studies were notable for bilateral infiltrates on chest radiograph, pancytopenia, elevated brain natriuretic peptide, and international normalized ratio. Electrolytes, liver function tests, cardiac enzymes, and urinalysis were unremarkable. Computed tomography scan of the head revealed chronic small vessel changes. Echocardiogram was normal. Initial diagnosis of pneumonia was made and the patient was treated with antibiotics, diuretics, stress steroids, and sirolimus dose reduction.
The patient did not respond to this treatment and within days he experienced a progressive neurological decompensation. His findings on hospital day 2 to 5 included confusion and hallucinations; he then became nonverbal and ultimately lost motor control of his extremities. He appeared to be "locked-in" with a fixed forward gaze with eyes opening to stimulation. On day 5, a neurologist was consulted. Magnetic resonance imaging (MRI) revealed "extensive deep white matter ischemic changes." Lumbar puncture reveal cloudy cerebrospinal fluid (CSF) with a significantly elevated protein level of 275 mg/dL (normal values: 15-45 mg/dL). Electroencephalogram revealed "marked slowing." The infectious disease consultant ordered comprehensive testing on the CSF, blood, and urine that included cultures for mycobacteria and fungi. Serologic testing for cytomegalovirus, West Nile virus, lyme disease, meningiococcus, toxoplasma, coccidiomycosis, and cryptococcus was negative. The herpes simplex virus and enterovirus by polymerase chain reaction (PCR) testing were also negative. JC virus (JCV) detection by PCR could not be performed on the CSF because of insufficient sample collection.
On day 8, the patient began having seizures and anticonvulsants were administered. On day 9, the MRI and EEG were repeated; the MRI was unchanged but the EEG revealed a "profound metabolic coma." On day 10, JCV was detected in the urine by PCR; serum for JCV was negative. Acyclovir was administered. On day 12, a brain biopsy was requested because the patient's seizures persisted. The family denied consent for the biopsy. On day 13, the patient was comatose and continued to seize. The family requested comfort measures only. The patient expired the following day.
The autopsy revealed discolored meninges. Definitive diagnosis was not made. The postmortem diagnosis was "suspected" progressive multifocal leukoencephalopathy (PML) secondary to JCV.
Progressive Multifocal Leukoencephalopathy
PML is a subacute and usually fatal demyelinating disease of the brain caused by the opportunistic neurotropic polyomaviral infection JCV that occurs exclusively in severely immunocompromised patients. PML was first found in 1958 in patients with leukemia and Hodgkin disease.' More recently, the majority of PML cases have involved patients diagnosed with endstage human immunodeficiency virus (HIV) infections, but is also emerging in transplant recipients.2'8
The human polyomavirus JC was named after the initials of the patient from whom the particles were recovered in 1971.4,5 Researchers believe that an asymptomatic JCV infection occurs during childhood and early adolescence via respiratory inhalation.46 The JCV remains latent in the kidney and lymphoid organs and is excreted in the urine. The JCV may later be reactivated in the setting of immunodeficiency and cause PML.6,7 This reactivated virus causes a lysis of oligodendrocytes, resulting in myelin breakdown that coalesces producing enlarging lesions within the brain. The virus also infects astrocytes causing lesions that can be seen on MRI.
Twenty-four cases of transplant recipients infected with JCV have been reported in the literature. The age range of those infected was 21 to 69 years, with a median age of 46 years. Fifty-four percent of the cases reported were men (13 of 24).3 In an expanded review of the literature, 50 cases of immunosuppressive-associated leukoencephalopathy were found, but there was no discussion of the underlying virus or disease that caused the leukoencephalopathy," but some of the cases could have been a result of JCV. In these additional 50 cases, the ages ranged from 4 to 67 years, with a median age of 42.5; 58% of the patients were women. The majority of the cases involved liver transplant recipients (31 of 50).2
Reported time of onset ranged from 1 week to 132 months after transplantation. Patients diagnosed with PML typically deteriorated rapidly and death ranged from 2 weeks to 15 months after diagnosis. In more than 70% of patients, death occurred within 2.5 months of diagnosis.3
JCV should be considered in any immunocompromised patient experiencing a neurological deficit. To date, this disease had not been reported in a transplant patient receiving sirolimus. All reported cases have been found in patients receiving either cyclosporine or tacrolimus in combination with azathioprine, corticosteroids, or MMF.3
Diagnosis is based on clinical presentation, laboratory findings, and neuroimaging studies. The reported subacute clinical presentation of PML may present with changes in mental status and cognitve or motor functions. These symptoms range from monoparesis or hemiparesis to tetraplegia, apathy, confusion, headache, speech disturbances, weakness, seizures, and visual changes (Table 1).3,9,10 The symptoms progressively worsen over days to months as the lesions in the brain enlarge and spread.3 A step-wise comprehensive diagnostic evaluation is performed to identify the source of the illness. This initial evaluation is aimed at looking for common illnesses. The targeted JCV evaluation including the detection by PCR, MRI, lumbar puncture, and brain biopsy commonly occur when a diagnosis cannot be made and the patient's condition continues to decline (Table 2). Laboratory tests include JCV in CSF, blood, or urine; detection of JCV in the CSF has the highest correlation with PML but is not required for diagnosis. Also, a high protein concentration is found in the CSF when PML is present because of oligoclonal band formation in the brain.3,8 JCV can be detected in the blood and urine of patients without neurological disease; therefore, finding JCV in blood and urine is not used alone for definitive diagnosis of PML." Brain biopsy is considered the gold standard for definitive diagnosis of PML. Pathologically, JCVrelated PML is characterized by a triad of findings: (1) multifocal sites of demyelination with axon sparing, (2) giant bizarre astrocytes with large pleomorphic nuclei, and (3) large hyperchromic oligodendrocytes at the periphery of the lesion.38 Upon neuroimaging, these lesions can be visualized best on T2-weighted MRI as areas of increased signal intensity to the cerebral white matter consistent with a brain lesion.3,5,1112
There is no evidenced-based treatment for JCVrelated PML. To date, all reported cases attributed the immunosuppressive- associated PML as a complication of cyclosporine or tacrolimus therapy.3,12 Most centers attempt to delay or stop the progression of the disease by reducing immunosuppression. In kidney transplantation, in which dialysis is available after graft failure, complete removal of immunosuppression has been documented as a successful treatment for PML.11 In other solid-organ transplantation, in which there is no dialysis safety net, antiviral agents are the typical line of therapy. Cidofovir, a nucleoside analog, emerged recently as the most selective antipolyomavirus agent; it has been reported to stop progression of PML in a few recipients.3 Regression has also been documented in HIV-infected patients with JCV using highly active antiretroviral therapy with cidofovir and cytarabine in combination with interleukin-2.3,5 Other drugs that directly target JCV are camptothecin and topotean. There is no established treatment regimen for PML. The best outcomes occur when the virus is detected early, immunosuppression is reduced, and antiviral treatment is initiated.35
Early recognition and treatment are keys for survival. Retrospective review of the patient in the case study revealed a classic PML presentation of confusion, hallucinations, visual changes, ataxia, speech disturbances, paralysis, and seizures. These symptoms were vaguely present for 2 months before the patient's admission to the hospital and were dismissed because of secondary diseases. Confusion, hallucination, and weakness were attributed to the patient's chronic pain treatments for peripheral neuropathy. Visual disturbances were attributed to cataracts, and when his vision did not improve following cataract surgery, no explanation was given.
Upon extensive literature search, all reported transplant cases received cyclosporine or tacroliumus therapy. We could not find any sirolimus cases. Our clinical finding is significant for discovering a case of JCV in a heart transplant patient receiving sirolimus for immunosuppression. Therefore, we believe that JCV-related PML should be considered in any transplant recipients demonstrating the PML neurological presentation regardless of his or her immunosuppression regimen.
The authors wish to thank the patient's family for their consent and encouragement to publish this case study. We would also like to acknowledge the entire heart transplant team at Sharp Memorial Hospital in San Diego for their support during the writing of this article. We would also like to thank Brian Jaski, MD, and Raymond Chinn, MD, for their expert input into the content of this article.
Table 1 Progressive multifocal leukoencephalopathy symptoms
Cognitive disturbance, confusion, apathy
Visual field deficits (homonymous hemianopsia) and vision loss
Cranial nerve deficits and sensory deficits
Ataxia, gait disturbance, loss of balance
Speech disturbance, dysphasia, dysarthria, apraxia
Table 2 Diagnostic evaluation for JC virus
Complete blood count
Comprehensive metabolic panel
Drug levels on immunosuppression medications (sirolimus, cyclosporine, tacrolimus, or mycophenolate mofetil)
Urinalysis and urine culture
Polymerase chain reaction testing for JC virus using blood, urine, and cerebrospinal fluid
Cell count and protein
Gram stain, culture, and sensitivity
JC virus detection by polymerase chain reaction
Magnetic resonance imaging of the brain
Cardiac evaluation if rejection is suspected can also be performed
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9. Flomebbaum M, Jarcho J, Schoen F. Progressive mulitfocal leukoencephalopathy fifty seven months after heart transplantation. J Heart Lung Transplant. 1991;10:888-893.
10. Angela R, Lanning B, Pinkard N. Visual loss due to progressive multifocal leukoencephalopathy in the heart transplant patient. J Clin Neuroophthalmol. 1993;13:237-241.
11. Crowder CD, Oyure KA, Drachenberg CB, et al. Successful outcomes of progressive multifocal leukoencephalopathy in a renal transplant patient. Am J Transplant. 2005;5:1151-1158.
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Vicki McCalmont, MS, ANP,
APRN-BC, CNS, CCTC,
Kristi Bennett, MS, ANP,
APRN-BC, CNS, CCTC
Sharp Memorial Hospital, San Diego,
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