Progressive Multifocal Leukoencephalopathy With Peripheral Demyelinating Neuropathy in a Liver Transplant Patient

Progressive multifocal leukoencephalopathy (PML) is a rare demyelinating disorder of the central nervous system, which is caused by the JC virus. Even though PML has been documented in organ transplant recipients, peripheral demyelinating neuropathy associated with PML has not been reported in solid organ transplant recipients. We present a case of PML associated with both central and peripheral nervous system involvement in a liver transplant patient. Seven weeks after orthotopic liver transplant, a 45-year-old woman developed myalgias, decreased vision, and paresthesia in the fourth and fifth fingers of both hands as well as a right foot drop. Neuroradiologic imaging of the brain showed a nonspecific low attenuation lesion in the right frontal lobe of the brain consistent with PML, which was later confirmed by a JC virus, DNA-specific polymerase chain reaction (PCR) of the cerebrospinal fluid (CSF) and characteristic autopsy findings of the brain, including in-situ hybridization (ISH) of brain tissue.

Background

Latent infection with JC virus, of the papovavirus family, is common in the general population. However, immunosuppressive drugs may predispose to reactivation of the latent form of JC virus in organ transplant recipients, which may lead to the development of PML, a rare demyelinating disease of the central nervous system.¹ The first two reported cases of PML, in 1958, were in association with chronic lymphatic leukemia and Hodgkin disease, respectively.² In recent years, the incidence of PML has significantly risen with a parallel rise in human immunodeficiency virus (HIV) infections and organ transplantation. There have been 2 case reports of cytomegalovirus (CMV) infection preceding PML after bone marrow transplantation that presented with peripheral demyelination.^3,4 However, there has yet to be a reported case of PML in the literature with regard to peripheral demyelination in a patient with solid organ transplantation, including liver transplantation. Hence, we present the first case of PML associated with peripheral demyelination in a liver transplant recipient.

Case Report

A 45-year-old woman received an orthotopic liver transplant in May 1998 for cirrhosis of the liver associated with chronic hepatitis C virus (HCV) infection. Immunosuppressive therapy was initiated with tacrolimus, 9 mg twice daily, and prednisone, 20 mg 4 times daily. The posttransplant course was complicated by CMV hepatitis at 4 weeks, which was treated with ganciclovir (Cytovene, Roche). The patient was hospitalized 3 weeks later for an elevation of liver enzymes, and a liver biopsy revealed changes consistent with recurrent HCV infection, cholestasis, and acute cellular rejection of the liver. She was treated with prednisone 80 mg daily for 5 days and a tapering dose over several days for acute cellular rejection. However, despite this intervention, her liver enzyme measure continued to climb. A Doppler ultrasound of the liver showed normal blood flow in the hepatic artery, hepatic vein, and portal vein without any bile duct dilatation. A repeat liver biopsy showed an improvement in inflammation but worsening cholestasis. In addition, she complained of increased fatigue, myalgia, decreased vision, paresthesia in her fourth and fifth fingers of both hands, and a right foot drop. This was thought to be due to aggressive recurrent HCV infection, and she was treated with interferon alfa-2b injection (Intron-A, Schering), 3 million units subcutaneously 3 times weekly, and ribavirin, 1,000 mg daily, in divided doses. Due to the above neurologic findings, a computed tomography (CT) scan of the head and spine were obtained and were unremarkable. Further evaluation via electromyogram and nerve conduction studies showed evidence of an axonal sensory and motor neuropathy. A sural nerve biopsy showed severe loss of myelinated fibers and segmental demyelination. This was assumed to be related to mixed cryoglobulinemia associated with recurrent hepatitis C. However, cryoglobulin level was undetectable in multiple measurements in serum during this evaluation. The patient's tacrolimus dose was significantly reduced due to possible neurotoxicity, based on the above neurologic symptoms and histopathologic findings.

Despite this, the patient was admitted to the hospital again 4 months after transplantation with complaints of continued right foot drop and painful peripheral neuropathy, as well as elevated liver enzymes. Interferon and ribavarin were discontinued due to continued neurologic symptoms. Again, Doppler ultrasound of the liver was normal with good blood flow in the hepatic vessels and portal vein. Liver biopsy again showed cholestasis and was not significantly different from the previous biopsy. Due to concerns of possible rejection, the patient was treated with 1 g of methylprednisolone, followed by a daily oral tapering regimen of prednisone consisting of 200 mg, 160 mg, 120 mg, 80 mg, 40 mg, and 20 mg, and with mycophenolate mofetil (Cellcept, Roche), 1 mg twice daily. Tacrolimus was changed to cyclosporine 300 mg twice daily for probable drug-induced cholestasis and neurotoxicity. However, her neurologic symptoms did not improve despite discontinuation of tacrolimus. She continued to have progressively increasing weakness of the right upper and lower extremities and left upper extremity, as well as continued right foot drop and persistently elevated liver enzymes. Both abdominal ultrasound and endoscopic retrograde cholangiopancreatography were unremarkable. She was relisted for a new liver transplant due to continued liver failure and was transferred to a skilled nursing facility.

Due to continued weakness involving the right and left upper extremities and right lower extremity, she was readmitted 2 months later and a follow-up CT scan of her brain revealed nonspecific low-attenuation lesions in the right frontal lobe, which were confirmed by magnetic resonance imaging (MRI) showing a lesion in the right frontal lobe white matter, with an extension across the corpus callosum. A positron emission tomography (PET) scan of the brain revealed extensive areas of hypometabolism involving white matter of the right frontal, right parietal, and right temporal lobes and right thalamic region. All of these findings were suggestive of PML. Her cyclosporin dose was reduced to maintain very low levels and prevent further neurotoxicity. During this hospitalization, she became drowsier and disoriented, with decreased motor function and development of recurrent episodes of fever. However, no etiology of infection was identified in her blood (Table 1), urine, or CSF. CSF cytology, protein, and glucose levels were normal, including CSF protein electrophoresis. However, a JC-virus-DNA-specific PCR assay of the CSF was positive for JC virus. Herpes simplex virus and varicela zoster virus infection by PCR from serum and CSF were negative. HIV 1–2 and human T-lymphotropic virus 1-2 serologies were also negative. Epstein-Barr virus serology and CMV serology were positive for IgG antibodies. Serum vitamin B-12, syphilis serologies, thiamine, and thyrotropic hormone levels were all within normal range. She did not have any evidence of hyperglycemia or diabetes. Her clinical condition continued to decline and she expired due to multiorgan failure.

Table 1.

Laboratory Test Results

Test	Baseline*	4 weeks postoperative	10 weeks postoperative	26 weeks postoperative
Aspartate aminotransferase (U/L)	106	118	103	199
Alanine aminotransferase (U/L)	116	139	186	263
Total bilirubin (mg/dL)	1.8	2.3	15.3	13.3
Direct bilirubin (mg/dL)	0.8	1.5	12.3	9.7
Alkaline phosphatase (U/L)	90	464	780	768
Gamma glutamyl transferase (U/L)	34	699	2,474	2,177
Parathyroid hormone (pg/mL)	14	18	11	11
International normalized ratio	1.1	1.5	0.8	0.8
Albumin (g/dL)	3.5	2.6	3.0	2.7
White blood cells (per mL)	5.5	6.1	7.5	8.0
Hematocrit (%)	35	31	32	30
Blood urea nitrogen (mg/dL)	19			50
Creatinine (mg/dL)	1.6			1.0

^*Baseline measures taken the day before transplantation.

An autopsy was performed, and central nervous system tissue samples revealed a 4 X 4 X 1.5 cm sunken area of white matter with grey discoloration in the right superior frontal gyrus (Figure 1). On microscopic examination, there were multiple areas of the brain-demonstrated foci of demyelination. Surrounding those foci were numerous oligodendrocytes with deeply basophilic nuclei and multinucleated giant atypical astrocytes with large pleomorphic nuclei. ISH of brain tissue revealed numerous infected oligodendrocytes containing JC virus. All of these findings were consistent with PML.

Figure 1.

Brain histopathology. Foci of demyelination, oligodendrocytes with deeply basophilic nuclei and multinucleated atypical astrocytes.

Discussion

Our patient developed CMV hepatitis 4 weeks after orthotopic liver transplant and, subsequently, her clinical course was complicated with multiple episodes of rejection, cholestasis, and elevated enzymes. She also became significantly immunosuppressed with continued use of high-dose steroids including tacrolimus, and developed recurrent HCV infection. Neurologic symptoms including weakness, paresthesia, and right foot drop developed 6 weeks after transplantation. In addition, she developed peripheral demyelinating neuropathy. Her neurologic studies, including MRI and CT scan of the brain, were suggestive of PML. Later, the diagnosis of PML was confirmed by JC-virus-specific DNA PCR from CSF and ISH, both positive for JC virus from autopsied brain tissue.

The human polyoma JC virus is responsible for PML in immunocompromised individuals. Epidemiologic studies have shown that 60–80% of adults in the United States and Europe have developed antibodies to JC virus.^5,6 It is thought that the primary infection of JC virus is associated with viremia that results in seeding of the kidney where a clinically latent infection is established.⁷ Reactivation of the virus may occur in immunocompromised states such as pregnancy, acquired immunodeficiency syndrome (AIDS), and organ transplantation. The dynamic and pathogenesis of JC virus reactivation among organ transplant recipients is largely unknown. JC virus-infected mononuclear cells may play a role in the transport of the virus to the central nervous system, where it can present with rapidly progressive focal neurologic deficits such as hemiparesis, visual field deficits, and cognitive impairment. In late stages of disease, patients can develop cortical blindness, quadriparesis, severe dementia and even coma. Death usually occurs within 6 months of diagnosis.

The characteristic CT and MRI finding for PML is loss of white matter. MRI is found to be superior to CT in detection of demyelination. MRI shows multifocal lesions in the white matter, as well as at the junction of the gray and white matter, which are hypointense on T1-weighted images and hyperintense on T2-weighted images.⁸

On histopathology, oligodendrocytes demonstrate characteristic nuclear enlargement, loss of chromatin pattern, and intranuclear accumulation of deeply basophilic homogenous staining material.⁹ Astrocytes also undergo marked enlargement with presence of intensely hyperchromatic and irregularly shaped nuclei.

In our case, CMV infection was detected 1 month after transplantation and may have had an enhancing effect on the appearance of PML and on the associated peripheral demyelinating neuropathy, as suggested in 2 earlier reports in bone marrow transplant patients with PML.^3,4 To further support that the CMV infection may have contributed to PML with demyelinating neuropathy, our patient also presented with CMV infection after liver transplantation and preceding onset of PML. In addition, increased immunosuppression might have contributed to the reactivation of a latent virus such as the JC virus. It is not completely clear whether increased immunosuppression and/or posttransplant CMV infection contributed to PML-associated peripheral demyelination. JC virus has a restrictive host range with human glial cells, the only tissue in which it can replicate with reasonable efficiency. It has also been shown that herpes virus can induce papovavirus replication in nonpermissive cell lines.¹⁰ It was speculated that CMV may possess the same ability to induce JC virus infection and replication, and it was further evidenced when human embryo fibroblasts cell lines infected with CMV were electroporated with cloned JC virus DNA. The replications of JC virus DNA within fibroblast cells were detected by a JC virus-specific DNA probe and then with a CMV-specific probe.¹⁰ It was also shown that ganciclovir-induced inhibition of CMV replication is associated with a concomitant inhibition of JC virus replication.¹⁰

These findings have been supported by 2 case reports of CMV infection preceding PML after bone marrow transplantation. Coppo and associates³ reported that 1 patient underwent autologous bone marrow transplantation for acute myeloblastic leukemia and developed both CMV-IgM antibody and CMV viremia during the second induction course and 7 months after transplantation. Later, the clinical course was complicated with progressive bilateral symmetric paresthesia from toes to thigh and in the fingers, which was confirmed by an electromygraphy (EMG) and a nerve conduction study showing axonal demyelinating neuropathy. Our case is similar in that our patient developed paresthesia in her fourth and fifth fingers of both hands, and a right foot drop, which was confirmed by an EMG and a nerve conduction study showing axonal demyelinating neuropathy. However, JC virus-specific DNA PCR and ISH on nerve biopsy were not performed, similar to the Coppo case.³ One could argue for interferon and HCV-related multifocal process leading to peripheral demyelinating neuropathy in our case. However, our patient developed paresthesia and foot drop before receiving interferon for recurrent HCV infection. Certainly, recurrent HCV with mixed cryoglobulinemia could lead to peripheral neuropathy as an extrahepatic manifestation, but our patient did not show cryoglobulinemia after multiple measurements of cryoglobulin in the blood. To our knowledge, our patient represents the first case of PML presenting with peripheral demyelinating neuropathy after solid organ transplantation, especially liver transplantation, and the second case of PML with peripheral demyelinating neuropathy in any transplant patient.

There are no effective treatments for PML at this time. Although clinical trials are lacking, there is the possibility that the progression of disease may stop or even improve with termination of immunosuppressive therapy.¹¹ There have been several case reports of the successful use of the nucleoside analog cidofovir (Vistide, Gilead) in AIDS-related PML.¹² However, there is no data regarding improvement of PML in an organ transplant recipient with any nucleoside analogs.

In summary, PML is a rare demyelinating disease in patients with immunosuppression and should be considered in cases with declining mental status or progressive neurologic symptoms, especially among organ transplant recipients. Imaging studies such as CT or MRI of the brain as well as JC virus-specific PCR testing of the CSF are practical means for the diagnosis of PML. The incidence of PML may increase as more transplants are performed. It is unclear whether reactivation of a latent infection or a new primary infection is the cause of PML in solid organ transplant recipients. The clinical utility of screening donors and recipients for human polyoma virus is not clear at this point.