- Email: [email protected]
Acute Disseminated Encephalomyelitis in a Renal Transplant Recipient: A Case Report
Acute Disseminated Encephalomyelitis in a Renal Transplant Recipient: A Case Report M. Aboagye-Kumi, A. Yango, Jr., S. Fischer, J. Donahue, P. Morrissey, N. Taylor, A. Gautam, C. Mendonca, S. Kumar, and R. Gohh ABSTRACT Acute disseminated encephalomyelitis (ADEM) is an acute demyelinating disorder of the central nervous system, mostly seen in children after viral or bacterial infection and vaccinations. Cases of ADEM, albeit rare, have been reported in renal transplant recipients. The pathophysiology of posttransplant ADEM remains unclear but has been hypothesized to be due to aberrant T-cell reactivity to myelin basic protein triggered by a bacterial or viral infection. We report an unusual case of a 34-year-old white female with ADEM developing 5 years after a living related renal transplant.
A
CUTE disseminated encephalomyelitis (ADEM) is an acute demyelinating disorder of the central nervous system that is mostly seen in children. Typically, ADEM occurs after exposure to an antigenic challenge from viral or bacterial infections.1 The pathogenesis is not completely understood. Inflammation of the central nervous system (CNS), either from direct infection with a neurotropic pathogen or a primary autoimmune process, has been proposed. The latter may be a triggered response to a pathogen or to CNS-confined autoantigens released to the systemic circulation.2 Typically, a febrile episode precedes the onset of neurological signs and symptoms, which may present as paresthesia, paralysis, ataxia, and seizures. Fever and headaches predominate in pediatric cases while motor and sensory deficits predominate in adult cases.3 ADEM is typically a monophasic disease, although relapses have been reported in 25% to 30% of cases.1 Magnetic resonance imaging (MRI) of the brain typically shows diffuse CNS demyelination with extensive white matter involvement.4,5 Moderate pleocytosis with increased protein content may be seen in cerebrospinal fluid (CSF). Histologically, there is perivascular infiltration of T cells and macrophages in the white matter of the brain and spinal cord.2 Reports on ADEM occurring after organ transplantation are rare, and in most cases the etiology is unclear.6,7 The following describes an unusual case of ADEM in a 34-yearold patient presenting 5 years after a living related renal transplantation. CASE REPORT
Patient SP is a 34-year-old female with end-stage renal disease from chronic glomerulonephritis who received a
living related renal transplant from her mother in January 1999. Her maintenance immunosuppression consisted of rapamycin (Wyeth, Madison, New Jersey), azathioprine (Roxane, Ridgefield, Conn), and corticosteroids. The patient presented with 9 days of intermittent fever (Tmax 103° F) and nonproductive cough. Six days prior to her admission, she was seen by her family physician and was prescribed quinolones and bronchodilators for bronchitis. On presentation, her blood pressure was 124/74 but tachycardic (124 beats/min) and tachypneic (24/min). The remaining physical and neurological exams were unremarkable. Initial laboratory studies revealed a WBC count of 4400/ mm3, with 85% segmented neutrophils, 8% lymphocytes, and 7% monocytes; Hgb of 9.3 g/dL and a platelet count of 161,000. Blood urea nitrogen was 12 mg/dL, creatinine 1.7 mg/dL (baseline 1.4 –1.6), glucose 183 mg/dL, potassium 3.8 mEq/L, sodium 135 mEq/L, and bicarbonate 22 mEq/L. The rest of her metabolic panel was normal. Chest roentgenogram demonstrated a left lower lobe infiltrate. She was started on Imipenem/cilastatin 500 mg intravenously (IV) every 6 hours. A follow-up chest X ray after 3 days showed worsening infiltrate in the left lower lobe. A noncontrast CT of her chest demonstrated left lower and upper lobe infiltrates without lymphadenopathy or cavitations. Azithromycin 500 mg IV daily was added and rapaFrom the Division of Organ Transplantation, Rhode Island Hospital, Providence, Rhode Island. Address reprint requests to Dr. Angelito Yango, Jr., Division of Organ Transplantation, Rhode Island Hospital, 593 Eddy Street, Providence, RI 02903. E-mail: [email protected]
© 2008 by Elsevier Inc. All rights reserved. 360 Park Avenue South, New York, NY 10010-1710
0041-1345/08/$–see front matter doi:10.1016/j.transproceed.2007.11.073
Transplantation Proceedings, 40, 1751–1753 (2008)
1751
1752
mycin was discontinued. Serial blood and sputum cultures and urine legionella antigen were all negative. Serologies for mycoplasma, cytomegalovirus (CMV), Epstein-Barr virus (EBV), herpes simplex virus types 1 and 2 (HSV), human immunodeficiency virus (HIV), and West Nile virus were likewise negative. On hospital day 4, a bronchoscopy was performed that showed no endobronchial lesions. Bronchio-alveolar lavage (BAL) cultures were negative for bacteria, fungi, and acid-fast bacilli. Direct fluorescent antigen (DFA) for Pneumocystis jivoveckii was negative as well as polymerase chain reaction (PCR) studies for CMV, EBV, HSV, and human herpes virus-6 (HHV). A transbronchial biopsy of the left lower lobe showed chronic and acute bronchitis, peribronchiolitis, and acute interstitial inflammation. On hospital day 13, the patient developed a dense right-sided weakness. An MRI of the brain (Fig 1) showed a large infiltrating enhancing mass involving the left temporal, parietal, and occipital regions. The corpus callosum and region of the atria of both lateral ventricles were also involved, with edema in these areas. The CSF analysis showed 57 red blood cells c.mm., 6 nucleated cells/c.mm., glucose of 113 mg/dL, and protein of 19 mg/dL. The CSF Gram stain, culture, cryptococcal antigen, Venereal Disease Research Laboratory (VDRL) test and Lyme PCR were negative. The PCR studies for CMV, EBV, and HSV types 1 and 2 were likewise negative. A stereotactic needle biopsy of the left frontal white matter revealed hypercellular, gliotic brain tissue with perivenular foci of demyelination, axonal disruption, and macrophage infiltration (Fig 2). Staining for myelin basic protein was absent around the blood vessels, which were
ABOAGYE-KUMI, YANGO, FISCHER ET AL
surrounded by macrophages. No lymphocytic infiltration was seen, thus ruling out posttransplant lymphoproliferative disorder (PTLD). Despite treatment with high-dose corticosteroids and mannitol, her intracranial pressures remained persistently elevated and she had recurrent tonic-clonic seizures. Her course was further complicated by bilateral pulmonary embolism for which she was started on anticoagulation with IV heparin. Special stains on the brain tissue were negative for bacteria, fungi, and acid fast bacilli. Immunohistochemistry studies for CMV, EBV, polyoma JC virus, and Toxoplasma gondii were negative. Plasmapheresis was attempted once after she failed to show improvement with high-dose corticosteroids, but the patient did not tolerate the procedure owing to persistent hypotension. Her condition continued to deteriorate, at which point the family decided to withdraw care. The patient expired on her hospital day 27. DISCUSSION
Acute disseminated encephalomyelitis has also been rarely described as a complication following renal, stem cell, bone marrow, heart–lung, and liver transplantation. The mechanisms involved in posttransplant ADEM remain unclear. Aberrant T-cell reactivity against myelin basic protein triggered by either a viral or bacterial infection in the setting of active immunosuppression has been proposed.7 In this patient, we hypothesized that a respiratory infection may have triggered an aberrant autoimmune response heralding the development of ADEM. This is consistent with previous reports of upper respiratory tract infection
Fig 1. Standard MRI of the brain with and without contrast (gadolinium). There is extensive abnormally increased T2 and flair signal throughout the white matter diffusely. This indicates a large infiltrative lesion involving the left temporal, parietal, and occipital regions. There is a mild subfalcine left to right shift.
ENCEPHALOMYELITIS IN RENAL TRANSPLANT
Fig 2. Stereotactic needle biopsy, high-power, of the left frontal white matter showing perivascular macrophages and macrophage infiltration in the white matter. H&E stain, ⫻200.
preceding the initial presentation of ADEM in nearly 50% of cases.5 In addition, many bacterial and viral pathogens associated with ADEM may also cause upper respiratory tract infections.1 Despite extensive workup, we failed to identify a definite pathogen as our patient had been on empiric antibiotic coverage for 6 days prior to our obtaining appropriate blood and bronchial fluid cultures. Because the clinical presentation is often nonspecific, viral encephalitis and other CNS infections need to be excluded in the initial evaluation of a patient with possible ADEM. Moreover, distinguishing ADEM from the first episode of multiple sclerosis (MS) is important but often difficult as there are no generally accepted clinical, radiologic, and biochemical criteria for the differentiation of ADEM from MS. There are no identified MRI criteria specific for ADEM. Cortical involvement and lesions involving the basal ganglia and thalamus are highly suggestive of ADEM, but these patterns are not consistently seen and require further validation.8,9 In our patient, the temporal relationship between her febrile episode and the onset of acute multifocal neurologic deficits coupled with the demonstration of demyelinating features on the MRI strongly suggest the clinical diagnosis of ADEM. The pathologic findings of perivascular (especially perivenular) demyelination and macrophage infiltration in this case were also highly suggestive of ADEM. Though there is relative axonal preservation, axons within the lesion were swollen and tortuous with spheroid formation. Based on these histologic findings, differential diagnoses also include medication-induced leukoencephalopathy, infection, or malignancy. In this case, an infectious etiology has been ruled out or at least eluded detection by all microbial stains, cultures, and amplification techniques. Likewise, we did not find any existing reports of demyelinating disorders secondary to the standard immunosuppressive drugs given our patients. Furthermore, the absence of widespread lym-
1753
phocytic infiltration makes the diagnosis of posttransplant lymphoproliferative disorder (PTLD) unlikely. There are no published controlled therapeutic trials for ADEM. Spontaneous improvement has been reported in some patients.10 Corticosteroids are considered first-line treatment with reported response in up to 64% of patients with ADEM. Long-term prognosis is good especially when steroids are initiated early. Plasmapheresis, cytotoxic agents, and IV immunoglobulin (IVIG) have been used in cases where corticosteroids have failed but with variable results.11,12 However, despite improvements in therapy, recent reports still show a mortality rate of up to 5%.1 Our patient did not respond to high-dose steroids and did not tolerate plasmapheresis. Eventually, she succumbed after a course complicated by recurrent seizures, elevated intracranial pressure, massive pulmonary embolism, and hemodynamic instability. Although ADEM occurring in renal transplant recipients is rare, this disease entity should be included in the differential diagnosis of transplant patients presenting with acute and rapidly progressive neurologic deficit after a febrile episode. Early diagnosis is paramount so that early therapeutic intervention may be undertaken to improve outcome. REFERENCES 1. Bennetto L, Scolding N, Inflammatory/post-infectious encephalomyelitis. J Neurol Neurosurg Psych 75(suppl 1):22, 2004 2. Menge T, Hemmer B, Nessler S, et al: Acute disseminated encephalomyelitis. An update. Arch Neurol 62:1673, 2005 3. Leake JA, Albani S, Kao AS, et al: Acute disseminated encephalomyelitis in childhood: epidemiologic, clinical and laboratory features. Pediatr Infec Dis J 23:756, 2004 4. Andreula CF, Recchia Luciana NMA, Milella D: Magnetic resonance imaging in the diagnosis of acute disseminated encephalomyelitis. Int J Neuroradiol 3:21, 1997 5. Schwaz S, Mohar A, Knanth M, et al: Acute disseminated encephalomyelitis: a follow-up study of 40 patients. Neurology 56:1383, 2001 6. Kim SC, Jang HJ, Han DJ: Acute disseminated encephalomyelitis after renal transplantation in patients with positive Epstein-Barr virus antibody. Transplant Proc 30:3139, 1998 7. Lindzen E, Gilani A, Markovic-Plese S, et al: Acute disseminated encephalomyelitis after liver transplant. Arch Neurol 6:650, 2005 8. Singh S, Alexander M, Korah IP: Acute disseminated encephalomyelitis: MR imaging features AJR. Am J Roentgenol 173:1101, 1999 9. Caldemeyer KS, Smith RR, Harris TM, et al: MRI in acute disseminated encephalomyelitis. Neuroradiology 36:216, 1994 10. Rust RS, Dodson D, Prensky A, et al: Classification and outcome of acute disseminated encephalomyelitis. Ann Neurol 42:491, 1997 11. Kanter DS, Horensky D, Sperling RA, et al: Plasmapheresis in fulminant acute disseminated encephalomyelitis. Neurology 45:824, 1995 12. Pradhan S, Gupta RP, Shashank S: Intravenous immunoglobulin therapy in acute disseminated encephalomyelitis. J Neurol Sci 165:56, 1999
A
CUTE disseminated encephalomyelitis (ADEM) is an acute demyelinating disorder of the central nervous system that is mostly seen in children. Typically, ADEM occurs after exposure to an antigenic challenge from viral or bacterial infections.1 The pathogenesis is not completely understood. Inflammation of the central nervous system (CNS), either from direct infection with a neurotropic pathogen or a primary autoimmune process, has been proposed. The latter may be a triggered response to a pathogen or to CNS-confined autoantigens released to the systemic circulation.2 Typically, a febrile episode precedes the onset of neurological signs and symptoms, which may present as paresthesia, paralysis, ataxia, and seizures. Fever and headaches predominate in pediatric cases while motor and sensory deficits predominate in adult cases.3 ADEM is typically a monophasic disease, although relapses have been reported in 25% to 30% of cases.1 Magnetic resonance imaging (MRI) of the brain typically shows diffuse CNS demyelination with extensive white matter involvement.4,5 Moderate pleocytosis with increased protein content may be seen in cerebrospinal fluid (CSF). Histologically, there is perivascular infiltration of T cells and macrophages in the white matter of the brain and spinal cord.2 Reports on ADEM occurring after organ transplantation are rare, and in most cases the etiology is unclear.6,7 The following describes an unusual case of ADEM in a 34-yearold patient presenting 5 years after a living related renal transplantation. CASE REPORT
Patient SP is a 34-year-old female with end-stage renal disease from chronic glomerulonephritis who received a
living related renal transplant from her mother in January 1999. Her maintenance immunosuppression consisted of rapamycin (Wyeth, Madison, New Jersey), azathioprine (Roxane, Ridgefield, Conn), and corticosteroids. The patient presented with 9 days of intermittent fever (Tmax 103° F) and nonproductive cough. Six days prior to her admission, she was seen by her family physician and was prescribed quinolones and bronchodilators for bronchitis. On presentation, her blood pressure was 124/74 but tachycardic (124 beats/min) and tachypneic (24/min). The remaining physical and neurological exams were unremarkable. Initial laboratory studies revealed a WBC count of 4400/ mm3, with 85% segmented neutrophils, 8% lymphocytes, and 7% monocytes; Hgb of 9.3 g/dL and a platelet count of 161,000. Blood urea nitrogen was 12 mg/dL, creatinine 1.7 mg/dL (baseline 1.4 –1.6), glucose 183 mg/dL, potassium 3.8 mEq/L, sodium 135 mEq/L, and bicarbonate 22 mEq/L. The rest of her metabolic panel was normal. Chest roentgenogram demonstrated a left lower lobe infiltrate. She was started on Imipenem/cilastatin 500 mg intravenously (IV) every 6 hours. A follow-up chest X ray after 3 days showed worsening infiltrate in the left lower lobe. A noncontrast CT of her chest demonstrated left lower and upper lobe infiltrates without lymphadenopathy or cavitations. Azithromycin 500 mg IV daily was added and rapaFrom the Division of Organ Transplantation, Rhode Island Hospital, Providence, Rhode Island. Address reprint requests to Dr. Angelito Yango, Jr., Division of Organ Transplantation, Rhode Island Hospital, 593 Eddy Street, Providence, RI 02903. E-mail: [email protected]
© 2008 by Elsevier Inc. All rights reserved. 360 Park Avenue South, New York, NY 10010-1710
0041-1345/08/$–see front matter doi:10.1016/j.transproceed.2007.11.073
Transplantation Proceedings, 40, 1751–1753 (2008)
1751
1752
mycin was discontinued. Serial blood and sputum cultures and urine legionella antigen were all negative. Serologies for mycoplasma, cytomegalovirus (CMV), Epstein-Barr virus (EBV), herpes simplex virus types 1 and 2 (HSV), human immunodeficiency virus (HIV), and West Nile virus were likewise negative. On hospital day 4, a bronchoscopy was performed that showed no endobronchial lesions. Bronchio-alveolar lavage (BAL) cultures were negative for bacteria, fungi, and acid-fast bacilli. Direct fluorescent antigen (DFA) for Pneumocystis jivoveckii was negative as well as polymerase chain reaction (PCR) studies for CMV, EBV, HSV, and human herpes virus-6 (HHV). A transbronchial biopsy of the left lower lobe showed chronic and acute bronchitis, peribronchiolitis, and acute interstitial inflammation. On hospital day 13, the patient developed a dense right-sided weakness. An MRI of the brain (Fig 1) showed a large infiltrating enhancing mass involving the left temporal, parietal, and occipital regions. The corpus callosum and region of the atria of both lateral ventricles were also involved, with edema in these areas. The CSF analysis showed 57 red blood cells c.mm., 6 nucleated cells/c.mm., glucose of 113 mg/dL, and protein of 19 mg/dL. The CSF Gram stain, culture, cryptococcal antigen, Venereal Disease Research Laboratory (VDRL) test and Lyme PCR were negative. The PCR studies for CMV, EBV, and HSV types 1 and 2 were likewise negative. A stereotactic needle biopsy of the left frontal white matter revealed hypercellular, gliotic brain tissue with perivenular foci of demyelination, axonal disruption, and macrophage infiltration (Fig 2). Staining for myelin basic protein was absent around the blood vessels, which were
ABOAGYE-KUMI, YANGO, FISCHER ET AL
surrounded by macrophages. No lymphocytic infiltration was seen, thus ruling out posttransplant lymphoproliferative disorder (PTLD). Despite treatment with high-dose corticosteroids and mannitol, her intracranial pressures remained persistently elevated and she had recurrent tonic-clonic seizures. Her course was further complicated by bilateral pulmonary embolism for which she was started on anticoagulation with IV heparin. Special stains on the brain tissue were negative for bacteria, fungi, and acid fast bacilli. Immunohistochemistry studies for CMV, EBV, polyoma JC virus, and Toxoplasma gondii were negative. Plasmapheresis was attempted once after she failed to show improvement with high-dose corticosteroids, but the patient did not tolerate the procedure owing to persistent hypotension. Her condition continued to deteriorate, at which point the family decided to withdraw care. The patient expired on her hospital day 27. DISCUSSION
Acute disseminated encephalomyelitis has also been rarely described as a complication following renal, stem cell, bone marrow, heart–lung, and liver transplantation. The mechanisms involved in posttransplant ADEM remain unclear. Aberrant T-cell reactivity against myelin basic protein triggered by either a viral or bacterial infection in the setting of active immunosuppression has been proposed.7 In this patient, we hypothesized that a respiratory infection may have triggered an aberrant autoimmune response heralding the development of ADEM. This is consistent with previous reports of upper respiratory tract infection
Fig 1. Standard MRI of the brain with and without contrast (gadolinium). There is extensive abnormally increased T2 and flair signal throughout the white matter diffusely. This indicates a large infiltrative lesion involving the left temporal, parietal, and occipital regions. There is a mild subfalcine left to right shift.
ENCEPHALOMYELITIS IN RENAL TRANSPLANT
Fig 2. Stereotactic needle biopsy, high-power, of the left frontal white matter showing perivascular macrophages and macrophage infiltration in the white matter. H&E stain, ⫻200.
preceding the initial presentation of ADEM in nearly 50% of cases.5 In addition, many bacterial and viral pathogens associated with ADEM may also cause upper respiratory tract infections.1 Despite extensive workup, we failed to identify a definite pathogen as our patient had been on empiric antibiotic coverage for 6 days prior to our obtaining appropriate blood and bronchial fluid cultures. Because the clinical presentation is often nonspecific, viral encephalitis and other CNS infections need to be excluded in the initial evaluation of a patient with possible ADEM. Moreover, distinguishing ADEM from the first episode of multiple sclerosis (MS) is important but often difficult as there are no generally accepted clinical, radiologic, and biochemical criteria for the differentiation of ADEM from MS. There are no identified MRI criteria specific for ADEM. Cortical involvement and lesions involving the basal ganglia and thalamus are highly suggestive of ADEM, but these patterns are not consistently seen and require further validation.8,9 In our patient, the temporal relationship between her febrile episode and the onset of acute multifocal neurologic deficits coupled with the demonstration of demyelinating features on the MRI strongly suggest the clinical diagnosis of ADEM. The pathologic findings of perivascular (especially perivenular) demyelination and macrophage infiltration in this case were also highly suggestive of ADEM. Though there is relative axonal preservation, axons within the lesion were swollen and tortuous with spheroid formation. Based on these histologic findings, differential diagnoses also include medication-induced leukoencephalopathy, infection, or malignancy. In this case, an infectious etiology has been ruled out or at least eluded detection by all microbial stains, cultures, and amplification techniques. Likewise, we did not find any existing reports of demyelinating disorders secondary to the standard immunosuppressive drugs given our patients. Furthermore, the absence of widespread lym-
1753
phocytic infiltration makes the diagnosis of posttransplant lymphoproliferative disorder (PTLD) unlikely. There are no published controlled therapeutic trials for ADEM. Spontaneous improvement has been reported in some patients.10 Corticosteroids are considered first-line treatment with reported response in up to 64% of patients with ADEM. Long-term prognosis is good especially when steroids are initiated early. Plasmapheresis, cytotoxic agents, and IV immunoglobulin (IVIG) have been used in cases where corticosteroids have failed but with variable results.11,12 However, despite improvements in therapy, recent reports still show a mortality rate of up to 5%.1 Our patient did not respond to high-dose steroids and did not tolerate plasmapheresis. Eventually, she succumbed after a course complicated by recurrent seizures, elevated intracranial pressure, massive pulmonary embolism, and hemodynamic instability. Although ADEM occurring in renal transplant recipients is rare, this disease entity should be included in the differential diagnosis of transplant patients presenting with acute and rapidly progressive neurologic deficit after a febrile episode. Early diagnosis is paramount so that early therapeutic intervention may be undertaken to improve outcome. REFERENCES 1. Bennetto L, Scolding N, Inflammatory/post-infectious encephalomyelitis. J Neurol Neurosurg Psych 75(suppl 1):22, 2004 2. Menge T, Hemmer B, Nessler S, et al: Acute disseminated encephalomyelitis. An update. Arch Neurol 62:1673, 2005 3. Leake JA, Albani S, Kao AS, et al: Acute disseminated encephalomyelitis in childhood: epidemiologic, clinical and laboratory features. Pediatr Infec Dis J 23:756, 2004 4. Andreula CF, Recchia Luciana NMA, Milella D: Magnetic resonance imaging in the diagnosis of acute disseminated encephalomyelitis. Int J Neuroradiol 3:21, 1997 5. Schwaz S, Mohar A, Knanth M, et al: Acute disseminated encephalomyelitis: a follow-up study of 40 patients. Neurology 56:1383, 2001 6. Kim SC, Jang HJ, Han DJ: Acute disseminated encephalomyelitis after renal transplantation in patients with positive Epstein-Barr virus antibody. Transplant Proc 30:3139, 1998 7. Lindzen E, Gilani A, Markovic-Plese S, et al: Acute disseminated encephalomyelitis after liver transplant. Arch Neurol 6:650, 2005 8. Singh S, Alexander M, Korah IP: Acute disseminated encephalomyelitis: MR imaging features AJR. Am J Roentgenol 173:1101, 1999 9. Caldemeyer KS, Smith RR, Harris TM, et al: MRI in acute disseminated encephalomyelitis. Neuroradiology 36:216, 1994 10. Rust RS, Dodson D, Prensky A, et al: Classification and outcome of acute disseminated encephalomyelitis. Ann Neurol 42:491, 1997 11. Kanter DS, Horensky D, Sperling RA, et al: Plasmapheresis in fulminant acute disseminated encephalomyelitis. Neurology 45:824, 1995 12. Pradhan S, Gupta RP, Shashank S: Intravenous immunoglobulin therapy in acute disseminated encephalomyelitis. J Neurol Sci 165:56, 1999