Original Paper
Cerebral pathology post heart transplantation S. Van Peteghem, M. De Pauw Department of Cardiology, University Hospital Ghent, Ghent, Belgium Cerebral pathology is frequently encountered post heart transplantation with a cumulative incidence of about 80% after 15 years. A broad spectrum of disease entities is reported, from minor abnormalities to lifethreatening diseases. Although cerebral infections and malignancies are rare in this patient population, they have a high mortality rate. Since 1991, 171 orthotopic heart transplantations were performed at the Ghent University Hospital with a 10-year survival rate of 75%. Severe cerebral complications occurred in 10 patients, with epilepsy in 2 patients, cerebrovascular accidents in 4 patients, cerebral infections in 3 patients and a cerebral malignancy in 1 patient, resulting in a fatal outcome in 7 patients. We present four of these cases. Keywords: Heart transplantation, Mortality, Cerebral infection, Post-transplant lymphoproliferative disorder
Introduction The first heart transplantation was performed in 1967. Since then it has become a treatment option in selected patients with end-stage heart failure. Recent epidemiological data show that one-year survival is between 81 and 84% and 10-year survival for the most recent available era (1992–2001) is 52%.1 Outcome has improved over time mainly because of better immune suppression therapy and more intensive screening for complications including allograft rejection, infection, malignancy and renal dysfunction. Today standard maintenance therapy post heart transplant includes a combination of immunosuppressants with a calcineurin inhibitor (tacrolimus/ cyclosporine), an antimetabolite (mycophenolate mofetil) and a corticosteroid. The highest dose is given during the first year to prevent allograft rejection. Corticosteroids are tapered and preferably stopped during the first year because of their side effects.1 In a recent published registry the major causes of death in the first three years post heart transplant include graft failure (30%), non-CMV infections (18%) and acute rejection (11%). Beyond three years malignancy (22%), cardiac allograft vasculopathy (10%) and renal failure (6%) become more important.1 This emphasizes the importance of screening programmes in transplant populations to detect and treat complications such as infection or malignancy at an early stage. In most centers a prophylactic scheme is used during the first 6 to 12 months to prevent infection with Cytomegalovirus,
Pneumocystis jiroveci, Herpes simplex virus and Candida.2 Cerebral pathology is frequently encountered in heart transplant patients with a cumulative incidence of about 80% after 15 years. It is associated with a significant morbidity and mortality post-transplant.3 In the early post-transplant period neurologic complications including delirium or encephalopathy, diseases of the peripheral nerves and muscles and cerebrovascular disorders are reported.3 Seizures can occur and are mainly associated with drug-induced posterior reversible leukoencephalopathy syndrome and cortical ischemic stroke.4 After this period neurologic complications including depression, pain, sleeping disorders, polyneuropathy and cerebrovascular disorders become more prevalent.3 Although cerebral infections and malignancies are rare in this patient population, they have a high mortality rate. In case of clinical suspicion a diagnostic work up should minimally include a brain MRI and lumbar puncture. A brain biopsy should also be considered at an early stage in spite of the high procedure-related morbidity and mortality.2 Since 1991, 171 orthotopic heart transplantations were performed at the Ghent University Hospital with a 10-year survival rate of 75%. Severe cerebral complications occurred in 10 patients, with epilepsy in 2 patients, cerebrovascular accidents in 4 patients, cerebral infections in 3 patients and a cerebral malignancy in 1 patient, resulting in a fatal outcome in 7 patients. In the following section, we present four of these cases.
Case Series Cerebral infection Correspondence to: Sylvie Van Peteghem, Department of Cardiology, University Hospital Gent, De Pintelaan 185 B-9000, Ghent, Belgium. Email: [email protected]
112
ß Acta Clinica Belgica 2015 DOI 10.1179/2295333714Y.0000000082
Approximately 3% of patients develop a cerebral infection during the first 4 years post-transplant,
Acta Clinica Belgica
2015
VOL.
70
NO.
2
Van Peteghem and De Pauw
Cerebral pathology post heart transplantation
Figure 1 Brain MRI images of the four cases (case 1: T1 weighted image, case 2: T2 weighted image, case 3: T2 weighted image, case 4: T2 weighted image)
mainly cryptococcal meningitis, progressive multifocal leukoencephalopathy, varicella zoster virus encephalitis and cerebral aspergillosis. Early diagnosis is often difficult because of the vague presenting symptoms and non-specific abnormalities on physical examination. Lab examination consists of multiple blood cultures and tissue culture if possible. Analysis of cerebrospinal fluid (CSF) generally shows no leukocytosis and in nearly all cases an elevated protein count. A brain MRI with contrast media is the imaging modality of choice. If inconclusive, a brain biopsy with anatomopathological examination and molecular diagnostics should be performed to acquire a definite diagnosis. Antibiotic therapy is dependent on the causative organism and needs to be given on long term.2 Case 1: Rodococcus equi brain abscess A 62-year-old patient received a heart transplant in 1994 because of rhythm disturbances with a redo transplant in 1997 because of chronic rejection. One year before admission he was treated with antibiotics during 10 months because of an atypical pneumonia caused by Rodococcus equi. This organism had been found in bile cultures after an ERCP for cholecystitis.
In 2008 he was admitted to hospital with generalized tremor, clonus and memory disturbances. On admission he received therapy with mycophenolate mofetil 500 mg trice daily, cyclosporine 75 mg twice daily and prednisolon 4 mg in alternate-day schedule. A brain MRI with gadolinium contrast showed a large lesion in the right cerebellum with perilesional edema and several focal to miliary lesions in both hemispheres with contrast enhancement (Fig. 1, upper left panel). Analysis of CSF showed no leukocytosis (,5/ml) and an elevated protein level of 96.5 mg/dl; cultures were negative. Since his medical history of pulmonary and extrapulmonary infection with R. equi, the lesions were suspected to be brain abscesses caused by this organism and broadspectrum antibiotic therapy consisting of meropenem/linezolid/rifampicin was started. R. equi is an opportunistic pathogen known to cause atypical pneumonia, mainly in immunosuppressed patients. It is a gram-positive bacterium which is easily grown but often overlooked at as a contaminant. Via hematogenous spread it causes cerebral infection. Cerebral lesions, mainly brain
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Cerebral pathology post heart transplantation
abscesses or meningitis, usually become visible a few weeks up to two years after the initial antibiotic therapy for pneumonia was stopped. Hence it can be considered in some patients to continue prophylactic antibiotic therapy after initial treatment.5 Despite the broad-spectrum antibiotic therapy our patient died 2 months after admission. Autopsy showed presence of several supratentorial abscesses, without demonstration of a causative organism. Case 2: Nocardia brain abscess A 62-year-old patient received a heart transplant in 2012 because of ischemic cardiomyopathy. Four months post-transplant he was admitted to hospital with a left hemiparesis and coordination problems. On admission he received therapy with mycophenolate mofetil 500 mg twice daily, tacrolimus 0.5 mg twice daily and methylprednisolon 6 mg once daily. He also received prophylactic therapy with valgancyclovir 450 mg once daily. A brain MRI with gadolinium contrast showed a rolandic lesion with contrast enhancement and minor perilesional edema (Fig. 1, upper right panel). Analysis of CSF showed no leukocytosis (,5/ml) and an elevated protein count of 73.8 mg/dl; cultures were negative. A brain biopsy was performed with positive culture for Nocardia asteroides and antibiotic treatment with amoxicillin/clavulanic acid and trimethoprim–sulfamethoxazole was started during 12 months. Corticosteroid therapy was further tapered and stopped. Nocardia (asteroides) is an opportunistic pathogen known to cause infection in 2.5% of heart transplant patients during the first year, usually a pulmonary infection with several irregular nodules. Via hematogenous spread it causes extrapulmonary disease in about half of cases with cerebral infection, mostly parenchymal brain abscesses and rarely meningitis, in about one third. Nocardia is a gram-positive bacterium which slowly grows on culture media. In case of cerebral nocardiosis a combination antibiotic therapy, usually imipenem/amikacin or imipenem/amikacin/trimethoprim–sulfamethoxazole, is started. Duration of initial therapy is 9 to 12 months, under guidance of follow-up MRI. It can be considered to maintain prophylactic therapy with trimethoprim–sulfamethoxazole in high dose or doxycycline after initial treatment. Nevertheless there is a high mortality rate of 30 to 55%.6 Our patient was treated successfully with no severe sequelae except for gait disturbances. He remains in follow-up with 6-monthly surveillance brain MRI. Case 3: Progressive multifocal leukoencephalopathy A 40-year-old patient received a heart transplant in 1996 because of idiopathic congestive cardiomyopathy with a redo transplant in 2008 because of rapidly progressive cardiac allograft vasculopathy.
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He was admitted to hospital 5 months after the second transplant with ataxia and weakness. On admission he received therapy with mycophenolate mofetil 1 g twice daily, everolimus 0.75 mg twice daily and methylprednisolon 6 mg once daily. Analysis of CSF showed no leukocytosis (,5/ml) and a normal protein count of 36.7 mg/dl; cultures were negative. A brain MRI showed a single nodular lesion in the left cerebellum, with differential diagnosis of cerebrovascular infarction, local encephalitis, lymphoma or glioma (Fig. 1, lower left panel). A cerebral angiography was normal so a recent stroke could be excluded. A brain biopsy was performed with documentation of JC-virus DNA, which is pathognomonic for progressive multifocal leukoencephalopathy. Progressive multifocal leukoencephalopathy, also known as PML, is a multifocal white-matter demyelination disease typically located in the periventricular and subcortical regions of the brain with sparing of the spinal cord and optic nerves. It is caused by a reactivation of JC-polyoma virus in immunosuppressed patients. In heart/lung transplant patients the incidence rate is about 1.2 cases per 1000 posttransplantation years. Patients usually present with subacute development of neurologic deficits and seizures in 18%. Typically a brain MRI shows multifocal white-matter lesions with no restriction to a vascular territory and without a mass effect or contrast enhancement. However, other radiological patterns have been described. Diagnosis of PML is made when JC-virus DNA is found via PCR on spinal fluid (first choice) or brain biopsy specimen. The latter has a moderate high sensitivity of 64 to 96% and a high specificity of 100%. When looking at other causes mainly cerebrovascular accidents or brain tumors should be excluded in the transplant population. Partially this is possible via neuroimaging since PML is in theory a multifocal process which is not limited to one vascular area (in contrast to cerebrovascular accidents) and no mass effect or contrast enhancement (in contrast tot cerebrovascular accidents or tumors). A specific antiviral treatment is not available. Treatment usually consists of administration of cytarabin or mirtazapin. If possible the dose of the immunosuppressants should be reduced. Despite this, PML has a high mortality rate with a median survival rate of approximately 3 months.7 Our patient died shortly after diagnosis.
Cerebral malignancy Approximately 28% of patients develop a malignancy post heart transplant, with a 10-year incidence of skin cancer in 20% and lymphoproliferative malignancy in 2%. Main risk factors include redo transplantation, rejection before initial discharge, high dose of immune suppression, higher recipient age, longer
Van Peteghem and De Pauw
allograft ischemic time and lower center volume of transplantation.1 Post-transplant lymphoproliferative disorder, known as PTLD, is a rare complication after heart transplant. Early diagnosis is difficult because of the subacute development of symptoms and patients often present with lymphoma in an advanced stage. In 80 to 85% of cases there is an association with Ebstein Barr virus primary infection or reactivation. Involvement of the central nervous system, usually a primary diffuse large Bcell lymphoma, is rare.8 A brain MRI is the imaging modality of choice and a brain biopsy can give the anatomopathological diagnosis. PTLD can be treated with chemotherapy, rituximab, radiation therapy or surgery. If possible the dose or combination of immunosuppression should be altered, since there is evidence that some, like mTOR-inhibitors or mycophenolate mofetil, carry a lower risk of malignancy. However PTLD generally have a poor prognosis in case of CNS-involvement.9 Case 4: Post-transplant lymphoproliferative disorder A 51-year-old patient received a heart transplant in 1998 because of end-stage heart failure due to a congenital heart disease. In 2007 he was admitted to hospital with a rapidly progressive right hemiparesis. On admission he received therapy with mycophenolate mofetil 500 mg twice daily, everolimus 0.25 mg twice daily and methylprednisolon 6 mg once daily. A brain MRI showed a large mass with edema above the left intracerebral ventricle with an abnormal protein count in several parts of the cerebrospinal fluid (Fig. 1, lower right panel). On brain biopsy there were no signs of infection or malignancy. Initially he was treated with antibiotics because of a tentative diagnosis of cerebral nocardiosis, with association of high-dose IV corticosteroid therapy because of edema. A followup MRI after 4 weeks showed regression of the lesions (possibly corticosteroid effect). A new biopsy was performed without signs of infection or malignancy. A follow-up MRI 8 weeks hereafter showed progression of the first lesion and development of a second lesion located on the right temporoparietal side. The second lesion was resected neurosurgically and diagnosis of a large EBV-positive, B-cell non-Hodgkin lymphoma was made. In literature a combination therapy with high-dose methotrexate and rituximab, when EBVpositive, is the treatment of choice.8 Because of the poor performance status of our patient it was decided to start radiation monotherapy, but the patient died before finishing this therapy.
Cerebral pathology post heart transplantation
Conclusion Cerebral pathology occurs frequently post heart transplantation. A heterogeneous spectrum of diseases is reported in literature from minor abnormalities to life-threatening diseases, like cerebral infection or malignancy. Diagnosis is often difficult due to the vague presenting symptoms and nonspecific findings on physical examination. Whenever a cerebral problem such as an infection or a malignancy is clinically suspected a diagnostic work up with brain MRI with contrast media and lumbar puncture with analysis of the CSF should be performed. Furthermore a brain biopsy is often necessary in these patients. Treatment options are classic treatment with antibiotics in case of infection and chemotherapy/immunotherapy, radiation therapy or sometimes surgery in case of malignancy. Whenever possible the immune suppressant therapy should also be reduced or adjusted. However, in contrast to liver or kidney transplant patients the option of stopping immunosuppressants is not possible since the associated risk of rejection of the organ leading to death in heart transplant patients. In general the prognosis of cerebral infections and cerebral malignancy after heart transplantation is poor as illustrated in this case series.
References 1 Lund LH, Edwards LB, Kucheryavaya AY, Dipchand AI, Benden C, Christie JD, et al. The registry of the international society for heart and lung transplantation: thirtieth official adult heart transplant report – 2013: focus theme: age. J Heart Lung Transplant. 2013;32:951–64. 2 Van de Beek D, Patel R, Daly RC, McGregor CG, Wijdicks EF. Central nervous system infections in heart transplant patients. Arch Neurol. 2007;64:1715–20. 3 Van de Beek D, Kremers W, Daly RC, Edwards BS, Clavell AL, McGregor CGA, et al. Effect of neurologic complications on outcome after heart transplant. Arch Neurol. 2008;65(2):226–31. 4 Navarro V, Varnous S, Galanaud D, Vaissier E, Granger B, Gandjbakhch I, et al. Incidence and risk factors for seizures after heart transplantation. J Neurol. 2010;257(4):563–8. 5 Verville TD, Huycke MM, Greenfield RA, Fine DP, Kuhls TL, Slater L. Rodococcus equi infection of humans. 12 cases and review of the literature. Medicine (Baltimore). 1994;73:119–32. 6 Clark NM, Reid GE, AST Infectious Diseases Community of Practice. Nocardia infections in solid organ transplantion. Am J Transplant. 2013;13(4):83–92. 7 Mateen FJ, Muralidharan R, Carone M, van de Beek D, Harrison DM, Aksamit AJ, et al. Progressive multifocal leukoencefalopathy in transplant recipients. Ann Neurol. 2011;70:305–22. 8 Dierickx D, Tousseyn T, Sagaert X, Fieuws S, Wlodarska I, Morscio J, et al. Single-center analysis of biopsy-confirmed posttransplant lymphoproliferative disorder: incidence, clinicopathological characteristics and prognostic factors. Leuk Lymhoma. 2013;54(11):2433–40. 9 Ghobrial IM, Habermann TM, Maurer MJ, Geyer SM, Ristow KM, Larson TS, et al. Prognostic analysis for survival in adult solid organ transplant recipients with post-transplantation lymphoproliferative disorders. J Clin Oncol. 2005;23:7574–82.
Acta Clinica Belgica
2015
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2
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Cerebral pathology post heart transplantation S. Van Peteghem, M. De Pauw Department of Cardiology, University Hospital Ghent, Ghent, Belgium Cerebral pathology is frequently encountered post heart transplantation with a cumulative incidence of about 80% after 15 years. A broad spectrum of disease entities is reported, from minor abnormalities to lifethreatening diseases. Although cerebral infections and malignancies are rare in this patient population, they have a high mortality rate. Since 1991, 171 orthotopic heart transplantations were performed at the Ghent University Hospital with a 10-year survival rate of 75%. Severe cerebral complications occurred in 10 patients, with epilepsy in 2 patients, cerebrovascular accidents in 4 patients, cerebral infections in 3 patients and a cerebral malignancy in 1 patient, resulting in a fatal outcome in 7 patients. We present four of these cases. Keywords: Heart transplantation, Mortality, Cerebral infection, Post-transplant lymphoproliferative disorder
Introduction The first heart transplantation was performed in 1967. Since then it has become a treatment option in selected patients with end-stage heart failure. Recent epidemiological data show that one-year survival is between 81 and 84% and 10-year survival for the most recent available era (1992–2001) is 52%.1 Outcome has improved over time mainly because of better immune suppression therapy and more intensive screening for complications including allograft rejection, infection, malignancy and renal dysfunction. Today standard maintenance therapy post heart transplant includes a combination of immunosuppressants with a calcineurin inhibitor (tacrolimus/ cyclosporine), an antimetabolite (mycophenolate mofetil) and a corticosteroid. The highest dose is given during the first year to prevent allograft rejection. Corticosteroids are tapered and preferably stopped during the first year because of their side effects.1 In a recent published registry the major causes of death in the first three years post heart transplant include graft failure (30%), non-CMV infections (18%) and acute rejection (11%). Beyond three years malignancy (22%), cardiac allograft vasculopathy (10%) and renal failure (6%) become more important.1 This emphasizes the importance of screening programmes in transplant populations to detect and treat complications such as infection or malignancy at an early stage. In most centers a prophylactic scheme is used during the first 6 to 12 months to prevent infection with Cytomegalovirus,
Pneumocystis jiroveci, Herpes simplex virus and Candida.2 Cerebral pathology is frequently encountered in heart transplant patients with a cumulative incidence of about 80% after 15 years. It is associated with a significant morbidity and mortality post-transplant.3 In the early post-transplant period neurologic complications including delirium or encephalopathy, diseases of the peripheral nerves and muscles and cerebrovascular disorders are reported.3 Seizures can occur and are mainly associated with drug-induced posterior reversible leukoencephalopathy syndrome and cortical ischemic stroke.4 After this period neurologic complications including depression, pain, sleeping disorders, polyneuropathy and cerebrovascular disorders become more prevalent.3 Although cerebral infections and malignancies are rare in this patient population, they have a high mortality rate. In case of clinical suspicion a diagnostic work up should minimally include a brain MRI and lumbar puncture. A brain biopsy should also be considered at an early stage in spite of the high procedure-related morbidity and mortality.2 Since 1991, 171 orthotopic heart transplantations were performed at the Ghent University Hospital with a 10-year survival rate of 75%. Severe cerebral complications occurred in 10 patients, with epilepsy in 2 patients, cerebrovascular accidents in 4 patients, cerebral infections in 3 patients and a cerebral malignancy in 1 patient, resulting in a fatal outcome in 7 patients. In the following section, we present four of these cases.
Case Series Cerebral infection Correspondence to: Sylvie Van Peteghem, Department of Cardiology, University Hospital Gent, De Pintelaan 185 B-9000, Ghent, Belgium. Email: [email protected]
112
ß Acta Clinica Belgica 2015 DOI 10.1179/2295333714Y.0000000082
Approximately 3% of patients develop a cerebral infection during the first 4 years post-transplant,
Acta Clinica Belgica
2015
VOL.
70
NO.
2
Van Peteghem and De Pauw
Cerebral pathology post heart transplantation
Figure 1 Brain MRI images of the four cases (case 1: T1 weighted image, case 2: T2 weighted image, case 3: T2 weighted image, case 4: T2 weighted image)
mainly cryptococcal meningitis, progressive multifocal leukoencephalopathy, varicella zoster virus encephalitis and cerebral aspergillosis. Early diagnosis is often difficult because of the vague presenting symptoms and non-specific abnormalities on physical examination. Lab examination consists of multiple blood cultures and tissue culture if possible. Analysis of cerebrospinal fluid (CSF) generally shows no leukocytosis and in nearly all cases an elevated protein count. A brain MRI with contrast media is the imaging modality of choice. If inconclusive, a brain biopsy with anatomopathological examination and molecular diagnostics should be performed to acquire a definite diagnosis. Antibiotic therapy is dependent on the causative organism and needs to be given on long term.2 Case 1: Rodococcus equi brain abscess A 62-year-old patient received a heart transplant in 1994 because of rhythm disturbances with a redo transplant in 1997 because of chronic rejection. One year before admission he was treated with antibiotics during 10 months because of an atypical pneumonia caused by Rodococcus equi. This organism had been found in bile cultures after an ERCP for cholecystitis.
In 2008 he was admitted to hospital with generalized tremor, clonus and memory disturbances. On admission he received therapy with mycophenolate mofetil 500 mg trice daily, cyclosporine 75 mg twice daily and prednisolon 4 mg in alternate-day schedule. A brain MRI with gadolinium contrast showed a large lesion in the right cerebellum with perilesional edema and several focal to miliary lesions in both hemispheres with contrast enhancement (Fig. 1, upper left panel). Analysis of CSF showed no leukocytosis (,5/ml) and an elevated protein level of 96.5 mg/dl; cultures were negative. Since his medical history of pulmonary and extrapulmonary infection with R. equi, the lesions were suspected to be brain abscesses caused by this organism and broadspectrum antibiotic therapy consisting of meropenem/linezolid/rifampicin was started. R. equi is an opportunistic pathogen known to cause atypical pneumonia, mainly in immunosuppressed patients. It is a gram-positive bacterium which is easily grown but often overlooked at as a contaminant. Via hematogenous spread it causes cerebral infection. Cerebral lesions, mainly brain
Acta Clinica Belgica
2015
VOL .
70
NO .
2
113
Van Peteghem and De Pauw
Cerebral pathology post heart transplantation
abscesses or meningitis, usually become visible a few weeks up to two years after the initial antibiotic therapy for pneumonia was stopped. Hence it can be considered in some patients to continue prophylactic antibiotic therapy after initial treatment.5 Despite the broad-spectrum antibiotic therapy our patient died 2 months after admission. Autopsy showed presence of several supratentorial abscesses, without demonstration of a causative organism. Case 2: Nocardia brain abscess A 62-year-old patient received a heart transplant in 2012 because of ischemic cardiomyopathy. Four months post-transplant he was admitted to hospital with a left hemiparesis and coordination problems. On admission he received therapy with mycophenolate mofetil 500 mg twice daily, tacrolimus 0.5 mg twice daily and methylprednisolon 6 mg once daily. He also received prophylactic therapy with valgancyclovir 450 mg once daily. A brain MRI with gadolinium contrast showed a rolandic lesion with contrast enhancement and minor perilesional edema (Fig. 1, upper right panel). Analysis of CSF showed no leukocytosis (,5/ml) and an elevated protein count of 73.8 mg/dl; cultures were negative. A brain biopsy was performed with positive culture for Nocardia asteroides and antibiotic treatment with amoxicillin/clavulanic acid and trimethoprim–sulfamethoxazole was started during 12 months. Corticosteroid therapy was further tapered and stopped. Nocardia (asteroides) is an opportunistic pathogen known to cause infection in 2.5% of heart transplant patients during the first year, usually a pulmonary infection with several irregular nodules. Via hematogenous spread it causes extrapulmonary disease in about half of cases with cerebral infection, mostly parenchymal brain abscesses and rarely meningitis, in about one third. Nocardia is a gram-positive bacterium which slowly grows on culture media. In case of cerebral nocardiosis a combination antibiotic therapy, usually imipenem/amikacin or imipenem/amikacin/trimethoprim–sulfamethoxazole, is started. Duration of initial therapy is 9 to 12 months, under guidance of follow-up MRI. It can be considered to maintain prophylactic therapy with trimethoprim–sulfamethoxazole in high dose or doxycycline after initial treatment. Nevertheless there is a high mortality rate of 30 to 55%.6 Our patient was treated successfully with no severe sequelae except for gait disturbances. He remains in follow-up with 6-monthly surveillance brain MRI. Case 3: Progressive multifocal leukoencephalopathy A 40-year-old patient received a heart transplant in 1996 because of idiopathic congestive cardiomyopathy with a redo transplant in 2008 because of rapidly progressive cardiac allograft vasculopathy.
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He was admitted to hospital 5 months after the second transplant with ataxia and weakness. On admission he received therapy with mycophenolate mofetil 1 g twice daily, everolimus 0.75 mg twice daily and methylprednisolon 6 mg once daily. Analysis of CSF showed no leukocytosis (,5/ml) and a normal protein count of 36.7 mg/dl; cultures were negative. A brain MRI showed a single nodular lesion in the left cerebellum, with differential diagnosis of cerebrovascular infarction, local encephalitis, lymphoma or glioma (Fig. 1, lower left panel). A cerebral angiography was normal so a recent stroke could be excluded. A brain biopsy was performed with documentation of JC-virus DNA, which is pathognomonic for progressive multifocal leukoencephalopathy. Progressive multifocal leukoencephalopathy, also known as PML, is a multifocal white-matter demyelination disease typically located in the periventricular and subcortical regions of the brain with sparing of the spinal cord and optic nerves. It is caused by a reactivation of JC-polyoma virus in immunosuppressed patients. In heart/lung transplant patients the incidence rate is about 1.2 cases per 1000 posttransplantation years. Patients usually present with subacute development of neurologic deficits and seizures in 18%. Typically a brain MRI shows multifocal white-matter lesions with no restriction to a vascular territory and without a mass effect or contrast enhancement. However, other radiological patterns have been described. Diagnosis of PML is made when JC-virus DNA is found via PCR on spinal fluid (first choice) or brain biopsy specimen. The latter has a moderate high sensitivity of 64 to 96% and a high specificity of 100%. When looking at other causes mainly cerebrovascular accidents or brain tumors should be excluded in the transplant population. Partially this is possible via neuroimaging since PML is in theory a multifocal process which is not limited to one vascular area (in contrast to cerebrovascular accidents) and no mass effect or contrast enhancement (in contrast tot cerebrovascular accidents or tumors). A specific antiviral treatment is not available. Treatment usually consists of administration of cytarabin or mirtazapin. If possible the dose of the immunosuppressants should be reduced. Despite this, PML has a high mortality rate with a median survival rate of approximately 3 months.7 Our patient died shortly after diagnosis.
Cerebral malignancy Approximately 28% of patients develop a malignancy post heart transplant, with a 10-year incidence of skin cancer in 20% and lymphoproliferative malignancy in 2%. Main risk factors include redo transplantation, rejection before initial discharge, high dose of immune suppression, higher recipient age, longer
Van Peteghem and De Pauw
allograft ischemic time and lower center volume of transplantation.1 Post-transplant lymphoproliferative disorder, known as PTLD, is a rare complication after heart transplant. Early diagnosis is difficult because of the subacute development of symptoms and patients often present with lymphoma in an advanced stage. In 80 to 85% of cases there is an association with Ebstein Barr virus primary infection or reactivation. Involvement of the central nervous system, usually a primary diffuse large Bcell lymphoma, is rare.8 A brain MRI is the imaging modality of choice and a brain biopsy can give the anatomopathological diagnosis. PTLD can be treated with chemotherapy, rituximab, radiation therapy or surgery. If possible the dose or combination of immunosuppression should be altered, since there is evidence that some, like mTOR-inhibitors or mycophenolate mofetil, carry a lower risk of malignancy. However PTLD generally have a poor prognosis in case of CNS-involvement.9 Case 4: Post-transplant lymphoproliferative disorder A 51-year-old patient received a heart transplant in 1998 because of end-stage heart failure due to a congenital heart disease. In 2007 he was admitted to hospital with a rapidly progressive right hemiparesis. On admission he received therapy with mycophenolate mofetil 500 mg twice daily, everolimus 0.25 mg twice daily and methylprednisolon 6 mg once daily. A brain MRI showed a large mass with edema above the left intracerebral ventricle with an abnormal protein count in several parts of the cerebrospinal fluid (Fig. 1, lower right panel). On brain biopsy there were no signs of infection or malignancy. Initially he was treated with antibiotics because of a tentative diagnosis of cerebral nocardiosis, with association of high-dose IV corticosteroid therapy because of edema. A followup MRI after 4 weeks showed regression of the lesions (possibly corticosteroid effect). A new biopsy was performed without signs of infection or malignancy. A follow-up MRI 8 weeks hereafter showed progression of the first lesion and development of a second lesion located on the right temporoparietal side. The second lesion was resected neurosurgically and diagnosis of a large EBV-positive, B-cell non-Hodgkin lymphoma was made. In literature a combination therapy with high-dose methotrexate and rituximab, when EBVpositive, is the treatment of choice.8 Because of the poor performance status of our patient it was decided to start radiation monotherapy, but the patient died before finishing this therapy.
Cerebral pathology post heart transplantation
Conclusion Cerebral pathology occurs frequently post heart transplantation. A heterogeneous spectrum of diseases is reported in literature from minor abnormalities to life-threatening diseases, like cerebral infection or malignancy. Diagnosis is often difficult due to the vague presenting symptoms and nonspecific findings on physical examination. Whenever a cerebral problem such as an infection or a malignancy is clinically suspected a diagnostic work up with brain MRI with contrast media and lumbar puncture with analysis of the CSF should be performed. Furthermore a brain biopsy is often necessary in these patients. Treatment options are classic treatment with antibiotics in case of infection and chemotherapy/immunotherapy, radiation therapy or sometimes surgery in case of malignancy. Whenever possible the immune suppressant therapy should also be reduced or adjusted. However, in contrast to liver or kidney transplant patients the option of stopping immunosuppressants is not possible since the associated risk of rejection of the organ leading to death in heart transplant patients. In general the prognosis of cerebral infections and cerebral malignancy after heart transplantation is poor as illustrated in this case series.
References 1 Lund LH, Edwards LB, Kucheryavaya AY, Dipchand AI, Benden C, Christie JD, et al. The registry of the international society for heart and lung transplantation: thirtieth official adult heart transplant report – 2013: focus theme: age. J Heart Lung Transplant. 2013;32:951–64. 2 Van de Beek D, Patel R, Daly RC, McGregor CG, Wijdicks EF. Central nervous system infections in heart transplant patients. Arch Neurol. 2007;64:1715–20. 3 Van de Beek D, Kremers W, Daly RC, Edwards BS, Clavell AL, McGregor CGA, et al. Effect of neurologic complications on outcome after heart transplant. Arch Neurol. 2008;65(2):226–31. 4 Navarro V, Varnous S, Galanaud D, Vaissier E, Granger B, Gandjbakhch I, et al. Incidence and risk factors for seizures after heart transplantation. J Neurol. 2010;257(4):563–8. 5 Verville TD, Huycke MM, Greenfield RA, Fine DP, Kuhls TL, Slater L. Rodococcus equi infection of humans. 12 cases and review of the literature. Medicine (Baltimore). 1994;73:119–32. 6 Clark NM, Reid GE, AST Infectious Diseases Community of Practice. Nocardia infections in solid organ transplantion. Am J Transplant. 2013;13(4):83–92. 7 Mateen FJ, Muralidharan R, Carone M, van de Beek D, Harrison DM, Aksamit AJ, et al. Progressive multifocal leukoencefalopathy in transplant recipients. Ann Neurol. 2011;70:305–22. 8 Dierickx D, Tousseyn T, Sagaert X, Fieuws S, Wlodarska I, Morscio J, et al. Single-center analysis of biopsy-confirmed posttransplant lymphoproliferative disorder: incidence, clinicopathological characteristics and prognostic factors. Leuk Lymhoma. 2013;54(11):2433–40. 9 Ghobrial IM, Habermann TM, Maurer MJ, Geyer SM, Ristow KM, Larson TS, et al. Prognostic analysis for survival in adult solid organ transplant recipients with post-transplantation lymphoproliferative disorders. J Clin Oncol. 2005;23:7574–82.
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