Handbook of Clinical Neurology, Vol. 121 (3rd series) Neurologic Aspects of Systemic Disease Part III Jose Biller and Jose M. Ferro, Editors © 2014 Elsevier B.V. All rights reserved
Chapter 82
Neurologic aspects of heart transplantation 1
ALAIN HEROUX1* AND SALPY V. PAMBOUKIAN2 Heart Failure and Heart Transplant Program, Loyola University Medical Center, Maywood, IL, USA
2
Section of Advanced Heart Failure, Cardiac Transplant, Mechanical Circulatory Support and Pulmonary Vascular Disease, University of Alabama at Birmingham, Birmingham, AL, USA
INTRODUCTION Approximately 5 million Americans have heart failure, with National Hospital Discharge Survey data from 1979 to 2004 indicating that the number of hospitalizations with any mention of heart failure tripled from 1 274 000 in 1979 to 3 860 000 in 2004 (Roger, 2010). Currently, heart transplantation remains the best longterm therapy for patients with end-stage heart failure who have failed conventional medical therapies. However, due to organ shortages and other factors, heart transplant rates have remained static. In 2008, approximately 2000 heart transplants were performed in the US (Wolfe et al., 2010). Therefore, the appropriate selection of patients with the best chance of survival after cardiac transplantation is an important part in the allocation of this limited resource. The neurologic evaluation of the potential transplant recipient includes evaluation by a multidisciplinary team including the transplant cardiologist, neurologist, and neurosurgeon. The presence and severity of concomitant neurologic conditions must be defined in order to determine if outcome after cardiac transplant would be adversely affected, making cardiac transplantation ill advised.
PREOPERATIVE EVALUATION OF NEUROLOGIC DISEASE Central neurologic disease A detailed history regarding possible previous neurologic events, such as stroke or transient ischemic attack (TIA), or concomitant diseases that can have central manifestations should be obtained. Examples of diseases that have central nervous system manifestations and could impact on post-transplant survival would
include vascular diseases, connective tissue diseases, dementias, multiple sclerosis, sarcoidosis, and amyloidosis. In conjunction with a detailed history, thorough physical examination should be performed. After history and physical examination have been performed, imaging studies should follow. Because many, if not all, endstage heart failure patients have implantable cardiac defibrillators and/or pacing devices, magnetic resonance imaging (MRI) may not be feasible as many consider these devices a contraindication. (Farling et al., 2010) Therefore, unenhanced and/or enhanced head computed tomography (CT) should be obtained. Patients who have had previous stroke, age > 40, or who are at risk of vascular disease (for example, those with known coronary artery disease or diabetes), should have carotid artery imaging. If an abnormality is found, it is important to assess the extent of disease burden. In general, dementias, systemic diseases limiting survival, or systemic diseases exacerbated by immunosuppressive therapy post-transplant are considered contraindications to cardiac transplantation. Previous stroke is not an absolute contraindication to cardiac transplantation, unless there are significant neurologic sequelae and late effects. Patients with significant cognitive impairment and limited potential for cardiac rehabilitation are not considered appropriate for transplant in most centers. The presence of high-grade, asymptomatic, focal carotid artery disease may not preclude cardiac transplantation, but may require revascularization, either with carotid endarterectomy, or alternatively stenting, depending on the patient’s clinical condition (Hertzer, 2010). In contrast, diffuse disease may progress post-transplant in the presence of steroid therapy, drug-induced diabetes, hypertension, and dyslipidemia, and may render cardiac transplant ill advised.
*Correspondence to: Alain Heroux, M.D., Professor, Heart Failure/Heart Transplant Program, Loyola University Medical Center, 2160 South First Avenue, Maywood, IL 60153, USA. E-mail: [email protected]
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Peripheral nervous system disease As above, a detailed history and physical examination assessing for the presence of peripheral nervous system disease should be performed at the time of heart transplant evaluation. Systemic diseases with peripheral nervous system manifestations that would preclude long-term survival post-transplant or interfere with rehabilitation would be considered contraindications to heart transplant. Many patients with diabetes mellitus and concomitant heart disease are referred for heart transplant evaluation, therefore peripheral neuropathy as a complication of diabetes is the most commonly encountered peripheral neurologic disorder in this population. Patients with uncomplicated diabetes have been shown to do well after cardiac transplantation although they may be at increased risk of infections (Marelli et al., 2003; Russo et al., 2006). However, in one large study of over 20 000 heart transplant recipients transplanted between 1995 and 2005, patients with increased severity of diabetes characterized by the presence of obesity (BMI 35 kg/m2), previous stroke, renal insufficiency (creatinine 2.5 mg/dL) or peripheral vascular disease had lower median survival post-transplant, with decreasing survival for each diabetes-related complication present (Russo et al., 2006). Those without diabetes had a median survival of 10.1 years versus 3.6 years for those with two or more diabetic-related complications (Russo et al., 2006). Traditionally, individuals with peripheral neuropathy as a complication of diabetes have been declined heart transplantation, and therefore excluded from published series. However, extrapolating from published data, the presence of peripheral neuropathy (characterized by nerve conduction study) as a marker of worse disease severity would need to be carefully considered along with other disease indicators to determine suitability for cardiac transplantation.
POSTOPERATIVE NEUROLOGIC COMPLICATIONS Central Perioperative cerebrovascular complications are more common after cardiac transplantation compared to routine cardiac surgery such as coronary artery bypass grafting (van de Beek et al., 2008). Rates range from 4% to 42% (Andrews et al., 1990; Jarquin-Valdivia et al., 1999; Malheiros et al., 2002; Perez-Miralles et al., 2005; van de Beek et al., 2008). Ischemic stroke is the most common cerebrovascular complication (Perez-Miralles et al., 2005; van de Beek et al., 2008) and may result from anoxic-hypoperfusion events resulting in watershed infarcts. Other cerebrovascular complications include hemorrhagic stroke,
encephalopathy, and TIA. Early perioperative hemorrhagic stroke may occur in the setting of pretransplant low cardiac output followed by post-transplant relative hyperperfusion associated with disordered cerebral autoregulatory pressor response (Sila, 1989a; Zivkovic, 2007). Transcranial Doppler ultrasound after heart transplantation shows an increase of velocity of up to 50% or higher (Massaro et al., 2006). Seizures and posterior reversible encephalopathy syndrome (PRES) may occur perioperatively, likely related to the introduction of immunosuppressive agents, specifically calcineurin inhibitors (CNI), in the early postoperative period. Substitution of one CNI for another with close monitoring of drug levels may be necessary. Perioperative stroke is associated with 1 year mortality in contrast to perioperative delirium or encephalopathy, diseases of peripheral nerves and muscles, and seizures, which are not associated with worse outcome (van de Beek et al., 2008). CNS infections are relatively uncommon early posttransplant, but are associated with decreased survival (van de Beek et al., 2008). Imaging studies including head CT (unenhanced or enhanced) should be undertaken, but may be nondiagnostic. MRI can be performed as pacing/defibrillating devices were removed at the time of cardiac transplant; however, it may be limited by the clinical condition and the patient’s ability to lie in the scanner for a prolonged period. The evaluation of possible neurologic complication post-transplant should include expert input from a neurologist familiar with issues related to solid organ transplantation.
Peripheral nervous system complications Postoperative peripheral nervous system complications most commonly include brachial plexopathy, peroneal nerve mononeuropathy, critical illness neuropathy or myopathy, (Adair et al., 1993; Perea et al., 2001; Mateen et al., 2009), and vocal cord paralysis (van de Beek et al., 2008). Although patient survival after transplantation may not be affected by these complications, they do contribute to the morbidity of the procedure and prolong rehabilitation time. With careful patient management and attention to patient positioning and monitoring, most of these complications are avoidable.
LONG-TERM NEUROLOGIC ASPECTS OF HEART TRANSPLANTATION The incidence of neurologic complications following solid organ transplantation is frequent. Approximately one-third of recipients (10–59%) present with neurologic symptoms (van de Beek et al., 2008; Marco et al., 2009). It is most frequently related to side-effects of the immunosuppressive regimen, drug toxicity, and complications
NEUROLOGIC ASPECTS OF HEART TRANSPLANTATION 1231 due to immunosuppression. Symptoms related to the increasing endothelium, with secondary increase of tromimmunosuppressive regimen following heart transplanboxane and decrease in nitric oxide. The drugs may also tation include tremors, seizures, strokes, central nervous cause an impairment of neuronal transmission by (1) system infections, encephalopathy, and tumors (van de decreasing g-aminobutyric acid which can lead to Beek et al., 2008). Risk factors that may enhance neuroincreased seizure activity, (2) decreasing neuronal serotologic complications following heart transplantation nin leading to more susceptibility to depression and include pre-existing conditions such as a prior sroke tremor, and (3) the inhibition of glutaminergic Nand comorbidities such as diabetes, hypertension, and methyl-D-aspartate receptors which could be a possible hypercoagulable states. Neurologic complication is the cause of delirium (Bechstein, 2000). primary cause of death in 20% of transplant recipients The treatment of neurotoxic side-effects related to (Perez-Miralles et al., 2005). calcineurin inhibitors consists of switching from ciclosporin to tacrolimus or vice versa, decreasing the dose of the drugs or switching from mycophenolate mofetil or Current immunosuppression azathioprine to a Thor inhibitor such as evrolimus or The current immunosuppressive regimen in solid organ sirolimus to decrease the level of calcineurin inhibitors. transplantation can be divided into three phases: inducb-Blockers can also be used to decrease tremors. tion, maintenance, and rescue. The induction phase The use of steroids in the induction, maintenance, and occurs at the time of transplantation and consists of rescue phases can cause behavioral disorders such as the use of monoclonal antibodies such as OKT3 and confusion, mood disturbances, manic states, and psydacluzimab or polyclonal antibodies such as antithymochosis. These can be exacerbated by underlying metacyte globulin (ATG). The aim of induction is to prevent bolic abnormalities. Treatment consists of lowering the the early occurrence of acute cellular rejection. It is given dose or stopping intravenous steroids and correcting over the course of a few days while the serum level of the underlying metabolic abnormalities. maintenance immunosuppressive agent can be raised to Monoclonal and polyclonal antibodies used during therapeutic levels to prevent rejection. the induction and rescue phases of immunosuppression Maintenance immunosuppressive regimen consists of: can cause acute aseptic meningitis in 5–10% of patients (1) calcineurin inhibitors such as Cyclosporine and tacroli(Adair et al., 1991; Pittock et al., 2003). These symptoms mus (FK506); (2) mycophenolate mofetil (MMF) and azaare due to proinflammatory cytokine release, due to T thioprine; (3) mTOR (mammalian target of rapamycin) cell lysis with OKT3 and lymphocyte inactivation with inhibitors such sirolimus and everolimus; (4) steroids. ATG. The symptoms resolve without stopping the drugs. Finally, the rescue phase of immunosuppression is Inhibitors of DNA synthesis such mycophenolate related to the treatment of acute cellular rejection and mofetil and azathioprine work by selective and nonseleccirculating antibody-mediated rejection. Intravenous or tive blocking of enzymes involved in purine synthesis. oral steroids, monoclonal or polyclonal antibodies, are They inhibit both T cells and B cells. Mycophenolate the most frequently used agents. mofetil use has been reported as a cause of progressive Calcineurin inhibitors (CNI) such as ciclosporin and multifocal encephalopathy resulting from the activation tacrolimus inhibit T cell proliferation and activation by of the JC virus. Finally, Thor inhibitors such as sirolimus inhibiting the transcription of cytokine genes that proand evrolimus have not been reported as a cause of duce lymphocyte-specific growth factor interleukin 2 neurologic symptoms following transplantation. (IL2). Both drugs have similar toxicity profiles although Although calcineurin inhibitors are the most frequent neurotoxicity is more frequent and more severe with culprits for neurologic side-effects, the incidence can tacrolimus. Approximately 10–28% of patients on calciincrease due to drug interactions (Lake and Canafax, neurin inhibitors experience neurotoxic side-effects 1995) that increase their concentration, such as erythromy(Bechstein, 2000). Symptoms range from mild to severe cin, increase absorption of ciclosporin, such as Metoand include tremors, insomnia, nightmares, headaches, clopramide, and agents that decrease the metabolism vertigo, dysesthesia, photophobia, mood disturbances, of ciclosporin, such as diltiazem, nicardipine, rapamil, akinetic mutism, seizures, cortical blindness, focal neuketoconazole, fluconazole, itraconazole, erythromycin, rologic deficit, psychosis, and encephalopathy. josamycin, oral contraceptives, and tacrolimus (FK506). The mechanism of neurotoxicity with calcineurin It is also important to note that the use of antiseizure inhibitors may be related to binding with immunophilins, medications can decrease the level of ciclosporin and which facilitate protein folding and transportation. increase the risk of rejection. Phenytoin decreases abWhen bound to calcineurin inhbilitors, immunophilins sorption and increases the metabolism of ciclosporin. are less available for normal physiologic processes. CalPhenobarbital and carbamazepine both increase the cineurin inhibitors cause vasoconstriction of vessels by metabolism and decrease the serum level of ciclosporin.
1232 A. HEROUX AND S.V. PAMBOUKIAN Finally neurologic complications of the immunoreactivation of Mycobacterium tuberculosis rarely suppressive regimen are also related to the state causes brain abscesses. Its incidence has been reported of immunosuppression rather than side-effects from at 1%. Listeria monocytogenes can manifest itself immunosuppressive drugs or drug toxicity. They include with symptoms of meningitis but also with brainstem central nervous system infection, stroke, and tumors. encephalitis with cranial nerve palsy and cerebellar signs. Opportunistic infections caused by a Candida Encephalopathy species rarely cause central nervous system infections. Aspergillus fumigatus is the most frequent cause of Following heart transplantation, patients can present fungal brain abscesses (Hotson and Enzmann, 1988b). with mildly altered level of consciousness to delirium Like Nocardia, the route of entry for Aspergillus is and coma (Chang et al., 2001). This can be associated the lung. There is evidence of pulmonary infection in with impaired vision, tremor, multifocal myoclonous, 83–90% of patients. Aspergillus CNS infection can chorea, and seizures. Electrolyte, glucose, and other cause ischemic or hemorrhagic infarction and multiple metabolic disorders as well as ciclosporin, tacrolimus, abscesses. Patients can present with altered mental state and to a lesser extent OKT3 have been associated with (86%), seizures (41%), focal neurologic deficits (32%), these symptoms. Levels of these drugs can be elevated and meningeal signs (19%). Cryptococcus neoformans but symptoms can occur with normal serum levels. is an encapsulated yeast. It is a rare cause of CNS infecThe EEG usually shows a diffuse slowing and correction tion (0.36%). Symptoms develop between 2 and 90 days of the underlying metabolic abnormalities and modifyafter infection and are compatible with subacute mening the immunosuppressive regimen can reverse the ingitis (Wu et al., 2002). symptoms. Infection with a protozoal agent is also increased in immunocompromised patients. Toxoplasma gondii is Central nervous system infections an obligate intercellular parasite. It is the second cause Central nervous system infections occur in 5–7% of solid of meningeal encephalitis and brain abscesses. Brain organ transplant patients (Sila, 1989a). Patients affected abscesses are usually multiple. It can also, like the other with central nervous system infections have a high moragents, cause other infections such as chorioretinitis, tality. Infections usually occur 2—6 months after transmyocarditis, and pneumonitis. plantation. Bacterial infections occur with a higher Focal encephalitis is the usual presentation of patients incidence early, between 0 and 2 months. Viral and funwith herpes virus (HSV) and HHV-6 agent. Cytomegalogal infections occur later, with a higher incidence at 6 virus (CMV) is an uncommon cause of CNS infection months post-transplantation. Their occurrence is related due to prophylaxis with valganciclovir (Valcyte). The risk to higher dose of immunosuppression especially early of infection is increased in patients who are CMVafter transplantation and are associated with systemic negative at the time of transplantation receiving an infections. They are often caused by opportunistic organ from a CMV-positive donor. There is an increased agents. These can be bacterial, such as Nocardia, Mycorisk of reactivation in CMV-positive recipients who do bacterium tuberculosis (Singh and Paterson, 1998), not receive Valcyte prophylaxis or patients who are Listeria monocytogenes; fungal, such as Cryptococcus receiving intense immunosuppression as rescue therapy neoformans (Wu et al., 2002), Aspergillus fumigatus for rejection of the heart. Finally, JC polyomavirus (Hall et al., 1989b), candida, and Pneumocystis carinii; causes progressive multifocal leukoencephalopathy and viral, such as cytomegalovirus (CMV), varicella zos(PML) with symptoms of dementia, ataxia, visual disturter, Epstein–Barr virus (EBV), herpes type 1, 2, 6 (Nash bances, and progression to a vegetative state in 6 months. et al., 2004), and less frequently, JC polyomaviruses There is no treatment for a polyoma infection (Hall et al., (Lewis et al., 1993). Patients can present symptoms com1988a; van de Beek et al., 2007). patible with meningitis, encephalitis (Murtagh et al., It is important to remember that the symptoms of 2005), and focal deficit with the presence of an abscess CNS infection can be subtle due to the presence of the (Weigel et al., 2003; Marchiori et al., 2007). These sympimmunosuppressive drugs. A high degree of suspicion toms may be blunted because of immunosuppression must be exercised to changes in mental status or focal which decreases symptoms related to inflammation. signs in the context of the systemic infection. Diagnostic Bacterial opportunistic infection by Nocardia has imaging should be used early and diagnostic invasive been reported in 16% of solid organ transplant patients. procedures such as lumbar puncture and brain biopsy The usual route of entry is through the lungs. After an to identify the opportunistic agent should be used if initial pneumonia the most frequent secondary dissemiother sites such as the lungs do not show evidence of nation site is the central nervous system. It can cause infection that would be amenable to a diagnostic a single or multiple brain abscesses. An infection or procedure.
NEUROLOGIC ASPECTS OF HEART TRANSPLANTATION
Stroke Strokes are rare but a significant cause of morbidity and mortality following heart transplantation (JarquinValdivia et al., 1999). The incidence is reported to be between 3% and 10%. Underlying etiologies for strokes are the presence of atherosclerosis, vasculitis, arrhythmias, hypercoagulable states, and endocarditis. A retrospective study of 314 patients having undergone heart transplantation (46 14 years of age; 78% male) between 1984 and 2002 with a mean follow-up of 54 57 months have shown a 7% incidence of patients presenting symptoms compatible with a cerebral vascular accident (Belvis et al., 2005). Of these, 60% were ischemic stroke, 28% were transient ischemic attack (TIA), and 12% were hemorrhagic. Early postoperative strokes (less than 2 weeks) occurred in 20% of this population whereas late stroke incidence accounted for 80%. The clinical presentation of ischemic strokes was compatible with occlusion of the total anterior circulation in 23.1%, partial occlusion of the anterior circulation in 38.4%, lacunar infarction in 15.4%, and posterior circulation occlusion in 23.1%. The etiology of ischemic stroke was related to large artery atherosclerosis in 15.4% of the patients, cardioembolism in 14.4%, small vessel disease in 15.4%, unusual causes in 15.4%, and undetermined etiology in 38.4%. The presence of a prior stroke increased the risk of stroke after heart transplantation. The risk of developing a stroke 5 years after heart transplantation was 4.1% in patients who had a prior stroke compared to 1.1% of patients without a history of stroke. The incidence of echo contrast or thrombi in the left atrium is significantly lower in patients having undergone the bicaval anastomosis technique at the time of transplantation then the standard biatrial anastomosis. Older age and the presence of extracranial carotid artery stenosis over 50% seems to increase the risk of stroke. The recurrence of stroke was 18% in patients having presented with a stroke following heart transplantation.
Central nervous system malignancies Patients having undergone solid organ transplantation are three to four times more at risk of developing central nervous system (CNS) malignancies than the general population. The most common type of malignancies are lymphomas and gliomas. The incidence of posttransplant lymphoproliferative disorder (PTLD) is 5% in the Registry of the University of Cincinnati (Penn, 2000). Heart and lung transplant recipients are at an increased risk of developing PTLD. Based on the University of Cincinnati’s Tumor Registry, nonrenal transplant recipients account for 45% of the total reported cases of
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PTLD compared to renal transplant recipients, who account for 12%. A heavy immunosuppression regimen increases the potential for the development of PTLD. PTLD is diagnosed in 1% of renal, 3% of heart, 3% of liver, 8% of lung, and 19% of intestinal transplant recipients. Positive seroconversion to the Epstein–Barr virus (EBV), especially if the recipient was seronegative at the time of transplantation, has been reported as a risk factor for the development of PTLD. Cytomegalovirus (CMV) infection may be a cofactor with EBV as a risk. This may be due to an increase in immunosuppression. The presence of an increased EBV load increases the incidence of B cell lymphoma. Based on the Cardiac Transplant Research Database (CTRD), pediatric transplant recipients are at higher risk. The high occurrence may be related to the fact that children have more lymphoid tissue.
CLASSIFICATION OF POST-TRANSPLANT LYMPHOPROLIFERATIVE DISORDER
1.
2.
Hyperplasia: these types of lymphoproliferation are all polyclonal. Examples are infectious mononucleosis and plasma cell hyperplasia. Neoplasia: these types of malignancies can be polymorphic or monomorphic, such as B cell, T cell, natural killer, and all plasma cell lymphomas. Other forms include myeloma, plasmacytomas, and Hodgkin’s disease, which are uncommon. Some 4% of PTLDs are myeloma and 3% are Hodgkin’s disease.
The detection of the disease is based on clinical symptoms and imaging. The final diagnosis is based on brain biopsy. The treatment of PTLD is based on the cellular type and may include radiation therapy, chemotherapy, and surgery. Early PTLD (up to 24 months) are more frequently EBV þ, affect children more frequently, and have a tendency to respond to a decrease in immunosuppression and the use of antiviral agents. Late PTLD (25–300 months) are usually EBV and do not respond to a decreased immunosuppression and the use of antiviral agents.
Seizures Seizures following heart transplantation are usually related to immunosuppression toxicity, electrolyte or osmolar changes, CNS infection, ischemic or hemorrhagic stroke, tumor, and a history of epilepsy prior to transplantation. (van de Beek et al., 2007; Zierer et al., 2007; Zivkovic, 2007; Navarro et al., 2010). Seizures are partial or generalized, usually tonic-clonic, and rarely nonconvulsive. In the majority of patients they
1234 A. HEROUX AND S.V. PAMBOUKIAN are usually isolated events that usually do not require left heart syndrome not corrected (n ¼ 6), (2) hypoplastic long-term therapy. Investigation of seizures should left heart syndrome with Norwood repair (n ¼ 3), and (3) include an EEG, CT and MRI of the head (Zivkovic, cardiomyopathy (n ¼ 8). Overall the population had an 2007), serum chemistry for magnesium, sodium, and 82% survival rate during follow-up. One patient in group glucose, and a lumbar puncture if the patient has signs 1 presented with a stroke followed by seizures necessitatof meningismus. ing long-term antiepileptic therapy. Three had minor At the moment, there is no controlled drug trial for neurologic abnormalities such as tremors and absent the management of seizures after orthotopic heart transreflexes, and seven had normal neurologic examination. plantation. It is important to remember that there is an Risk factors for seizures have been reported by Raja interaction between antiepileptic therapy and immunoet al. (2003). This study population included 127 infants suppressive medications. Phenytoin, phenobarbital, who had undergone orthotopic heart transplantation due and carbamazepine can decrease the ciclosporin serum to hypoplastic left heart syndrome (HLHS). Their ages level by decreasing the absorption or by increasing the ranged from 9 to 90 days at the time of transplantation. metabolism of ciclosporin. Thus it is important to check Seizures occurred in 27 patients (21%) during follow-up. drug levels for both antiseizure and immunosuppressive The group was compared to 27 patients of comparable regimen. First-line therapy includes phenytoin, phospheage who had undergone heart transplantation without nytoin, and phenobarbital that can be administered intraseizures. The study concluded that risk factors for seivenously. Seizures lasting more than 4–5 minutes or zures included a prolonged total cardiopulmonary progressing into status epilepticus require prolonged antibypass time, especially if it was associated with the presepileptic drug treatment with oral medications such as ence of other complications following transplantation. gabapentin, levetiracetam, carbamazepine, valproic acid, Deep hypothermic circulatory arrest was inversely correand other agents (Chabolla and Wszolek, 2006). Status lated with seizure severity. Infants presenting with an epilepticus represents 16–25% of all poststroke seizures. abnormal pretransplantation EEG and a high total Most poststroke seizures are focal and typically controlled bypass time had a higher frequency of seizures requiring with intravenous phenytoin, phosphophenytoin, and valprolonged use of antiepileptic therapy. Abnormalities in proic acid. This intravenous treatment would be followed post-transplantation EEGs were not associated with the by an oral monotherapy. Hemodialysis should be consineed for continued antiepileptic treatment. dered for drug-induced seizures, especially if renal failure Acute myopathy of intensive care has been described reduces drug elimination. Finally, patients with a history of with an acute onset of hypotonia and flaccid quadriplegia seizures pretransplantation may warrant prophylactic use (Chetaille et al., 2000). The patient had undergone a preof antiepileptic drug therapy, especially early following operative muscle biopsy because of family history of heart transplantation when drug levels of immunosupperipheral myopathy. The biopsy was near normal with pressive medications such as ciclosporin and FK506 are nonspecific mitochondrial disorder. Postoperatively with at their higher serum levels and predispose the patient to symptoms of flaccid quadriplegia, the biopsy showed seizures along with metabolic changes occurring early severe loss of myosin and ATPase activity in type 2 fibers. after heart transplantation. The patient had normal nerve conduction and the electromyogram showed myopathic changes. Recovery Peripheral nervous system complications occurred within 3 weeks and the biopsy performed a few months later was normal. Progressive visual deterioPeripheral nervous system complications following heart ration due to pseudotumor cerebri leading to blindness transplantation can present with peripheral neuropathy has been reported (Schowengerdt et al., 1993), as well associated with immunosuppressive regimens as previas Friedreich’s ataxia presenting clinically after cardiac ously discussed and complications related to comorbidtransplantation (Leonard and Forsyth, 2001). In this case ities such as diabetes and osteopenia (Malheiros et al., the patient underwent a muscle biopsy preoperatively 2002). Compression of nerve roots by an infectious probecause of weakness. The biopsy and histochemical stains cess or a tumor, although less frequent, should also be were normal. The weakness was felt to be due to congesconsidered (Malheiros et al., 2002). tive heart failure. The patient underwent successful orthotopic heart transplantation and continued to develop Neurologic complications in children muscle weakness with normal allograft function. Genetic It has been reported that up to 50% of children undergostudies performed were compatible with Friedreich’s ing heart transplantation had neurologic complications ataxia. Finally, neurodevelopmental outcome in two (Starnes et al., 1989; Martin et al., 1992). A study by groups of age-matched pediatric patients has been Lynch et al. (1994) reported a 60 month follow-up in 17 described (Fleisher et al., 2002). The investigator compatients divided into three populations: (1) hypoplastic pared 18 pediatric patients who had undergone heart
NEUROLOGIC ASPECTS OF HEART TRANSPLANTATION transplantation versus 18 who had undergone cardiopulmonary bypass for nontransplant cardiac procedures. Pediatric patients having undergone orthotopic heart transplantation had difficulties with growth and development, an increase in neurologic abnormalities as well as speech, language delays, and hearing problems. Comparison of neurologic complications between adults and children having undergone heart transplantation has been described (Mayer et al., 2002). A 14 year retrospective study (1986–2000) consisted of 184 patients (107 adults and 77 children). Forty-seven neurologic complications occurred in 29.9% of adults whereas 22 complications occurred in 18 children (23.4%). Peripheral neuropathy was the most frequent neurologic complication in adults and seizures the most frequent complication in children. Other complications such as infections, encephalopathy, cerebral vascular accidents, and neoplasm were comparable in both groups. Early complications (
Chapter 82
Neurologic aspects of heart transplantation 1
ALAIN HEROUX1* AND SALPY V. PAMBOUKIAN2 Heart Failure and Heart Transplant Program, Loyola University Medical Center, Maywood, IL, USA
2
Section of Advanced Heart Failure, Cardiac Transplant, Mechanical Circulatory Support and Pulmonary Vascular Disease, University of Alabama at Birmingham, Birmingham, AL, USA
INTRODUCTION Approximately 5 million Americans have heart failure, with National Hospital Discharge Survey data from 1979 to 2004 indicating that the number of hospitalizations with any mention of heart failure tripled from 1 274 000 in 1979 to 3 860 000 in 2004 (Roger, 2010). Currently, heart transplantation remains the best longterm therapy for patients with end-stage heart failure who have failed conventional medical therapies. However, due to organ shortages and other factors, heart transplant rates have remained static. In 2008, approximately 2000 heart transplants were performed in the US (Wolfe et al., 2010). Therefore, the appropriate selection of patients with the best chance of survival after cardiac transplantation is an important part in the allocation of this limited resource. The neurologic evaluation of the potential transplant recipient includes evaluation by a multidisciplinary team including the transplant cardiologist, neurologist, and neurosurgeon. The presence and severity of concomitant neurologic conditions must be defined in order to determine if outcome after cardiac transplant would be adversely affected, making cardiac transplantation ill advised.
PREOPERATIVE EVALUATION OF NEUROLOGIC DISEASE Central neurologic disease A detailed history regarding possible previous neurologic events, such as stroke or transient ischemic attack (TIA), or concomitant diseases that can have central manifestations should be obtained. Examples of diseases that have central nervous system manifestations and could impact on post-transplant survival would
include vascular diseases, connective tissue diseases, dementias, multiple sclerosis, sarcoidosis, and amyloidosis. In conjunction with a detailed history, thorough physical examination should be performed. After history and physical examination have been performed, imaging studies should follow. Because many, if not all, endstage heart failure patients have implantable cardiac defibrillators and/or pacing devices, magnetic resonance imaging (MRI) may not be feasible as many consider these devices a contraindication. (Farling et al., 2010) Therefore, unenhanced and/or enhanced head computed tomography (CT) should be obtained. Patients who have had previous stroke, age > 40, or who are at risk of vascular disease (for example, those with known coronary artery disease or diabetes), should have carotid artery imaging. If an abnormality is found, it is important to assess the extent of disease burden. In general, dementias, systemic diseases limiting survival, or systemic diseases exacerbated by immunosuppressive therapy post-transplant are considered contraindications to cardiac transplantation. Previous stroke is not an absolute contraindication to cardiac transplantation, unless there are significant neurologic sequelae and late effects. Patients with significant cognitive impairment and limited potential for cardiac rehabilitation are not considered appropriate for transplant in most centers. The presence of high-grade, asymptomatic, focal carotid artery disease may not preclude cardiac transplantation, but may require revascularization, either with carotid endarterectomy, or alternatively stenting, depending on the patient’s clinical condition (Hertzer, 2010). In contrast, diffuse disease may progress post-transplant in the presence of steroid therapy, drug-induced diabetes, hypertension, and dyslipidemia, and may render cardiac transplant ill advised.
*Correspondence to: Alain Heroux, M.D., Professor, Heart Failure/Heart Transplant Program, Loyola University Medical Center, 2160 South First Avenue, Maywood, IL 60153, USA. E-mail: [email protected]
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Peripheral nervous system disease As above, a detailed history and physical examination assessing for the presence of peripheral nervous system disease should be performed at the time of heart transplant evaluation. Systemic diseases with peripheral nervous system manifestations that would preclude long-term survival post-transplant or interfere with rehabilitation would be considered contraindications to heart transplant. Many patients with diabetes mellitus and concomitant heart disease are referred for heart transplant evaluation, therefore peripheral neuropathy as a complication of diabetes is the most commonly encountered peripheral neurologic disorder in this population. Patients with uncomplicated diabetes have been shown to do well after cardiac transplantation although they may be at increased risk of infections (Marelli et al., 2003; Russo et al., 2006). However, in one large study of over 20 000 heart transplant recipients transplanted between 1995 and 2005, patients with increased severity of diabetes characterized by the presence of obesity (BMI 35 kg/m2), previous stroke, renal insufficiency (creatinine 2.5 mg/dL) or peripheral vascular disease had lower median survival post-transplant, with decreasing survival for each diabetes-related complication present (Russo et al., 2006). Those without diabetes had a median survival of 10.1 years versus 3.6 years for those with two or more diabetic-related complications (Russo et al., 2006). Traditionally, individuals with peripheral neuropathy as a complication of diabetes have been declined heart transplantation, and therefore excluded from published series. However, extrapolating from published data, the presence of peripheral neuropathy (characterized by nerve conduction study) as a marker of worse disease severity would need to be carefully considered along with other disease indicators to determine suitability for cardiac transplantation.
POSTOPERATIVE NEUROLOGIC COMPLICATIONS Central Perioperative cerebrovascular complications are more common after cardiac transplantation compared to routine cardiac surgery such as coronary artery bypass grafting (van de Beek et al., 2008). Rates range from 4% to 42% (Andrews et al., 1990; Jarquin-Valdivia et al., 1999; Malheiros et al., 2002; Perez-Miralles et al., 2005; van de Beek et al., 2008). Ischemic stroke is the most common cerebrovascular complication (Perez-Miralles et al., 2005; van de Beek et al., 2008) and may result from anoxic-hypoperfusion events resulting in watershed infarcts. Other cerebrovascular complications include hemorrhagic stroke,
encephalopathy, and TIA. Early perioperative hemorrhagic stroke may occur in the setting of pretransplant low cardiac output followed by post-transplant relative hyperperfusion associated with disordered cerebral autoregulatory pressor response (Sila, 1989a; Zivkovic, 2007). Transcranial Doppler ultrasound after heart transplantation shows an increase of velocity of up to 50% or higher (Massaro et al., 2006). Seizures and posterior reversible encephalopathy syndrome (PRES) may occur perioperatively, likely related to the introduction of immunosuppressive agents, specifically calcineurin inhibitors (CNI), in the early postoperative period. Substitution of one CNI for another with close monitoring of drug levels may be necessary. Perioperative stroke is associated with 1 year mortality in contrast to perioperative delirium or encephalopathy, diseases of peripheral nerves and muscles, and seizures, which are not associated with worse outcome (van de Beek et al., 2008). CNS infections are relatively uncommon early posttransplant, but are associated with decreased survival (van de Beek et al., 2008). Imaging studies including head CT (unenhanced or enhanced) should be undertaken, but may be nondiagnostic. MRI can be performed as pacing/defibrillating devices were removed at the time of cardiac transplant; however, it may be limited by the clinical condition and the patient’s ability to lie in the scanner for a prolonged period. The evaluation of possible neurologic complication post-transplant should include expert input from a neurologist familiar with issues related to solid organ transplantation.
Peripheral nervous system complications Postoperative peripheral nervous system complications most commonly include brachial plexopathy, peroneal nerve mononeuropathy, critical illness neuropathy or myopathy, (Adair et al., 1993; Perea et al., 2001; Mateen et al., 2009), and vocal cord paralysis (van de Beek et al., 2008). Although patient survival after transplantation may not be affected by these complications, they do contribute to the morbidity of the procedure and prolong rehabilitation time. With careful patient management and attention to patient positioning and monitoring, most of these complications are avoidable.
LONG-TERM NEUROLOGIC ASPECTS OF HEART TRANSPLANTATION The incidence of neurologic complications following solid organ transplantation is frequent. Approximately one-third of recipients (10–59%) present with neurologic symptoms (van de Beek et al., 2008; Marco et al., 2009). It is most frequently related to side-effects of the immunosuppressive regimen, drug toxicity, and complications
NEUROLOGIC ASPECTS OF HEART TRANSPLANTATION 1231 due to immunosuppression. Symptoms related to the increasing endothelium, with secondary increase of tromimmunosuppressive regimen following heart transplanboxane and decrease in nitric oxide. The drugs may also tation include tremors, seizures, strokes, central nervous cause an impairment of neuronal transmission by (1) system infections, encephalopathy, and tumors (van de decreasing g-aminobutyric acid which can lead to Beek et al., 2008). Risk factors that may enhance neuroincreased seizure activity, (2) decreasing neuronal serotologic complications following heart transplantation nin leading to more susceptibility to depression and include pre-existing conditions such as a prior sroke tremor, and (3) the inhibition of glutaminergic Nand comorbidities such as diabetes, hypertension, and methyl-D-aspartate receptors which could be a possible hypercoagulable states. Neurologic complication is the cause of delirium (Bechstein, 2000). primary cause of death in 20% of transplant recipients The treatment of neurotoxic side-effects related to (Perez-Miralles et al., 2005). calcineurin inhibitors consists of switching from ciclosporin to tacrolimus or vice versa, decreasing the dose of the drugs or switching from mycophenolate mofetil or Current immunosuppression azathioprine to a Thor inhibitor such as evrolimus or The current immunosuppressive regimen in solid organ sirolimus to decrease the level of calcineurin inhibitors. transplantation can be divided into three phases: inducb-Blockers can also be used to decrease tremors. tion, maintenance, and rescue. The induction phase The use of steroids in the induction, maintenance, and occurs at the time of transplantation and consists of rescue phases can cause behavioral disorders such as the use of monoclonal antibodies such as OKT3 and confusion, mood disturbances, manic states, and psydacluzimab or polyclonal antibodies such as antithymochosis. These can be exacerbated by underlying metacyte globulin (ATG). The aim of induction is to prevent bolic abnormalities. Treatment consists of lowering the the early occurrence of acute cellular rejection. It is given dose or stopping intravenous steroids and correcting over the course of a few days while the serum level of the underlying metabolic abnormalities. maintenance immunosuppressive agent can be raised to Monoclonal and polyclonal antibodies used during therapeutic levels to prevent rejection. the induction and rescue phases of immunosuppression Maintenance immunosuppressive regimen consists of: can cause acute aseptic meningitis in 5–10% of patients (1) calcineurin inhibitors such as Cyclosporine and tacroli(Adair et al., 1991; Pittock et al., 2003). These symptoms mus (FK506); (2) mycophenolate mofetil (MMF) and azaare due to proinflammatory cytokine release, due to T thioprine; (3) mTOR (mammalian target of rapamycin) cell lysis with OKT3 and lymphocyte inactivation with inhibitors such sirolimus and everolimus; (4) steroids. ATG. The symptoms resolve without stopping the drugs. Finally, the rescue phase of immunosuppression is Inhibitors of DNA synthesis such mycophenolate related to the treatment of acute cellular rejection and mofetil and azathioprine work by selective and nonseleccirculating antibody-mediated rejection. Intravenous or tive blocking of enzymes involved in purine synthesis. oral steroids, monoclonal or polyclonal antibodies, are They inhibit both T cells and B cells. Mycophenolate the most frequently used agents. mofetil use has been reported as a cause of progressive Calcineurin inhibitors (CNI) such as ciclosporin and multifocal encephalopathy resulting from the activation tacrolimus inhibit T cell proliferation and activation by of the JC virus. Finally, Thor inhibitors such as sirolimus inhibiting the transcription of cytokine genes that proand evrolimus have not been reported as a cause of duce lymphocyte-specific growth factor interleukin 2 neurologic symptoms following transplantation. (IL2). Both drugs have similar toxicity profiles although Although calcineurin inhibitors are the most frequent neurotoxicity is more frequent and more severe with culprits for neurologic side-effects, the incidence can tacrolimus. Approximately 10–28% of patients on calciincrease due to drug interactions (Lake and Canafax, neurin inhibitors experience neurotoxic side-effects 1995) that increase their concentration, such as erythromy(Bechstein, 2000). Symptoms range from mild to severe cin, increase absorption of ciclosporin, such as Metoand include tremors, insomnia, nightmares, headaches, clopramide, and agents that decrease the metabolism vertigo, dysesthesia, photophobia, mood disturbances, of ciclosporin, such as diltiazem, nicardipine, rapamil, akinetic mutism, seizures, cortical blindness, focal neuketoconazole, fluconazole, itraconazole, erythromycin, rologic deficit, psychosis, and encephalopathy. josamycin, oral contraceptives, and tacrolimus (FK506). The mechanism of neurotoxicity with calcineurin It is also important to note that the use of antiseizure inhibitors may be related to binding with immunophilins, medications can decrease the level of ciclosporin and which facilitate protein folding and transportation. increase the risk of rejection. Phenytoin decreases abWhen bound to calcineurin inhbilitors, immunophilins sorption and increases the metabolism of ciclosporin. are less available for normal physiologic processes. CalPhenobarbital and carbamazepine both increase the cineurin inhibitors cause vasoconstriction of vessels by metabolism and decrease the serum level of ciclosporin.
1232 A. HEROUX AND S.V. PAMBOUKIAN Finally neurologic complications of the immunoreactivation of Mycobacterium tuberculosis rarely suppressive regimen are also related to the state causes brain abscesses. Its incidence has been reported of immunosuppression rather than side-effects from at 1%. Listeria monocytogenes can manifest itself immunosuppressive drugs or drug toxicity. They include with symptoms of meningitis but also with brainstem central nervous system infection, stroke, and tumors. encephalitis with cranial nerve palsy and cerebellar signs. Opportunistic infections caused by a Candida Encephalopathy species rarely cause central nervous system infections. Aspergillus fumigatus is the most frequent cause of Following heart transplantation, patients can present fungal brain abscesses (Hotson and Enzmann, 1988b). with mildly altered level of consciousness to delirium Like Nocardia, the route of entry for Aspergillus is and coma (Chang et al., 2001). This can be associated the lung. There is evidence of pulmonary infection in with impaired vision, tremor, multifocal myoclonous, 83–90% of patients. Aspergillus CNS infection can chorea, and seizures. Electrolyte, glucose, and other cause ischemic or hemorrhagic infarction and multiple metabolic disorders as well as ciclosporin, tacrolimus, abscesses. Patients can present with altered mental state and to a lesser extent OKT3 have been associated with (86%), seizures (41%), focal neurologic deficits (32%), these symptoms. Levels of these drugs can be elevated and meningeal signs (19%). Cryptococcus neoformans but symptoms can occur with normal serum levels. is an encapsulated yeast. It is a rare cause of CNS infecThe EEG usually shows a diffuse slowing and correction tion (0.36%). Symptoms develop between 2 and 90 days of the underlying metabolic abnormalities and modifyafter infection and are compatible with subacute mening the immunosuppressive regimen can reverse the ingitis (Wu et al., 2002). symptoms. Infection with a protozoal agent is also increased in immunocompromised patients. Toxoplasma gondii is Central nervous system infections an obligate intercellular parasite. It is the second cause Central nervous system infections occur in 5–7% of solid of meningeal encephalitis and brain abscesses. Brain organ transplant patients (Sila, 1989a). Patients affected abscesses are usually multiple. It can also, like the other with central nervous system infections have a high moragents, cause other infections such as chorioretinitis, tality. Infections usually occur 2—6 months after transmyocarditis, and pneumonitis. plantation. Bacterial infections occur with a higher Focal encephalitis is the usual presentation of patients incidence early, between 0 and 2 months. Viral and funwith herpes virus (HSV) and HHV-6 agent. Cytomegalogal infections occur later, with a higher incidence at 6 virus (CMV) is an uncommon cause of CNS infection months post-transplantation. Their occurrence is related due to prophylaxis with valganciclovir (Valcyte). The risk to higher dose of immunosuppression especially early of infection is increased in patients who are CMVafter transplantation and are associated with systemic negative at the time of transplantation receiving an infections. They are often caused by opportunistic organ from a CMV-positive donor. There is an increased agents. These can be bacterial, such as Nocardia, Mycorisk of reactivation in CMV-positive recipients who do bacterium tuberculosis (Singh and Paterson, 1998), not receive Valcyte prophylaxis or patients who are Listeria monocytogenes; fungal, such as Cryptococcus receiving intense immunosuppression as rescue therapy neoformans (Wu et al., 2002), Aspergillus fumigatus for rejection of the heart. Finally, JC polyomavirus (Hall et al., 1989b), candida, and Pneumocystis carinii; causes progressive multifocal leukoencephalopathy and viral, such as cytomegalovirus (CMV), varicella zos(PML) with symptoms of dementia, ataxia, visual disturter, Epstein–Barr virus (EBV), herpes type 1, 2, 6 (Nash bances, and progression to a vegetative state in 6 months. et al., 2004), and less frequently, JC polyomaviruses There is no treatment for a polyoma infection (Hall et al., (Lewis et al., 1993). Patients can present symptoms com1988a; van de Beek et al., 2007). patible with meningitis, encephalitis (Murtagh et al., It is important to remember that the symptoms of 2005), and focal deficit with the presence of an abscess CNS infection can be subtle due to the presence of the (Weigel et al., 2003; Marchiori et al., 2007). These sympimmunosuppressive drugs. A high degree of suspicion toms may be blunted because of immunosuppression must be exercised to changes in mental status or focal which decreases symptoms related to inflammation. signs in the context of the systemic infection. Diagnostic Bacterial opportunistic infection by Nocardia has imaging should be used early and diagnostic invasive been reported in 16% of solid organ transplant patients. procedures such as lumbar puncture and brain biopsy The usual route of entry is through the lungs. After an to identify the opportunistic agent should be used if initial pneumonia the most frequent secondary dissemiother sites such as the lungs do not show evidence of nation site is the central nervous system. It can cause infection that would be amenable to a diagnostic a single or multiple brain abscesses. An infection or procedure.
NEUROLOGIC ASPECTS OF HEART TRANSPLANTATION
Stroke Strokes are rare but a significant cause of morbidity and mortality following heart transplantation (JarquinValdivia et al., 1999). The incidence is reported to be between 3% and 10%. Underlying etiologies for strokes are the presence of atherosclerosis, vasculitis, arrhythmias, hypercoagulable states, and endocarditis. A retrospective study of 314 patients having undergone heart transplantation (46 14 years of age; 78% male) between 1984 and 2002 with a mean follow-up of 54 57 months have shown a 7% incidence of patients presenting symptoms compatible with a cerebral vascular accident (Belvis et al., 2005). Of these, 60% were ischemic stroke, 28% were transient ischemic attack (TIA), and 12% were hemorrhagic. Early postoperative strokes (less than 2 weeks) occurred in 20% of this population whereas late stroke incidence accounted for 80%. The clinical presentation of ischemic strokes was compatible with occlusion of the total anterior circulation in 23.1%, partial occlusion of the anterior circulation in 38.4%, lacunar infarction in 15.4%, and posterior circulation occlusion in 23.1%. The etiology of ischemic stroke was related to large artery atherosclerosis in 15.4% of the patients, cardioembolism in 14.4%, small vessel disease in 15.4%, unusual causes in 15.4%, and undetermined etiology in 38.4%. The presence of a prior stroke increased the risk of stroke after heart transplantation. The risk of developing a stroke 5 years after heart transplantation was 4.1% in patients who had a prior stroke compared to 1.1% of patients without a history of stroke. The incidence of echo contrast or thrombi in the left atrium is significantly lower in patients having undergone the bicaval anastomosis technique at the time of transplantation then the standard biatrial anastomosis. Older age and the presence of extracranial carotid artery stenosis over 50% seems to increase the risk of stroke. The recurrence of stroke was 18% in patients having presented with a stroke following heart transplantation.
Central nervous system malignancies Patients having undergone solid organ transplantation are three to four times more at risk of developing central nervous system (CNS) malignancies than the general population. The most common type of malignancies are lymphomas and gliomas. The incidence of posttransplant lymphoproliferative disorder (PTLD) is 5% in the Registry of the University of Cincinnati (Penn, 2000). Heart and lung transplant recipients are at an increased risk of developing PTLD. Based on the University of Cincinnati’s Tumor Registry, nonrenal transplant recipients account for 45% of the total reported cases of
1233
PTLD compared to renal transplant recipients, who account for 12%. A heavy immunosuppression regimen increases the potential for the development of PTLD. PTLD is diagnosed in 1% of renal, 3% of heart, 3% of liver, 8% of lung, and 19% of intestinal transplant recipients. Positive seroconversion to the Epstein–Barr virus (EBV), especially if the recipient was seronegative at the time of transplantation, has been reported as a risk factor for the development of PTLD. Cytomegalovirus (CMV) infection may be a cofactor with EBV as a risk. This may be due to an increase in immunosuppression. The presence of an increased EBV load increases the incidence of B cell lymphoma. Based on the Cardiac Transplant Research Database (CTRD), pediatric transplant recipients are at higher risk. The high occurrence may be related to the fact that children have more lymphoid tissue.
CLASSIFICATION OF POST-TRANSPLANT LYMPHOPROLIFERATIVE DISORDER
1.
2.
Hyperplasia: these types of lymphoproliferation are all polyclonal. Examples are infectious mononucleosis and plasma cell hyperplasia. Neoplasia: these types of malignancies can be polymorphic or monomorphic, such as B cell, T cell, natural killer, and all plasma cell lymphomas. Other forms include myeloma, plasmacytomas, and Hodgkin’s disease, which are uncommon. Some 4% of PTLDs are myeloma and 3% are Hodgkin’s disease.
The detection of the disease is based on clinical symptoms and imaging. The final diagnosis is based on brain biopsy. The treatment of PTLD is based on the cellular type and may include radiation therapy, chemotherapy, and surgery. Early PTLD (up to 24 months) are more frequently EBV þ, affect children more frequently, and have a tendency to respond to a decrease in immunosuppression and the use of antiviral agents. Late PTLD (25–300 months) are usually EBV and do not respond to a decreased immunosuppression and the use of antiviral agents.
Seizures Seizures following heart transplantation are usually related to immunosuppression toxicity, electrolyte or osmolar changes, CNS infection, ischemic or hemorrhagic stroke, tumor, and a history of epilepsy prior to transplantation. (van de Beek et al., 2007; Zierer et al., 2007; Zivkovic, 2007; Navarro et al., 2010). Seizures are partial or generalized, usually tonic-clonic, and rarely nonconvulsive. In the majority of patients they
1234 A. HEROUX AND S.V. PAMBOUKIAN are usually isolated events that usually do not require left heart syndrome not corrected (n ¼ 6), (2) hypoplastic long-term therapy. Investigation of seizures should left heart syndrome with Norwood repair (n ¼ 3), and (3) include an EEG, CT and MRI of the head (Zivkovic, cardiomyopathy (n ¼ 8). Overall the population had an 2007), serum chemistry for magnesium, sodium, and 82% survival rate during follow-up. One patient in group glucose, and a lumbar puncture if the patient has signs 1 presented with a stroke followed by seizures necessitatof meningismus. ing long-term antiepileptic therapy. Three had minor At the moment, there is no controlled drug trial for neurologic abnormalities such as tremors and absent the management of seizures after orthotopic heart transreflexes, and seven had normal neurologic examination. plantation. It is important to remember that there is an Risk factors for seizures have been reported by Raja interaction between antiepileptic therapy and immunoet al. (2003). This study population included 127 infants suppressive medications. Phenytoin, phenobarbital, who had undergone orthotopic heart transplantation due and carbamazepine can decrease the ciclosporin serum to hypoplastic left heart syndrome (HLHS). Their ages level by decreasing the absorption or by increasing the ranged from 9 to 90 days at the time of transplantation. metabolism of ciclosporin. Thus it is important to check Seizures occurred in 27 patients (21%) during follow-up. drug levels for both antiseizure and immunosuppressive The group was compared to 27 patients of comparable regimen. First-line therapy includes phenytoin, phospheage who had undergone heart transplantation without nytoin, and phenobarbital that can be administered intraseizures. The study concluded that risk factors for seivenously. Seizures lasting more than 4–5 minutes or zures included a prolonged total cardiopulmonary progressing into status epilepticus require prolonged antibypass time, especially if it was associated with the presepileptic drug treatment with oral medications such as ence of other complications following transplantation. gabapentin, levetiracetam, carbamazepine, valproic acid, Deep hypothermic circulatory arrest was inversely correand other agents (Chabolla and Wszolek, 2006). Status lated with seizure severity. Infants presenting with an epilepticus represents 16–25% of all poststroke seizures. abnormal pretransplantation EEG and a high total Most poststroke seizures are focal and typically controlled bypass time had a higher frequency of seizures requiring with intravenous phenytoin, phosphophenytoin, and valprolonged use of antiepileptic therapy. Abnormalities in proic acid. This intravenous treatment would be followed post-transplantation EEGs were not associated with the by an oral monotherapy. Hemodialysis should be consineed for continued antiepileptic treatment. dered for drug-induced seizures, especially if renal failure Acute myopathy of intensive care has been described reduces drug elimination. Finally, patients with a history of with an acute onset of hypotonia and flaccid quadriplegia seizures pretransplantation may warrant prophylactic use (Chetaille et al., 2000). The patient had undergone a preof antiepileptic drug therapy, especially early following operative muscle biopsy because of family history of heart transplantation when drug levels of immunosupperipheral myopathy. The biopsy was near normal with pressive medications such as ciclosporin and FK506 are nonspecific mitochondrial disorder. Postoperatively with at their higher serum levels and predispose the patient to symptoms of flaccid quadriplegia, the biopsy showed seizures along with metabolic changes occurring early severe loss of myosin and ATPase activity in type 2 fibers. after heart transplantation. The patient had normal nerve conduction and the electromyogram showed myopathic changes. Recovery Peripheral nervous system complications occurred within 3 weeks and the biopsy performed a few months later was normal. Progressive visual deterioPeripheral nervous system complications following heart ration due to pseudotumor cerebri leading to blindness transplantation can present with peripheral neuropathy has been reported (Schowengerdt et al., 1993), as well associated with immunosuppressive regimens as previas Friedreich’s ataxia presenting clinically after cardiac ously discussed and complications related to comorbidtransplantation (Leonard and Forsyth, 2001). In this case ities such as diabetes and osteopenia (Malheiros et al., the patient underwent a muscle biopsy preoperatively 2002). Compression of nerve roots by an infectious probecause of weakness. The biopsy and histochemical stains cess or a tumor, although less frequent, should also be were normal. The weakness was felt to be due to congesconsidered (Malheiros et al., 2002). tive heart failure. The patient underwent successful orthotopic heart transplantation and continued to develop Neurologic complications in children muscle weakness with normal allograft function. Genetic It has been reported that up to 50% of children undergostudies performed were compatible with Friedreich’s ing heart transplantation had neurologic complications ataxia. Finally, neurodevelopmental outcome in two (Starnes et al., 1989; Martin et al., 1992). A study by groups of age-matched pediatric patients has been Lynch et al. (1994) reported a 60 month follow-up in 17 described (Fleisher et al., 2002). The investigator compatients divided into three populations: (1) hypoplastic pared 18 pediatric patients who had undergone heart
NEUROLOGIC ASPECTS OF HEART TRANSPLANTATION transplantation versus 18 who had undergone cardiopulmonary bypass for nontransplant cardiac procedures. Pediatric patients having undergone orthotopic heart transplantation had difficulties with growth and development, an increase in neurologic abnormalities as well as speech, language delays, and hearing problems. Comparison of neurologic complications between adults and children having undergone heart transplantation has been described (Mayer et al., 2002). A 14 year retrospective study (1986–2000) consisted of 184 patients (107 adults and 77 children). Forty-seven neurologic complications occurred in 29.9% of adults whereas 22 complications occurred in 18 children (23.4%). Peripheral neuropathy was the most frequent neurologic complication in adults and seizures the most frequent complication in children. Other complications such as infections, encephalopathy, cerebral vascular accidents, and neoplasm were comparable in both groups. Early complications (
