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NEUROLOGIC COMPLICATIONS OF TRANSPLANTATION
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NEUROLOGIC COMPLICATIONS OF TRANSPLANTATION Jin-Moo Lee, MD, PhD, and Eric C. Raps, MD
Organ transplantation traces its birth to a landmark operation performed by Murray in Boston in 1954 in which an identical twin received a donated sibling kidney.72Over the decades since that seminal procedure, the field of organ transplantation has grown exponentially, largely fertilized by the advent of ever more powerful and precise immunosuppressive agents. With the increase in organ transplantation, health professionals have seen a considerable number of associated neurologic complications. In some instances, these complications are a function of the individual nature of the transplant surgery, whereas in others, neurologic dysfunction is the result of exposing an ill patient to a prolonged, often difficult operation. Complications may be familiar, such as perioperative encephalopathy or seizure, or they may be unique, such as suture line embolus in lung transplantation. The transplant team may call on the neurologist to assist in the management of neurologic complications before transplantation as a result of organ system failure and encephalopathy, during the perioperative period as a result of the surgical procedure and associated therapies, and in the weeks and months after transplantation as a result of nervous system dysfunction secondary to immunosuppression and organ rejection. The complications inherent to immunosuppression are discussed in detail elsewhere in this issue. PRETRANSPLANT NEUROLOGIC COMPLICATIONS IN ORGAN FAILURE
Before any discussion of perioperative neurologic complicationsin transplantation, an overview of organ failure and the brain is warranted. Transplantation is reserved for patients suffering imminent or impending organ failure. Symptoms referable to the central or peripheral nervous system are frequently apparent in From the Department of Neurology, University of Pennsylvania Medical Center, Philadelphia, Pennsylvania (ECR); and Department of Neurology, Washington University Medical Center, St. Louis, Missouri (JML) NEUROLOGIC CLINICS OF NORTH AMERICA
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VOLUME 16.NUMBER 1 FEBRUARY 1998
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patients awaiting transplantation. The degree of cerebral involvement, in particular, often correlates with the pace of organ failure because the brain is quite resilient if allowed sufficient time to compensate for chronic organ dysfunction.
Renal Failure Neurologic dysfunction, both peripheral and central, is a major cause of morbidity in patients with end-stage renal disease. Both acute and chronic uremia produce characteristic neurologic symptoms. Dialysis has been associated with at least two forms of neurologic disturbance-dialysis dysequilibrium syndrome and dialysis dementia.7,27,28,60,61,79 Although the patient awaiting renal transplantation may be managed with various forms of dialysis, ultimately the toxic effects of both renal failure and dialysis almost certainly produce neurologic impairment unless a donor kidney is found. The normal human kidney is designed to maintain continuous fluid and electrolyte homeostasis. Renal failure results in a steady, rapid rise in blood urea nitrogen (BUN). Acutely, this rise produces a progression of symptoms beginning with anorexia, nausea, insomnia, and restlessness; proceeding to paranoia, drowsiness, and sluggishness; and finally culminating in myoclonus, asterixis, seizures, stupor, and coma. Physical examination may reveal cranial nerve signs, nystagmus, fasciculations, and clonus.7,27,28,M),61,79 Although uremia results in a variety of biochemical and metabolic changes in the brain, the precise mechanism by which uremic encephalopathy occurs remains unclear. Certainly, abnormalities in brain energy utilization may contribute to the encephalopathy.@' In addition, excessive parathyroid hormone secretion in uremic patients may contribute to central nervous system t o x i ~ i t y . ~ ~ , ~ ~ , ~ ~
Hepatic Failure Hepatic encephalopathy refers to the constellation of neuropsychiatric abnormalities that occurs as the result of either acute or chronic liver disease. If the encephalopathydevelops within 2 to 8 weeks of the onset of jaundice, the patient has fulminant hepatic f~ilure.~~,'~,~~ Onset of encephalopathy from several weeks to 3 months after the onset of jaundice is referred to as subfulminant liver failure.Io Chronic hepatic encephalopathy is more common and refers to the episodic encephalopathic deteriorations seen in patients with chronic hepatocellular disease.84 Between 25% and 35% of the liver transplants performed at the University of Pennsylvania over the past 5 years were done on a stat basis for rapidly deteriorating liver function. The cause of hepatic encephalopathy remains controversial.Previously, studies have focused on ammonia and false neurotransmitters as possible mediators of neuronal d e p r e s ~ i o n .More ~ ~ , ~recent ~ work has implicated endogenous benzodiazepines as likely agents contributing to the en~ephalopathy.~~ It is well recognized that the administration of exogenous benzodiazepines, such as lorazepam or midazolam, to patients with hepatic failure can significantly worsen their level of consciousness and may well contribute to morbidity and mortality. Fulminant hepatic failure is a life-threatening condition characterized by the rapid development of encephalopathy after initial liver i n j ~ r y . * O , ~Up 5 , ~to~80% ,~ of patients with fulminant hepatic failure develop severe, often refractory cerebral edema.12,35,71 The associated elevation in intracranial pressure may be dramatic and is frequently the cause of death in these patient^.^^,^^,^^ The risk of cerebral edema in fulminant hepatic failure is often the driving force behind stat liver transplantation.
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Cardiopulmonary Failure
Patients awaiting heart transplantation develop neurologic complications on the basis of many factors-some of which may overlap. These include low cardiac output with hypotension and watershed infarction; cardioembolic stroke as a result of arrhythmia, mural thrombus, or valvular disease; medication effect; and the associated failure of other organs, including lungs, kidneys, and ~ive~~4.13.30.32.40.97 The neurologic complications of diminished cardiac output depend largely on the rate and depth of the fall-off in supply.3z~40,47,80 The patient with chronically low cardiac output may complain of fatigue, headache, or tremor. More than three decades ago, Adams and colleagues4 categorized the neuropathologic changes seen in patients with acute and subacute hypotensive injury. Two of the 11patients in this series suffered from underlying cardiomyopathy. Moderate hypotensive injury resulted in diffuse neuronal loss in the cerebral cortex, Purkinje cells, thalamus, and striatum with relative sparing of Ammon’s horns in the temporal lobe.4 More recently, Sulkawa and Erkinjuntiiy7identified 6 patients in a series of 133 patients with vascular dementia who suffered from chronic cerebral hypoperfusion. Five of the six patients had white matter low attenuation apparent on computed tomography (CT) scan without discrete infarction. All six exhibited persistent cognitive decline after onset of cardiac failure.97 Medications used in the therapy of cardiac failure and during the perioperative transplant period may contribute substantially to neurologic d y s f ~ n c t i o n . ~ ~ Additionally, drug metabolism may be significantly attenuated by poor perfusion and impaired hepatic and renal function. Table 1 lists neurologic complications associated with frequently used cardiac agents. The neurologic complications of acute and chronic organ failure remain an important cause of morbidity and mortality in patients awaiting transplantation. Kidney, liver, heart, and lung transplantation have become increasingly successful, and the role of the neurologic consultant to protect the brain during the perioperative period and identify reversible factors contributing to encephalopathy remains critical. PERIOPERATIVECOMPLICATIONS COMMON TO ALL TRANSPLANT PROCEDURES Encephalopathy
In the perioperative period, transplant patients may exhibit behavioral changes ranging from a mild confusional state or psychosis to severe encephalop-
Table 1. NEUROLOGIC COMPLICATIONS OF CARDIAC AGENTS Drug
Digitalis derivatives’ Quinidine Procainarnide Lidocaine Bretylium Amiodarone Calcium channel blockers p-Blockers
Complication
Visual disturbances,seizures,syncope Headache,tinnitus, diplopia Syncope, lupuslike syndrome, lightheadedness Seizures,agitation, psychosis, diplopia,tremor, myoclonus Vertigo, confusion, psychosis Tremor, ataxia, neuropathy Vertigo, headache,tremor, confusion weakness Depression, confusion
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LEE&RAPS
athy with obtundation or coma. The evaluation of encephalopathy in organ transplantation represents a challenge that requires knowledge of different subspecialties. A thorough review of the history, including laboratory and pharmacologic data, is needed. The time course for the onset of symptoms may help determine the underlying cause of the encephalopathy. In the immediate postoperative period (within 48 hours after surgery), acute confusional states are usually related to a global hypoxic-ischemic insult.42,8s Other potential causes include metabolic abnormalities, renal and hepatic dysfunction, multiple organ failure, and sepsis. In patients with impaired hepatic and renal function, poor metabolism and excretion of anesthetics and other sedating medications should be considered. Altered mental status occurring 2 to 5 days after surgery may be the result of intensive care psychosis, which may resolve with neuroleptics or environmental reorientati~n.~~ If the encephalopathic symptoms persist beyond 2 weeks despite correction of metabolic abnormalities, a careful search for opportunistic brain infection should be instituted. Encephalopathy is a severe side effect of cyclosporine and occurs in approximately 5% of patients taking the drugs1 These patients may present with decreased level of consciousness, headache, dysarthria, depression, mania, cortical blindness, visual hallucinations, and seizures.1wMagnetic resonance (MR) imaging studies may demonstrate widespread edema and leukoencephalopathy.81.'00 This syndrome is usually found in patients with elevated blood cyclosporine levels; however, other factors, such as hypocholesterolemia, hypomagnesemia,highdose steroids, hypertension, and uremia may, be involved as well.50,1w All symptoms are reversible with temporary discontinuation or decreased dosing. A similar constellation of symptoms is observed in patients with FK 506 t o ~ i c i t y . ~ ~ , ~ ~
Seizure Seizures are a common occurrence in transplant recipients, manifesting in 6% to 36% of As always, a seizure should be considered a symptom of central nervous system dysfunction, and an underlying cause must be determined. Often helpful is the determination of the seizure type at onset (partial versus generalized) and its localization. The most common causes of seizures in the transplant population include drug toxicity (especially cyclosporine, FK 506, and OKT3), metabolicderangements, and hypoxic-ischemicinj~ry.~5 Less common causes of seizures are strokes and infections. Central nervous system infections, another cause for seizures in this population, tend to occur several weeks to months after organ transplantation. Diagnostic evaluation of posttransplantation seizures should include routine electrolytes and drug levels (cyclosporineand FK 506) as well as neuroimaging (CT or preferably MR imaging) to assess the possibility of a structural lesion, such as infarct, hemorrhage, or abscess. The electroencephalogramis useful for determining background rhythms (as in encephalopathy) as well as paroxysmal activity. Periodic lateralized epileptiform discharges, for example, are often associated with acute cerebral events.l6In addition, the nature of the epileptifbrm discharges (focal versus generalized) may help in the selection of appropriate therapy. Lumbar puncture should be performed in patients with seizures if there is any suspicion of infection. The lumbar puncture should be preceded by brain imaging in the presence of focal neurologic findings or signs of increased intracranial pressure. Treatment of seizures with some anticonvulsants (i.e., phenytoin, phenobarbital, and carbamazepine) is complicated by their metabolism via the hepatic cy-
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tochrome oxygenase P-450 The most commonly used immunosuppressants (cyclosporine and FK 506) are metabolized by the same system and when combined with anticonvulsants may result in accelerated metabolism. For this reason, the decision to start antiepileptic therapy is a difficult one. Frequently the predisposition to seizures is transient and merely requires the correction of the metabolic derangement or adjustment of immunosuppressant dosing. Isolated seizures in the setting of organ transplantation rarely lead to epilepsy; therefore, long-term anticonvulsant drug therapy is seldom needed. In cases in which seizures are refractory, benzodiazepines are best for short-term management in this p ~ p u l a t i o n . ~Valproic ',~~ acid has been used for the long-term management of seizures in transplant recipients because the drug does not induce hepatic metabolism of cyclosporine or FK 506.7sIts side effects and the lack of a parenteral formulation, however, make it difficult to use in these settings. Gabapentin, a relatively new anticonvulsant, has no enzyme-inducing properties, few systemic side effects, and little interaction with commonly used drugs in tran~plantation.~'~ Although few data are available for its efficacy in the transplant population, its properties make this drug a promising alternative for seizure management.75 Neuropathies
In organ transplantation, as in other prolonged operations, peripheral nerve injuries can occur. The incidence ranges from 5% of renal transplant recipients to ~,~~ nerve as high as 13% of patients undergoing cardiac p r o c e d ~ r e s .Peripheral injuries may result from intraoperative rnalpositioning of pharmacologically paralyzed patients, stretching owing to prolonged retraction, or local hematoma formation with nerve compression. The most common nerve injured under general anesthesia is the ulnar nerve, usually at the cubital Accentuated extension or flexion at the elbow may cause injury at this site.ss Each transplantation procedure is associated with a predisposition to a unique set of peripheral nerve injuries. For example, femoral and lateral femoral cutaneous neuropathies are seen in renal transplant whereas lower brachial plexus stretch injuries occur in heart transplant r e c i p i e n t ~Another .~~ mechanism of nerve injury observed in cardiac transplantation is cold-induced phrenic nerve damage caused by packing the heart in ice at the time of the procedure.88 PERIOPERATIVE COMPLICATIONS UNIQUE TO SPECIFIC TRANSPLANT PROCEDURES Kidney Transplantation
The kidney is the most frequently transplanted organ with more than 10,000 transplants per year worldwide. It was the first successful organ transplanted from one identical twin to another by Murray and colleagues in 1954.72Since that historic operation, kidney transplants have developed into the best accepted therapy for most causes of end-stage renal failure. The indications for renal transplantation include glomerulonephritis, diabetes, hypertensive kidney disease, pyelonephritis, polycystic kidney disease, and systemic lupus erythematosus. The 1-year survival for transplant recipients is close to 100% with an 85% to 95% graft survival rate.53Despite these advances, neurologic complications of renal transplants remain relatively common. In one large series, neurologic events occurred in 30% of transplant recipient^.^ The renal transplantation procedure itself carries little risk. There are few
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LEE&RAPS
neurologic complications specific to the procedure, aside from the risk of general anesthesia. The most common compressive neuropathies after kidney transplantation involve the femoral and lateral femoral cutaneous nerves.49Compressive femoral neuropathies, usually caused by local hematoma formation rather than retraction injury, are seen in 1.5%to 8.4%of transplant recipient^.^^,^,^^ The lateral femoral cutaneous nerve, however, is usually exposed and retracted during the procedure and is affected in 2.4%of patients in one seriesE9Another rare complication of renal transplantation occurs in patients with anomalous blood supply to the distal spinal cord. In these patients, blood to the caudal spinal cord is supplied by branches of the internal iliac artery, rather than the intercostal arteries. When the iliac artery is used to supply blood to the allograft, spinal cord ischemia may result.& The most common neurologic complications after kidney transplant are cerebrovascular events, occurring in 9.5% of patients in one large retrospective review.3 Most of these events, however, occurred well after transplantation (>6 months).The high incidence of cerebrovascular events appears to be related to the underlying diseases for which renal transplants are performed, including diabetes, hypertension, and lupus.3In addition, disturbances in serum levels of cholesterol, triglycerides, and lipoproteins are frequently observed in this p o p ~ l a t i o nHe.~~ matologic abnormalities and secondary polycythemia, observed in renal transplant recipients, may also contribute to thromboembolic events.21,62 Liver Transplantation After the first human liver transplant was performed in 1963 by Starzl and colleaguesP it took another 20 years before the procedure was recognized as an effective treatment for end-stage liver disease.73Despite the current 1-yearsurvival rate of up to 83%,48liver transplantation carries a high incidence of complications, not only due to the surgical procedure itself, but also to the precarious state of the patient before surgery. Neurologic complications occur in up to 80%of adult transplant recipients and are among the most important causes for morbidity and mortality in this p ~ p u l a t i o n . ~70,78,94,96,99 , ~ ~ , ~ ~Liver , transplantation is carried out for a number of hepatic diseases, including viral hepatitis, alcoholic liver disease, primary biliary cirrhosis, acute liver failure or toxins, and c h o l a n g i t i ~ The . ~ , ~shortage ~ of organs frequently necessitates a long waiting period before transplantation. Therefore, transplant recipients are often critically ill and usually have some degree of hepatic encephalopathy before surgery.” In addition, this population is more prone to central nervous system hemorrhages in the perioperative period as a result of coagulopathies associated with liver failure. Orthotopic liver transplantation is a relatively standardized but demanding operative pr0~edui-e.~~ The operation may be broken down into three phases: dissection, anhepatic stage (removal of the diseased liver and implantation of the donor liver), and r e p e r f ~ s i o nIn . ~the ~ past, a venovenous bypass was used routinely in all operations during the anhepatic More recently in many institutions, venous bypass is used only if needed for hemodynamic stability.101 Bypass is initiated by dissection of the left axillary and saphenous veins. Cannulas are placed in the saphenous and portal veins to return blood via a centrifugal pump to the axillary vein. Significant blood loss during the procedure is not uncommon, and patients often require massive replacements of blood and electrol y t e ~ . ’predisposing ~.~~ them to diffuse hypoxic-ischemic damage to the brain or watershed infarctions. In several clinical series, the most common perioperative neurologic compli-
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cation of liver transplantation was encephalopathy, which ranged in severity from confusion to c 0 m a . ~ , a , ~ 0 ,The ~ 8 , ~myriad ~ , ~ ~ of causes of encephalopathy in this population includes metabolic derangements (including preexistent hepatic encephalopathy), drug toxicity (in particular, cyclosporine and FK 506), hypoxicischemic brain injury, and sepsis. Autopsy series in the perioperative period reveal that the most common causes for encephalopathy in liver transplant recipients were metabolic and hypoxic-ischemic injury.b4,65,78 Central pontine myelinolysis (CPM) is an unusual neurologic complication that occurs at increased frequency in liver transplant patients. In various neuropathologic studies, CPM has been consistently found in 7%to 19% of liver transplant recipient^.^^,^^,^^,^^^,^^ Typically the disorder results in symmetric noninflammatory demyelination of the basis pontis with relative sparing of neurons and a ~ o n s . ~Extrapontine O~ myelinolysis has also been ob~erved."~~ The cause is unknown, but it is thought to be the result of rapid correction of h y p ~ n a t r e m i a . ~ ~ , ~ ~ During the transplant procedure, wide fluctuations in serum sodium concentrations occur as a result of the rapid replacement of intraoperative blood loss with intravenous fluids and blood products that contain high concentrations of soIn the past, CPM has been an infrequent clinical diagnosis, usually found unexpectedly at autopsy. Advances in neuroimaging techniques, however, have made the diagnosis of CPM much more common. Clinical manifestations include altered mental status or coma, pseudobulbar palsy, and q ~ a d r i p l e g i a . ~ ~ , ' ~ ~ Injury to the lower brachial plexus is the most common peripheral nerve injury observed in liver transplantation, occurring in up to 6% of patient^.^^,^^,'^^ It is believed that the injury occurs during the axillary dissection required for access to the axillary vein for venovenous by pa^^.^^,^^,^^^ More recent changes in the use of venous bypass may reduce the rate of this complication. Heart Transplantation
Since the first human heart transplant was performed by Barnard in 1967," the procedure has become an accepted method for treating intractable heart failure. The introduction of effective immunosuppressants (in particular, cyclosporine) and advances in operative and postoperative management have dramatically improved survival in cardiac transplant patient^.^^^,^^ Conditions for which cardiac transplants are performed include cardiomyopathies, atherosclerotic cardiovascular disease, valvular heart disease, and congenital heart defects.7sAll of these conditions predispose patients to cerebrovascular events even before transplantation. Although graft rejection and infection are major causes of mortality, neurologic complications may occur in up to 60% of patients and substantially influence morbidity and subsequent quality of life.5~6~42~43~b3~b6~69~n6~8H Cardiopulmonary bypass is a potential cause of major neurologic complications independent of the heart surgery itself. Bypass begins with the cannulation of the ascending aorta and vena cava or right atrium, eventually followed by crossclamping of the aorta immediately before initiation of cardiopulmonary bypass. Cannulation of a diseased ascending aorta can dislodge atheromatous material, leading to cerebral emboli. There is an additional risk of introducing air emboli when the procedure is completed and the aortic cross-clamp is released. During extracorporeal circulation, exposure of the blood to nonendothelial surfaces increases the risk of embolus formation from platelet aggregation or disruption of fibrin. In addition, this exposure can result in platelet and coagulation factor consumption, leading to an incremental risk of intracranial h e m ~ r r h a g eThe . ~ ~use of anticoagulants during bypass further compounds this risk. Although mean arterial
and central venous pressures are monitored during cardiopulmonary bypass, prolonged bypass times increase the risk of exposure to periods of hypotension and hypo~ia.~~.~~ Autopsy series of cardiac transplant recipients surviving less than 1 month after surgery confirm the known risks of cardiac surgery with bypass. The most common neuropathologic finding is cerebral infarction (both focal and diffuse ischemic-anoxic injury), accounting for 16%to 43% in some autopsy ~ e r i e s .A~ ~ , ~ ~ clinical retrospective review revealed far fewer neurologic complications (5%)in the perioperative p e r i ~ dClinical .~ manifestations of the cerebrovascular events include stroke with focal neurologic deficits, a confusional state, or severe encephalopathy with obtundation or coma. Encephalopathy with psychosis in the immediate postoperative period usually implicates global hypoxic-ischemic mechanisms. Metabolic derangements, multiple organ failure, and sepsis, however, may present with encephalopathy as well. Rarely, seizures in the immediate postoperative period may be associated with focal embolic events.43Seizures occurring in the later postoperative period are more often due to metabolic disturbances, particularly hypomagnesemia related to cyclosporine use. Peripheral nervous system injuries are also relatively common in cardiac transplantation, similar to those complicating open heart surgery (present in 13% of cases)? The most common injury involves the lower brachial plexus caused by stretching during chest wall retraction or compression by a hematoma. Patients with lower brachial plexus injury present with weakness and numbness in the distal arm often with a diminished triceps reflex. Recurrent laryngeal injury leading to vocal cord paralysis may also be the result of traction. The phrenic nerve may be damaged by cold-induced injury from packing the heart in ice at the time of the tran~plantation.~~ Frequently, these patients manifest clinically with diaphragmatic paralysis and difficulty weaning from mechanical ventilation or prolonged postoperative hiccups. After transplantation, patients remain at risk for cerebrovascular events owing to cardiac emboli, underlying atherosclerosis, and postoperative arrhythmias.' Lung Transplantation
Pulmonary transplantation is a relatively new procedure with few data available regarding neurologic complications. The first successful human lung transplant was performed by the Toronto Lung Transplant Group in 1983.98Since that time, the number of transplants performed annually has continued to increase. The number of disease causes treated with lung transplantation has grown as well and includes emphysema (including a,-antitrypsin deficiency),cystic fibrosis, pulmonary hypertension, idiopathic pulmonary fibrosis, and obliterative bronchiolitis.20The 1-year survival for patients undergoing single-lung transplant exceeds 90%, whereas bilateral lung transplant approaches 80%.17,18,33 The lung transplant procedure has evolved over the past decade. The use of cardiopulmonarybypass in lung transplantation is dependent on right ventricular function after clamping the pulmonary artery before extraction of the diseased lung. If right ventricular function is significantly impaired after clamping, the single-lungtransplant is performed using cardiopulmonary bypass with the lungs deflated.20After implantation of the donor lung, the bronchial anastomosis is carried out, followed by pulmonary artery, then pulmonary vein/left atrial anastomosis.20The left atrial anastomosis has been the subject of some scrutiny after reports of thrombus formation on the anastomotic site in several patient^.^^,^^,^^," Few data exist regarding the neurologic complications associated with lung transplantation. Therefore, the authors have reviewed the perioperative neuro-
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logic complications after lung transplantation at the University of Pennsylvania Medical Center (unpublished observation). A total of 108 consecutive lung transplants were performed between October 1993 and October 1995. The records of these patients were reviewed up to 30 days after the transplant procedure, and neurologic complications were recorded. A total of 21 (19%)transplant recipients had 27 neurologic complications (Table 2). Encephalopathy (ranging from confusion to coma) was the most common neurologic sequela of transplantation, affecting 11 patients (10%). Although the majority of cases were due to metabolic causes (7.4%),drug toxicity also contributed in some (2.8%).Seizures occurred in four transplant recipients (3.7%)and were caused by metabolic derangements, cyclosporine toxicity, and stroke. Cerebrovascularevents were also relatively common: Hypotensive watershed infarcts were seen in four patients (3.7%),embolic infarcts in four, and a hemorrhage in the region of a watershed infarct in one patient. Investigations into potential sources of emboli revealed left atrial thrombi on transesophageal echocardiography (TEE)in two patients. The pulmonary vein/left atrial anastomosis may represent an important source of emboli in lung transplant recipients. Stang and associatesgoreported a cerebral infarct in a patient 4 weeks after bilateral lung transplant. A left atrial thrombus at the site of anastomosis was demonstrated on TEE. Moreover, in a prospective study of 21 lung transplant recipients, pulmonary vein thrombosis was detected on TEE in 5 patients (24%)in the immediate postoperative period.59 In the authors' series, complications involving the peripheral nervous system were present in three patients. Acute quadriplegic myopathys2was diagnosed in a patient requiring vecuronium for ventilation in the setting of routine steroid administration for immunosuppression. Another patient developed proximal muscle weakness thought to be due to steroid myopathy. Phrenic nerve injury was diagnosed on electromyography in a third patient.
SUMMARY
Despite the advances in organ transplantation technology, neurologic complications remain a significant cause of morbidity and mortality. Many of the complications, including encephalopathy, seizures, and peripheral nerve injuries, are common to all transplant types. Other complications are unique to each transplant procedure. Kidney transplantation is a fairly benign procedure and is not
Table 2. PERIOPERATIVE NEUROLOGIC COMPLICATIONS OF LUNG TRANSPLANTATION (UNIVERSITY OF PENNSYLVANIA MEDICAL CENTER SERIES) Complications Encephalopathy Metabolic Drug-related Cerebrovascular events Watershed infarcts Ernbolic infarcts Hemorrhage Seizures Neuropathylrnyopathy
No. Patients (YO) 8 (7.4) 3 (2.8)
4 (3.7) 4 (3.7) 1 (0.9) 4 (3.7)
3 (2.8)
Cause
Steroids and cyclosporine Hypotension Left atrial clot seen in 2 patients Hemorrhagic conversion of watershed infarct Metabolic derangements (2), cyclosporine toxicity ( l ) , cerebral infarct (1) Acute quadriplegic rnyopathy, steroid rnyopathy, phrenic nerve injury
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associated with significant perioperative morbidity. Liver transplantation is associated with significant neurologic complications, including hepatic encephalopathy and central pontine myelinolysis. Heart and lung transplants are often associated with both hypoxic-ischemic injury and cerebral infarction, frequently from a cardiac source of embolus. With increasing numbers of transplants being performed every year, it is important for the neurologist to be familiar with complications of organ transplants. The neurologist plays an important role in diagnosing and managing neurologic complications of transplantation. References 1. Adair J, Call G, OConnell J, et al: Cerebrovascular syndromes following cardiac transplantation. Neurology 422319, 1992 2. Adams D, Gunson B, Honigsberger L, et a1 Neurological complications following liver transplantation: Lancet 1:949, 1987 3. Adams H, Dawson G, Coffman T, et al: Stroke in renal transplant patients. Arch Neurol 43:113,1986 4. Adams J, Brierly J, Connor R, et al: The effects of systemic hypotension upon the human brain: Clinical and neuropathological observations in eleven cases. Brain 89:235, 1966 5. Andrews B, Hershon J, Calanchini P, et a1 Neurologic complications of cardiac transplantation. West J Med 153:146, 1990 6. Ang L, Gillett J, Kaufman J: Neuropathology of heart transplantation. Can J Neurol Sci 16:291, 1989 7. Arieff A, Cooper J, Armstrong D: Dementia, renal failure, and brain aluminum. Ann Intern Med 90:741, 1979 8. Barnard C: The operation-a human cardiac transplant: An interim report of a successful operation -performed at Groote Schuur Hospital, Cape Town.-S Afr Med J 41:1271,1967 9. Belle S, Detre K Report from the Pitt-UNOS liver transplant registry. Transplant Proc 251137,1993 10. Bernuau J, Rueff 8, Benhamou J: Fulminant and subfulminant liver failure: Definition and causes. Semin Liver Dis 6:97,1986 11. Blanco R, DeGirolami U, Jenkins R, et al: Neuropathology of liver transplantation. Clin Neuropathol14:109,1995 12. Blei A: Cerebral edema and intracranial hypertension in acute liver failure: Distinct aspects of the same problem. Hepatology 13:376,1991 13. Bogousslavsky J, Hachinski V, Boughner D, et al: Cardiac and arterial lesions in carotid transient ischemic attacks. Arch Neurol43:223, 1986 14. Busuttil R, Colonna J, Hiatt J, et al: The first 100 liver transplant at UCLA. Ann Surg 206:387, 1987 15. Capocaccia L, Angelic0 M: Fulminant hepatic failure: Clinical features, etioloav, -, epidemiology and current management. Digbis Sci 36:775,1991 16. Chatrian G , Shaw C, Leffman H: The significance of periodic epileptiform discharges in the EEG: An electrographic, clinical and pathological study. Electroencephalogr Clin Neurophysiol17:115, 1964 17. Cooper J, Patterson G, Pohl M: Current status of lung transplantation: Report of the St. Louis International Lung Transplantation Registry. Chest 103:46, 1992 18. Cooper J, Patterson G, Trulock E, et a1 Results of 131 consecutive single and bilateral lung transplant recipients. J Thorac Cardiovasc Surg 107460, 1994 19. Daverat P, Janvier G, Duche B, et a1 Myelinolyse centropontine apres transplantation hepatique. Rev Neurol (Paris) 148687,1992 20. Davis R. PasqueM..Pu\mocra.ry tcar\sp\ar\tatio. AnnSv.xg'X'XV.14.1995 21. Dintenfass L, Ibels L. Blood viscosity factors and occlusive arterial disease in renal transplant recipients. Nephron 15:456, 1975 22. JMelman B, Abu-Elmagd K, Wilson J, et al: Neurologic complications of 506. Transplant Proc 23:3175, 1991
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23. Eidelman B, Obrist W, Wagner W, et al: Cerebrovascular complications associated with the use of artificial circulatory support services. Neurol Clin 11:463, 1993 24. Estol C, Faris A, Martinez A, et a 1 Central pontine myelinolysis after liver transplantation. Neurology 39:493, 1989 25. Estol C, Lopez 0, Brenner R, et al: Seizures after liver transplantation: A clinicopathologic study. Neurology 39:1297, 1989 26. Ferreiro J, Robert M, Townsend J, et al: Neuropathologic findings after liver transplantation. Acta Neuropathol84:1, 1992 27. Fraser C: Neurologic manifestations of the uremic state in metabolic brain dysfunction in systemic disorders. Ann Intern Med 109:143, 1992 28. Fraser C, Arieff A: Nervous system complications in uremia. Ann Intern Med 109:143, 1988 29. Freise C, Rowley H, Lake J, et a1 Similar clinical presentation of neurotoxicity following FK 506 and cyclosporine in a liver transplant recipient. Transplant Proc 23:3173, 1991 30. Fuster V, Gersh B, Giuliani E, et a1 The natural history of idiopathic dilated cardiomyopathy. Am J Cardiol47525, 1981 31. Gilmore R Seizures and antiepileptic drug use in transplant patients. Neurol Clin 6:279, 1988 32. Ginsberg M, Hedley-White T, Richardson E: Hypoxic ischemic leukoencephalopathy in man. Arch Neurol33:5,1976 33. Griffith 8,Bando K, Armitage J, et al: Lung transplantation at the University of Pittsburgh. Clin Transpl13:149,1992 34. Griffith BP, Hardesty RL, Bahnson MT: Powerful but limited immunosupression for cardiac transplantation with cyclosporin and low-dose steroid. J Thorac Cardiovasc Surg 8735,1984 34a. Hall W, Martinez A: Neuropathology of pediatric liver transplantation. Pediatr Neurosci 15:269, 1989 35. Hanid M, Davies M, Mellon P, et al: Clinical monitoring of intracranial pressure in fulminant hepatic failure. Gut 21:866, 1980 36. Harden C: New antiepileptic drugs. Neurology 44:787,1994 38. Hausmann D, Daniel W, Mugge A, et a1 Imaging of pulmonary artery and vein anastomosis by transesophageal echocardiography after lung transplantation. Circulation 86:251, 1992 39. Heck C, Shumway S, Kaye M: The registry of the International Society for Heart Transplantation: 6th Official Report 1989. Chicago Int SOCHeart Transplant 8:271, 1989 40. Helgason C, Shaman D: Neurologic manifestations of cardiac disease. Neurol Clin 7469,1989 41. Holt A, McCAll PR, Gutteridge G, et al: Plasma osmolality changes during liver transplantation. Transplant Proc 23:1986,1991 42. Hotson J, Enzmann D: Neurologic complications of cardiac transplantation. Neurol Clin 6:349, 1988 43. Hotson J, Pedley T: The neurological complications of cardiac transplantation. Brain 99:673, 1976 44. Humphreys R, Hoffman H, Mustard W, et al: Cerebral hemorrhage following heart surgery. J Neurosurg 43:671,1975 45. Jbels L, Simons L, King J, et al: Studies on the nature and causes of hyperlipidemia in uremia, maintenance dialysis and renal transplantation. QJM New Series 44 176:601, 1981 46. Jablecki C, Aguilo J, Piepgras D, et al: Paraparesis after renal transplantation. Ann Neurol2:154, 1977 47. Jansen P, Gribnau F, Schulte 8,et al: Contribution of inappropriate treatment for hypertension to pathogenesis of stroke in the elderly. BMJ 293:914, 1986 48. Jenkins R Liver transplantation in the adult. Transplant Rev 1:1, 1987 49. Junaid I, Kwan J, Lord R Femoral neuropathy in renal transplantation. Transplantation 56:240, 1993 50. Kahan BD Cyclosporine. N Engl J Med 321:1725, 1989 51. Katelaris P, Jones D Fulminant hepatic failure. Med Clin North Am 73:955, 1989 52. Katirji M: Brachial plexus injury following liver transplantation. Neurology 39:736,1989 53. Keown P, Shackleton C, Ferguson B: Long-term mortality, morbidity, and rehabilitation
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in organ transplant recipients. In Leendert PC, Solez K (eds): Organ Transplantation: Long-Term Results. New York, Marcel Dekker, 1992, p. 57 54. Kramer D, Agganval S, Martin M, et al: Management options in fulminant hepatic failure. Transplant Proc 23:1895,1991 55. Kroll D, Caplan R, Posner K, et al: Nerve injury associated with anesthesia. Anesthesiology 73:202, 1990 56. Krom R, Wiesner R, Tettke S, et al: The first 100 liver transplantations at the Mayo Clinic. Mayo Clin Proc 64:84, 1989 57. Lake K: Management of drug interactions with cyclosporine. Pharmacotherapy ll:llOS, 1991 58. Lederman R, Breuer A, Hanson M, et a1 Peripheral nervous system complications of coronary artery bypass surgery. Ann Neuroll2297,1982 59. Leibowitz D, Smith C, Michler R, et al: Incidence of pulmonary vein complications after lung transplantation: A prospective transesophageal echocardiographic study. J Am Coll Cardiol24671,1994 60. Lockwood A. Neurologic complications of renal disease. Neurol Clin 7617,1989 61. Mahoney C, Arieff A Central and peripheral nervous system effects of chronic renal failure. Kidney Int 24:170, 1983 62. Makovi C, Williams C, Roman J: Polycythemia of renal transplantation. NC Med J 41:23, 1980 63. Martin A, Bricker J, Fishman M, et a1 Neurologic complications of heart transplantation in children. J Heart Lung Transplant 11:933,1992 64. Martinez A, Ahdab-Barmada M: The neuropathology of liver transplantation: Comparison of main complications in children and adults. Mod Pathol6:25, 1993 65. Martinez A, Conrad0 E, Faris A: Neurologic complications of liver transplantation. Neurol Clin 6:327, 1988 66. Martinez A, Puglia J: The neuropathology of liver, heart, and heart-lung transplantation. Transplant Proc 20:806, 1988 67. Mawk J, Shaw B, Wood R, et al: Neurosurgical complications of pediatric orthotopic liver transplantation. Child Nerv Syst 4:26, 1988 68. Menegaux F, Keeffe E, Andrews 8, et al: Neurological complications of liver transplantation in adult versus pediatric patients. Transplantation 58:447, 1994 69. Montero G, Martinez Neuropathology of heart transplantation: 23 cases. Neurology 36:1149, 1986 70. Moreno E, Gomez S, Gonzalez I, et a1 Neurologic complications in liver transplantation. Acta Neurol Scand 8725,1993 71. Munoz S, Robinson M, Northrup B: Elevated intracranial pressure and computed tomography of the brain in fulminant hepatocellular failure. Hepatology 13:209, 1991 72. Murray J, Merrill J, Harrison J: Renal homotransplantation in identical twins. Surg Forum 6:432,1955 73. NIH consensus development conference statement: Liver transplantation, June 20-23, 1983. Hepatology 4:107S, 1984 74. Norenberg M, Leslie K, Robertson A: Association between rise in serum sodium and central pontine myelinolysis. Ann Neurol 11:128, 1982 75. Patchell R Neurological complications of organ transplantation. Ann Neurol 36:688, 1994 76. Pham S, Armitage JM, Katz WE, et a1 Left atrial thrombus after lung transplantation. Ann Thorac Surg 59:513, 1995 77. Pontin A, Donaldson R, Jacobson J: Femoral neuropathy after renal transplantation. South Afr Med J 53:376,1978 78. Pujol A, Graus F, Rimola A, et al: Predictive factors of in-hospital CNS complications following liver transplantation. Neurology 441226, 1994 79. Raskin N, Fishman R: Neurologic disorders in renal failure. N Engl J Med 294:143,1976 80. Read W, Anderson R Effects of rapid blood pressure reduction on cerebral blood flow. Am Heart J 111:226,1986 81. Reece D, Frei-Lahr D, Shepherd J, et a1 Neurologic complications in allogeneic bone marrow transplant patients receiving cyclosporin. Bone Marrow Transplant 8393,1991 82. Rich M, Teener J, Raps E, et a1 Muscle is electrically inexcitable in acute quadriplegic myopathy. Neurology 46:731,1996 83. Rothstein J, Garland W, Puia G, et a 1 Purification and characterization of naturally
A:
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84. 85. 86. 87.
88. 89. 90. 91. 92. 93. 94. 95. 96. 97. 98. 99.
100. 101.
102. 103.
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occurring benzodiazepine receptor ligands in rat and human brain. J Neurochem 48:2102, 1992 Rothstein J, McKhann G: Hepatic encephalopathy. In Johnson RT: Current Therapy in Neurologic Disease, ed 3. Philadelphia, Mosby, 1990, p. 352 Schmid C, Gulba D, Heublein B, et al: Systemic recombinant tissue plasminogen activator lysis for left atrial thrombus formation after single-lung retransplantation. Ann Thorac Surg 53:338,1992 Schober R, Herman M: Neuropathy of cardiac transplantation: Survey of 31 cases. Lancet 1:962, 1973 Shaw B, Martin D, Marquez J, et al: Advantages of venous bypass during orthotopic transplantation of the liver. Semin Liver Dis 5:344, 1985 Sila C: Spectrum of neurologic events following cardiac transplantation. Stroke 20:1586, 1989 Sisto D, Chiu W, Geelhoed G, et al: Femoral neuropathy after renal transplantation. South Med J 73:1454, 1980 Stang M, Hinderliter A, Gott K, et al: Atrial anastomotic thrombus causes neurologic deficits in a lung transplant recipient. Transplantation 62693, 1996 Starzl T, Iwatsuki S, Esquivel C, et al: Refinements in the surgical technique of liver transplantation. Semin Liver Dis 5:349, 1985 Starzl T, Marchiaro T, Von Kaulla K, et al: Homotransplantation of the liver in humans. Surg Gynecol Obstet 117:659, 1963 Starzl T, Schneck S, Mazzoni G, et al: Acute neurological complications after liver transplantation with particular reference to intraoperative cerebral air embolus. Ann Surg 187236, 1978 Stein D, Lederman R, Vogt D, et al: Neurological complications following liver transplantation. Ann Neurol31:644, 1992 Sterns R, Eggs J, Schochet S: Osmotic demyelination syndrome following correction of hyponatremia. N Engl J Med 314:1535, 1986 Sterzi R, Santilli I, Donato M, et al: Neurologic complications following orthotopic liver transplantation. Transplant Proc 26:3679, 1994 Sulkawa R, Erkinjuntii T: Vascular dementia and systemic hypotension. Acta Neurol Scand 76:123,1987 Toronto Lung Transplant Group: Unilateral lung transplantation for pulmonary fibrosis. N Engl J Med 3141140,1986 Vogt D, Lederman R, Carey W, et al: Neurologic complications of liver transplantation. Transplantation 45:1057, 1988 Walker R, Brochstein J: Neurologic complications of immunosuppressive agents. Neurol Clin 6:261, 1988 Wall W, Grant D, Duff J, et al: Liver transplantation without venous bypass. Transplantation 4356, 1987 Winnock S, Janvier G, Parmentier F, et al: Pontine myelinolysis following liver transplantation: A report of two cases. Transpl Int 6:26, 1993 Wszolek Z, McComb R, Pfeiffer R, et al: Pontine and extrapontine myelinolysis following liver transplantation. Transplantation 48:1006, 1989
Address reprint requests to: Eric C . Raps, MD Department of Neurology University of Pennsylvania Medical Center 3400 Spruce Street, 3 West Gates Philadelphia, PA 19104
IATROGENIC DISORDERS
+ .OO
NEUROLOGIC COMPLICATIONS OF TRANSPLANTATION Jin-Moo Lee, MD, PhD, and Eric C. Raps, MD
Organ transplantation traces its birth to a landmark operation performed by Murray in Boston in 1954 in which an identical twin received a donated sibling kidney.72Over the decades since that seminal procedure, the field of organ transplantation has grown exponentially, largely fertilized by the advent of ever more powerful and precise immunosuppressive agents. With the increase in organ transplantation, health professionals have seen a considerable number of associated neurologic complications. In some instances, these complications are a function of the individual nature of the transplant surgery, whereas in others, neurologic dysfunction is the result of exposing an ill patient to a prolonged, often difficult operation. Complications may be familiar, such as perioperative encephalopathy or seizure, or they may be unique, such as suture line embolus in lung transplantation. The transplant team may call on the neurologist to assist in the management of neurologic complications before transplantation as a result of organ system failure and encephalopathy, during the perioperative period as a result of the surgical procedure and associated therapies, and in the weeks and months after transplantation as a result of nervous system dysfunction secondary to immunosuppression and organ rejection. The complications inherent to immunosuppression are discussed in detail elsewhere in this issue. PRETRANSPLANT NEUROLOGIC COMPLICATIONS IN ORGAN FAILURE
Before any discussion of perioperative neurologic complicationsin transplantation, an overview of organ failure and the brain is warranted. Transplantation is reserved for patients suffering imminent or impending organ failure. Symptoms referable to the central or peripheral nervous system are frequently apparent in From the Department of Neurology, University of Pennsylvania Medical Center, Philadelphia, Pennsylvania (ECR); and Department of Neurology, Washington University Medical Center, St. Louis, Missouri (JML) NEUROLOGIC CLINICS OF NORTH AMERICA
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VOLUME 16.NUMBER 1 FEBRUARY 1998
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patients awaiting transplantation. The degree of cerebral involvement, in particular, often correlates with the pace of organ failure because the brain is quite resilient if allowed sufficient time to compensate for chronic organ dysfunction.
Renal Failure Neurologic dysfunction, both peripheral and central, is a major cause of morbidity in patients with end-stage renal disease. Both acute and chronic uremia produce characteristic neurologic symptoms. Dialysis has been associated with at least two forms of neurologic disturbance-dialysis dysequilibrium syndrome and dialysis dementia.7,27,28,60,61,79 Although the patient awaiting renal transplantation may be managed with various forms of dialysis, ultimately the toxic effects of both renal failure and dialysis almost certainly produce neurologic impairment unless a donor kidney is found. The normal human kidney is designed to maintain continuous fluid and electrolyte homeostasis. Renal failure results in a steady, rapid rise in blood urea nitrogen (BUN). Acutely, this rise produces a progression of symptoms beginning with anorexia, nausea, insomnia, and restlessness; proceeding to paranoia, drowsiness, and sluggishness; and finally culminating in myoclonus, asterixis, seizures, stupor, and coma. Physical examination may reveal cranial nerve signs, nystagmus, fasciculations, and clonus.7,27,28,M),61,79 Although uremia results in a variety of biochemical and metabolic changes in the brain, the precise mechanism by which uremic encephalopathy occurs remains unclear. Certainly, abnormalities in brain energy utilization may contribute to the encephalopathy.@' In addition, excessive parathyroid hormone secretion in uremic patients may contribute to central nervous system t o x i ~ i t y . ~ ~ , ~ ~ , ~ ~
Hepatic Failure Hepatic encephalopathy refers to the constellation of neuropsychiatric abnormalities that occurs as the result of either acute or chronic liver disease. If the encephalopathydevelops within 2 to 8 weeks of the onset of jaundice, the patient has fulminant hepatic f~ilure.~~,'~,~~ Onset of encephalopathy from several weeks to 3 months after the onset of jaundice is referred to as subfulminant liver failure.Io Chronic hepatic encephalopathy is more common and refers to the episodic encephalopathic deteriorations seen in patients with chronic hepatocellular disease.84 Between 25% and 35% of the liver transplants performed at the University of Pennsylvania over the past 5 years were done on a stat basis for rapidly deteriorating liver function. The cause of hepatic encephalopathy remains controversial.Previously, studies have focused on ammonia and false neurotransmitters as possible mediators of neuronal d e p r e s ~ i o n .More ~ ~ , ~recent ~ work has implicated endogenous benzodiazepines as likely agents contributing to the en~ephalopathy.~~ It is well recognized that the administration of exogenous benzodiazepines, such as lorazepam or midazolam, to patients with hepatic failure can significantly worsen their level of consciousness and may well contribute to morbidity and mortality. Fulminant hepatic failure is a life-threatening condition characterized by the rapid development of encephalopathy after initial liver i n j ~ r y . * O , ~Up 5 , ~to~80% ,~ of patients with fulminant hepatic failure develop severe, often refractory cerebral edema.12,35,71 The associated elevation in intracranial pressure may be dramatic and is frequently the cause of death in these patient^.^^,^^,^^ The risk of cerebral edema in fulminant hepatic failure is often the driving force behind stat liver transplantation.
NEUROLOGIC COMPLICATIONS OF TRANSPLANTATION
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Cardiopulmonary Failure
Patients awaiting heart transplantation develop neurologic complications on the basis of many factors-some of which may overlap. These include low cardiac output with hypotension and watershed infarction; cardioembolic stroke as a result of arrhythmia, mural thrombus, or valvular disease; medication effect; and the associated failure of other organs, including lungs, kidneys, and ~ive~~4.13.30.32.40.97 The neurologic complications of diminished cardiac output depend largely on the rate and depth of the fall-off in supply.3z~40,47,80 The patient with chronically low cardiac output may complain of fatigue, headache, or tremor. More than three decades ago, Adams and colleagues4 categorized the neuropathologic changes seen in patients with acute and subacute hypotensive injury. Two of the 11patients in this series suffered from underlying cardiomyopathy. Moderate hypotensive injury resulted in diffuse neuronal loss in the cerebral cortex, Purkinje cells, thalamus, and striatum with relative sparing of Ammon’s horns in the temporal lobe.4 More recently, Sulkawa and Erkinjuntiiy7identified 6 patients in a series of 133 patients with vascular dementia who suffered from chronic cerebral hypoperfusion. Five of the six patients had white matter low attenuation apparent on computed tomography (CT) scan without discrete infarction. All six exhibited persistent cognitive decline after onset of cardiac failure.97 Medications used in the therapy of cardiac failure and during the perioperative transplant period may contribute substantially to neurologic d y s f ~ n c t i o n . ~ ~ Additionally, drug metabolism may be significantly attenuated by poor perfusion and impaired hepatic and renal function. Table 1 lists neurologic complications associated with frequently used cardiac agents. The neurologic complications of acute and chronic organ failure remain an important cause of morbidity and mortality in patients awaiting transplantation. Kidney, liver, heart, and lung transplantation have become increasingly successful, and the role of the neurologic consultant to protect the brain during the perioperative period and identify reversible factors contributing to encephalopathy remains critical. PERIOPERATIVECOMPLICATIONS COMMON TO ALL TRANSPLANT PROCEDURES Encephalopathy
In the perioperative period, transplant patients may exhibit behavioral changes ranging from a mild confusional state or psychosis to severe encephalop-
Table 1. NEUROLOGIC COMPLICATIONS OF CARDIAC AGENTS Drug
Digitalis derivatives’ Quinidine Procainarnide Lidocaine Bretylium Amiodarone Calcium channel blockers p-Blockers
Complication
Visual disturbances,seizures,syncope Headache,tinnitus, diplopia Syncope, lupuslike syndrome, lightheadedness Seizures,agitation, psychosis, diplopia,tremor, myoclonus Vertigo, confusion, psychosis Tremor, ataxia, neuropathy Vertigo, headache,tremor, confusion weakness Depression, confusion
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LEE&RAPS
athy with obtundation or coma. The evaluation of encephalopathy in organ transplantation represents a challenge that requires knowledge of different subspecialties. A thorough review of the history, including laboratory and pharmacologic data, is needed. The time course for the onset of symptoms may help determine the underlying cause of the encephalopathy. In the immediate postoperative period (within 48 hours after surgery), acute confusional states are usually related to a global hypoxic-ischemic insult.42,8s Other potential causes include metabolic abnormalities, renal and hepatic dysfunction, multiple organ failure, and sepsis. In patients with impaired hepatic and renal function, poor metabolism and excretion of anesthetics and other sedating medications should be considered. Altered mental status occurring 2 to 5 days after surgery may be the result of intensive care psychosis, which may resolve with neuroleptics or environmental reorientati~n.~~ If the encephalopathic symptoms persist beyond 2 weeks despite correction of metabolic abnormalities, a careful search for opportunistic brain infection should be instituted. Encephalopathy is a severe side effect of cyclosporine and occurs in approximately 5% of patients taking the drugs1 These patients may present with decreased level of consciousness, headache, dysarthria, depression, mania, cortical blindness, visual hallucinations, and seizures.1wMagnetic resonance (MR) imaging studies may demonstrate widespread edema and leukoencephalopathy.81.'00 This syndrome is usually found in patients with elevated blood cyclosporine levels; however, other factors, such as hypocholesterolemia, hypomagnesemia,highdose steroids, hypertension, and uremia may, be involved as well.50,1w All symptoms are reversible with temporary discontinuation or decreased dosing. A similar constellation of symptoms is observed in patients with FK 506 t o ~ i c i t y . ~ ~ , ~ ~
Seizure Seizures are a common occurrence in transplant recipients, manifesting in 6% to 36% of As always, a seizure should be considered a symptom of central nervous system dysfunction, and an underlying cause must be determined. Often helpful is the determination of the seizure type at onset (partial versus generalized) and its localization. The most common causes of seizures in the transplant population include drug toxicity (especially cyclosporine, FK 506, and OKT3), metabolicderangements, and hypoxic-ischemicinj~ry.~5 Less common causes of seizures are strokes and infections. Central nervous system infections, another cause for seizures in this population, tend to occur several weeks to months after organ transplantation. Diagnostic evaluation of posttransplantation seizures should include routine electrolytes and drug levels (cyclosporineand FK 506) as well as neuroimaging (CT or preferably MR imaging) to assess the possibility of a structural lesion, such as infarct, hemorrhage, or abscess. The electroencephalogramis useful for determining background rhythms (as in encephalopathy) as well as paroxysmal activity. Periodic lateralized epileptiform discharges, for example, are often associated with acute cerebral events.l6In addition, the nature of the epileptifbrm discharges (focal versus generalized) may help in the selection of appropriate therapy. Lumbar puncture should be performed in patients with seizures if there is any suspicion of infection. The lumbar puncture should be preceded by brain imaging in the presence of focal neurologic findings or signs of increased intracranial pressure. Treatment of seizures with some anticonvulsants (i.e., phenytoin, phenobarbital, and carbamazepine) is complicated by their metabolism via the hepatic cy-
NEUROLOGIC COMPLICATIONS OF TRANSPLANTATION
25
tochrome oxygenase P-450 The most commonly used immunosuppressants (cyclosporine and FK 506) are metabolized by the same system and when combined with anticonvulsants may result in accelerated metabolism. For this reason, the decision to start antiepileptic therapy is a difficult one. Frequently the predisposition to seizures is transient and merely requires the correction of the metabolic derangement or adjustment of immunosuppressant dosing. Isolated seizures in the setting of organ transplantation rarely lead to epilepsy; therefore, long-term anticonvulsant drug therapy is seldom needed. In cases in which seizures are refractory, benzodiazepines are best for short-term management in this p ~ p u l a t i o n . ~Valproic ',~~ acid has been used for the long-term management of seizures in transplant recipients because the drug does not induce hepatic metabolism of cyclosporine or FK 506.7sIts side effects and the lack of a parenteral formulation, however, make it difficult to use in these settings. Gabapentin, a relatively new anticonvulsant, has no enzyme-inducing properties, few systemic side effects, and little interaction with commonly used drugs in tran~plantation.~'~ Although few data are available for its efficacy in the transplant population, its properties make this drug a promising alternative for seizure management.75 Neuropathies
In organ transplantation, as in other prolonged operations, peripheral nerve injuries can occur. The incidence ranges from 5% of renal transplant recipients to ~,~~ nerve as high as 13% of patients undergoing cardiac p r o c e d ~ r e s .Peripheral injuries may result from intraoperative rnalpositioning of pharmacologically paralyzed patients, stretching owing to prolonged retraction, or local hematoma formation with nerve compression. The most common nerve injured under general anesthesia is the ulnar nerve, usually at the cubital Accentuated extension or flexion at the elbow may cause injury at this site.ss Each transplantation procedure is associated with a predisposition to a unique set of peripheral nerve injuries. For example, femoral and lateral femoral cutaneous neuropathies are seen in renal transplant whereas lower brachial plexus stretch injuries occur in heart transplant r e c i p i e n t ~Another .~~ mechanism of nerve injury observed in cardiac transplantation is cold-induced phrenic nerve damage caused by packing the heart in ice at the time of the procedure.88 PERIOPERATIVE COMPLICATIONS UNIQUE TO SPECIFIC TRANSPLANT PROCEDURES Kidney Transplantation
The kidney is the most frequently transplanted organ with more than 10,000 transplants per year worldwide. It was the first successful organ transplanted from one identical twin to another by Murray and colleagues in 1954.72Since that historic operation, kidney transplants have developed into the best accepted therapy for most causes of end-stage renal failure. The indications for renal transplantation include glomerulonephritis, diabetes, hypertensive kidney disease, pyelonephritis, polycystic kidney disease, and systemic lupus erythematosus. The 1-year survival for transplant recipients is close to 100% with an 85% to 95% graft survival rate.53Despite these advances, neurologic complications of renal transplants remain relatively common. In one large series, neurologic events occurred in 30% of transplant recipient^.^ The renal transplantation procedure itself carries little risk. There are few
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LEE&RAPS
neurologic complications specific to the procedure, aside from the risk of general anesthesia. The most common compressive neuropathies after kidney transplantation involve the femoral and lateral femoral cutaneous nerves.49Compressive femoral neuropathies, usually caused by local hematoma formation rather than retraction injury, are seen in 1.5%to 8.4%of transplant recipient^.^^,^,^^ The lateral femoral cutaneous nerve, however, is usually exposed and retracted during the procedure and is affected in 2.4%of patients in one seriesE9Another rare complication of renal transplantation occurs in patients with anomalous blood supply to the distal spinal cord. In these patients, blood to the caudal spinal cord is supplied by branches of the internal iliac artery, rather than the intercostal arteries. When the iliac artery is used to supply blood to the allograft, spinal cord ischemia may result.& The most common neurologic complications after kidney transplant are cerebrovascular events, occurring in 9.5% of patients in one large retrospective review.3 Most of these events, however, occurred well after transplantation (>6 months).The high incidence of cerebrovascular events appears to be related to the underlying diseases for which renal transplants are performed, including diabetes, hypertension, and lupus.3In addition, disturbances in serum levels of cholesterol, triglycerides, and lipoproteins are frequently observed in this p o p ~ l a t i o nHe.~~ matologic abnormalities and secondary polycythemia, observed in renal transplant recipients, may also contribute to thromboembolic events.21,62 Liver Transplantation After the first human liver transplant was performed in 1963 by Starzl and colleaguesP it took another 20 years before the procedure was recognized as an effective treatment for end-stage liver disease.73Despite the current 1-yearsurvival rate of up to 83%,48liver transplantation carries a high incidence of complications, not only due to the surgical procedure itself, but also to the precarious state of the patient before surgery. Neurologic complications occur in up to 80%of adult transplant recipients and are among the most important causes for morbidity and mortality in this p ~ p u l a t i o n . ~70,78,94,96,99 , ~ ~ , ~ ~Liver , transplantation is carried out for a number of hepatic diseases, including viral hepatitis, alcoholic liver disease, primary biliary cirrhosis, acute liver failure or toxins, and c h o l a n g i t i ~ The . ~ , ~shortage ~ of organs frequently necessitates a long waiting period before transplantation. Therefore, transplant recipients are often critically ill and usually have some degree of hepatic encephalopathy before surgery.” In addition, this population is more prone to central nervous system hemorrhages in the perioperative period as a result of coagulopathies associated with liver failure. Orthotopic liver transplantation is a relatively standardized but demanding operative pr0~edui-e.~~ The operation may be broken down into three phases: dissection, anhepatic stage (removal of the diseased liver and implantation of the donor liver), and r e p e r f ~ s i o nIn . ~the ~ past, a venovenous bypass was used routinely in all operations during the anhepatic More recently in many institutions, venous bypass is used only if needed for hemodynamic stability.101 Bypass is initiated by dissection of the left axillary and saphenous veins. Cannulas are placed in the saphenous and portal veins to return blood via a centrifugal pump to the axillary vein. Significant blood loss during the procedure is not uncommon, and patients often require massive replacements of blood and electrol y t e ~ . ’predisposing ~.~~ them to diffuse hypoxic-ischemic damage to the brain or watershed infarctions. In several clinical series, the most common perioperative neurologic compli-
NEUROLOGIC COMPLICATIONS OF TRANSPLANTATION
27
cation of liver transplantation was encephalopathy, which ranged in severity from confusion to c 0 m a . ~ , a , ~ 0 ,The ~ 8 , ~myriad ~ , ~ ~ of causes of encephalopathy in this population includes metabolic derangements (including preexistent hepatic encephalopathy), drug toxicity (in particular, cyclosporine and FK 506), hypoxicischemic brain injury, and sepsis. Autopsy series in the perioperative period reveal that the most common causes for encephalopathy in liver transplant recipients were metabolic and hypoxic-ischemic injury.b4,65,78 Central pontine myelinolysis (CPM) is an unusual neurologic complication that occurs at increased frequency in liver transplant patients. In various neuropathologic studies, CPM has been consistently found in 7%to 19% of liver transplant recipient^.^^,^^,^^,^^^,^^ Typically the disorder results in symmetric noninflammatory demyelination of the basis pontis with relative sparing of neurons and a ~ o n s . ~Extrapontine O~ myelinolysis has also been ob~erved."~~ The cause is unknown, but it is thought to be the result of rapid correction of h y p ~ n a t r e m i a . ~ ~ , ~ ~ During the transplant procedure, wide fluctuations in serum sodium concentrations occur as a result of the rapid replacement of intraoperative blood loss with intravenous fluids and blood products that contain high concentrations of soIn the past, CPM has been an infrequent clinical diagnosis, usually found unexpectedly at autopsy. Advances in neuroimaging techniques, however, have made the diagnosis of CPM much more common. Clinical manifestations include altered mental status or coma, pseudobulbar palsy, and q ~ a d r i p l e g i a . ~ ~ , ' ~ ~ Injury to the lower brachial plexus is the most common peripheral nerve injury observed in liver transplantation, occurring in up to 6% of patient^.^^,^^,'^^ It is believed that the injury occurs during the axillary dissection required for access to the axillary vein for venovenous by pa^^.^^,^^,^^^ More recent changes in the use of venous bypass may reduce the rate of this complication. Heart Transplantation
Since the first human heart transplant was performed by Barnard in 1967," the procedure has become an accepted method for treating intractable heart failure. The introduction of effective immunosuppressants (in particular, cyclosporine) and advances in operative and postoperative management have dramatically improved survival in cardiac transplant patient^.^^^,^^ Conditions for which cardiac transplants are performed include cardiomyopathies, atherosclerotic cardiovascular disease, valvular heart disease, and congenital heart defects.7sAll of these conditions predispose patients to cerebrovascular events even before transplantation. Although graft rejection and infection are major causes of mortality, neurologic complications may occur in up to 60% of patients and substantially influence morbidity and subsequent quality of life.5~6~42~43~b3~b6~69~n6~8H Cardiopulmonary bypass is a potential cause of major neurologic complications independent of the heart surgery itself. Bypass begins with the cannulation of the ascending aorta and vena cava or right atrium, eventually followed by crossclamping of the aorta immediately before initiation of cardiopulmonary bypass. Cannulation of a diseased ascending aorta can dislodge atheromatous material, leading to cerebral emboli. There is an additional risk of introducing air emboli when the procedure is completed and the aortic cross-clamp is released. During extracorporeal circulation, exposure of the blood to nonendothelial surfaces increases the risk of embolus formation from platelet aggregation or disruption of fibrin. In addition, this exposure can result in platelet and coagulation factor consumption, leading to an incremental risk of intracranial h e m ~ r r h a g eThe . ~ ~use of anticoagulants during bypass further compounds this risk. Although mean arterial
and central venous pressures are monitored during cardiopulmonary bypass, prolonged bypass times increase the risk of exposure to periods of hypotension and hypo~ia.~~.~~ Autopsy series of cardiac transplant recipients surviving less than 1 month after surgery confirm the known risks of cardiac surgery with bypass. The most common neuropathologic finding is cerebral infarction (both focal and diffuse ischemic-anoxic injury), accounting for 16%to 43% in some autopsy ~ e r i e s .A~ ~ , ~ ~ clinical retrospective review revealed far fewer neurologic complications (5%)in the perioperative p e r i ~ dClinical .~ manifestations of the cerebrovascular events include stroke with focal neurologic deficits, a confusional state, or severe encephalopathy with obtundation or coma. Encephalopathy with psychosis in the immediate postoperative period usually implicates global hypoxic-ischemic mechanisms. Metabolic derangements, multiple organ failure, and sepsis, however, may present with encephalopathy as well. Rarely, seizures in the immediate postoperative period may be associated with focal embolic events.43Seizures occurring in the later postoperative period are more often due to metabolic disturbances, particularly hypomagnesemia related to cyclosporine use. Peripheral nervous system injuries are also relatively common in cardiac transplantation, similar to those complicating open heart surgery (present in 13% of cases)? The most common injury involves the lower brachial plexus caused by stretching during chest wall retraction or compression by a hematoma. Patients with lower brachial plexus injury present with weakness and numbness in the distal arm often with a diminished triceps reflex. Recurrent laryngeal injury leading to vocal cord paralysis may also be the result of traction. The phrenic nerve may be damaged by cold-induced injury from packing the heart in ice at the time of the tran~plantation.~~ Frequently, these patients manifest clinically with diaphragmatic paralysis and difficulty weaning from mechanical ventilation or prolonged postoperative hiccups. After transplantation, patients remain at risk for cerebrovascular events owing to cardiac emboli, underlying atherosclerosis, and postoperative arrhythmias.' Lung Transplantation
Pulmonary transplantation is a relatively new procedure with few data available regarding neurologic complications. The first successful human lung transplant was performed by the Toronto Lung Transplant Group in 1983.98Since that time, the number of transplants performed annually has continued to increase. The number of disease causes treated with lung transplantation has grown as well and includes emphysema (including a,-antitrypsin deficiency),cystic fibrosis, pulmonary hypertension, idiopathic pulmonary fibrosis, and obliterative bronchiolitis.20The 1-year survival for patients undergoing single-lung transplant exceeds 90%, whereas bilateral lung transplant approaches 80%.17,18,33 The lung transplant procedure has evolved over the past decade. The use of cardiopulmonarybypass in lung transplantation is dependent on right ventricular function after clamping the pulmonary artery before extraction of the diseased lung. If right ventricular function is significantly impaired after clamping, the single-lungtransplant is performed using cardiopulmonary bypass with the lungs deflated.20After implantation of the donor lung, the bronchial anastomosis is carried out, followed by pulmonary artery, then pulmonary vein/left atrial anastomosis.20The left atrial anastomosis has been the subject of some scrutiny after reports of thrombus formation on the anastomotic site in several patient^.^^,^^,^^," Few data exist regarding the neurologic complications associated with lung transplantation. Therefore, the authors have reviewed the perioperative neuro-
NEUROLOGIC COMPLICATIONS OF TRANSPLANTATION
29
logic complications after lung transplantation at the University of Pennsylvania Medical Center (unpublished observation). A total of 108 consecutive lung transplants were performed between October 1993 and October 1995. The records of these patients were reviewed up to 30 days after the transplant procedure, and neurologic complications were recorded. A total of 21 (19%)transplant recipients had 27 neurologic complications (Table 2). Encephalopathy (ranging from confusion to coma) was the most common neurologic sequela of transplantation, affecting 11 patients (10%). Although the majority of cases were due to metabolic causes (7.4%),drug toxicity also contributed in some (2.8%).Seizures occurred in four transplant recipients (3.7%)and were caused by metabolic derangements, cyclosporine toxicity, and stroke. Cerebrovascularevents were also relatively common: Hypotensive watershed infarcts were seen in four patients (3.7%),embolic infarcts in four, and a hemorrhage in the region of a watershed infarct in one patient. Investigations into potential sources of emboli revealed left atrial thrombi on transesophageal echocardiography (TEE)in two patients. The pulmonary vein/left atrial anastomosis may represent an important source of emboli in lung transplant recipients. Stang and associatesgoreported a cerebral infarct in a patient 4 weeks after bilateral lung transplant. A left atrial thrombus at the site of anastomosis was demonstrated on TEE. Moreover, in a prospective study of 21 lung transplant recipients, pulmonary vein thrombosis was detected on TEE in 5 patients (24%)in the immediate postoperative period.59 In the authors' series, complications involving the peripheral nervous system were present in three patients. Acute quadriplegic myopathys2was diagnosed in a patient requiring vecuronium for ventilation in the setting of routine steroid administration for immunosuppression. Another patient developed proximal muscle weakness thought to be due to steroid myopathy. Phrenic nerve injury was diagnosed on electromyography in a third patient.
SUMMARY
Despite the advances in organ transplantation technology, neurologic complications remain a significant cause of morbidity and mortality. Many of the complications, including encephalopathy, seizures, and peripheral nerve injuries, are common to all transplant types. Other complications are unique to each transplant procedure. Kidney transplantation is a fairly benign procedure and is not
Table 2. PERIOPERATIVE NEUROLOGIC COMPLICATIONS OF LUNG TRANSPLANTATION (UNIVERSITY OF PENNSYLVANIA MEDICAL CENTER SERIES) Complications Encephalopathy Metabolic Drug-related Cerebrovascular events Watershed infarcts Ernbolic infarcts Hemorrhage Seizures Neuropathylrnyopathy
No. Patients (YO) 8 (7.4) 3 (2.8)
4 (3.7) 4 (3.7) 1 (0.9) 4 (3.7)
3 (2.8)
Cause
Steroids and cyclosporine Hypotension Left atrial clot seen in 2 patients Hemorrhagic conversion of watershed infarct Metabolic derangements (2), cyclosporine toxicity ( l ) , cerebral infarct (1) Acute quadriplegic rnyopathy, steroid rnyopathy, phrenic nerve injury
30
LEE&RAFS
associated with significant perioperative morbidity. Liver transplantation is associated with significant neurologic complications, including hepatic encephalopathy and central pontine myelinolysis. Heart and lung transplants are often associated with both hypoxic-ischemic injury and cerebral infarction, frequently from a cardiac source of embolus. With increasing numbers of transplants being performed every year, it is important for the neurologist to be familiar with complications of organ transplants. The neurologist plays an important role in diagnosing and managing neurologic complications of transplantation. References 1. Adair J, Call G, OConnell J, et al: Cerebrovascular syndromes following cardiac transplantation. Neurology 422319, 1992 2. Adams D, Gunson B, Honigsberger L, et a1 Neurological complications following liver transplantation: Lancet 1:949, 1987 3. Adams H, Dawson G, Coffman T, et al: Stroke in renal transplant patients. Arch Neurol 43:113,1986 4. Adams J, Brierly J, Connor R, et al: The effects of systemic hypotension upon the human brain: Clinical and neuropathological observations in eleven cases. Brain 89:235, 1966 5. Andrews B, Hershon J, Calanchini P, et a1 Neurologic complications of cardiac transplantation. West J Med 153:146, 1990 6. Ang L, Gillett J, Kaufman J: Neuropathology of heart transplantation. Can J Neurol Sci 16:291, 1989 7. Arieff A, Cooper J, Armstrong D: Dementia, renal failure, and brain aluminum. Ann Intern Med 90:741, 1979 8. Barnard C: The operation-a human cardiac transplant: An interim report of a successful operation -performed at Groote Schuur Hospital, Cape Town.-S Afr Med J 41:1271,1967 9. Belle S, Detre K Report from the Pitt-UNOS liver transplant registry. Transplant Proc 251137,1993 10. Bernuau J, Rueff 8, Benhamou J: Fulminant and subfulminant liver failure: Definition and causes. Semin Liver Dis 6:97,1986 11. Blanco R, DeGirolami U, Jenkins R, et al: Neuropathology of liver transplantation. Clin Neuropathol14:109,1995 12. Blei A: Cerebral edema and intracranial hypertension in acute liver failure: Distinct aspects of the same problem. Hepatology 13:376,1991 13. Bogousslavsky J, Hachinski V, Boughner D, et al: Cardiac and arterial lesions in carotid transient ischemic attacks. Arch Neurol43:223, 1986 14. Busuttil R, Colonna J, Hiatt J, et al: The first 100 liver transplant at UCLA. Ann Surg 206:387, 1987 15. Capocaccia L, Angelic0 M: Fulminant hepatic failure: Clinical features, etioloav, -, epidemiology and current management. Digbis Sci 36:775,1991 16. Chatrian G , Shaw C, Leffman H: The significance of periodic epileptiform discharges in the EEG: An electrographic, clinical and pathological study. Electroencephalogr Clin Neurophysiol17:115, 1964 17. Cooper J, Patterson G, Pohl M: Current status of lung transplantation: Report of the St. Louis International Lung Transplantation Registry. Chest 103:46, 1992 18. Cooper J, Patterson G, Trulock E, et a1 Results of 131 consecutive single and bilateral lung transplant recipients. J Thorac Cardiovasc Surg 107460, 1994 19. Daverat P, Janvier G, Duche B, et a1 Myelinolyse centropontine apres transplantation hepatique. Rev Neurol (Paris) 148687,1992 20. Davis R. PasqueM..Pu\mocra.ry tcar\sp\ar\tatio. AnnSv.xg'X'XV.14.1995 21. Dintenfass L, Ibels L. Blood viscosity factors and occlusive arterial disease in renal transplant recipients. Nephron 15:456, 1975 22. JMelman B, Abu-Elmagd K, Wilson J, et al: Neurologic complications of 506. Transplant Proc 23:3175, 1991
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Address reprint requests to: Eric C . Raps, MD Department of Neurology University of Pennsylvania Medical Center 3400 Spruce Street, 3 West Gates Philadelphia, PA 19104