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 85

Neurologic complications of liver transplantation EELCO F.M. WIJDICKS* AND SARA E. HOCKER Division of Critical Care Neurology, College of Medicine, Mayo Clinic, Rochester, MN, USA

INTRODUCTION Most major medical centers have developed a logistically successful liver transplantation program with good outcomes (Mandell et al., 2002). Yet, neurologic complications continue to dominate the postoperative care of patients. In the earlier days some of these manifestations were dramatic, unexpected, and even fatal (Adams et al., 1987; Vogt et al., 1988; Gridelli et al., 1994; Pujol et al., 1994; Vecino et al., 1999; Wijdicks, 1999; Bronster et al., 2000a). Most instructive were patients who would develop refractory status epilepticus and remained in a coma after large intravenous doses of immunosuppressive drugs. Now, in the modern era, next to seizures, “encephalopathy” is the major concern of the liver transplant surgeon and the postoperative medical team (Lewis and Howdle, 2003; Kim et al., 2007; Fernandez et al., 2010). In fact, acute confusional state occurs in more than 50% of patients who have a transplantation for alcoholic liver disease (Buis and Wijdicks, 2002). Any critically ill patient after a solid organ transplant is at risk of neurologic complications, but there are specific problems in liver recipients. First and urgently challenging is the management of acute fulminant hepatic failure that can only be treated with acute liver transplantation. When cerebral edema occurs patients present with multiple medical problems that are not only demanding to the medical team, but also to the neurosurgeon, who has to place an intracranial pressure monitor, and to the consulting neurologist, who has to advise on management of increased intracranial pressure while trying to make sense of a sedation-confounded neurologic examination. Second, liver transplantation has been used to treat Wilson’s disease (Stangou and Hawkins, 2004; Erol

et al., 2008) and amyloidosis, linking liver transplantation with a major disabling but curable disease. Third, with the increase in liver transplantation for patients with prior alcoholism, critical illness neuropathy and myopathy can be expected to occur more often as a direct result of their emaciated state. This subsection summarizes the major neurologic complications after liver transplantation.

LIVER TRANSPLANTION: PAST AND PRESENT For a long time liver transplantation was considered technically and medically too formidable and certain to fail. The development of liver transplantation can be credited to Dr. Thomas Starzl at the University of Colorado. In 1963, he pioneered liver transplantation in several patients, but all patients died from postoperative complications. Starzl recollects that, with this depressing first experience, most surgeons felt that liver transplantation was simply not feasible (Starzl and Fung, 2010). Nevertheless, several European teams in the early 1970s – and Starzl again – went on with a second try; this time, with much more effective immunosuppressive agents and a dedicated team of hepatologists and immunologists, patients survived. Liver transplantation has remained a major surgical procedure and continues to place patients at significant risk of complications – as opposed to kidney transplantation, which now rarely has recipients in an intensive care unit (ICU) for a prolonged period of time. Indications for liver transplantation are regional. In the UK, where acetaminophen/paracetamol intoxication is prevalent, approximately two-thirds of the liver transplantations are performed for that indication. Outside the UK and in the US, hepatitis C, B, and alcoholic cirrhosis are

*Correspondence to: Eelco F.M. Wijdicks, M.D., Ph.D., F.A.C.P., Professor of Neurology, Chair, Division of Critical Care Neurology, Mayo Clinic, 200 First Street SW, Rochester, MN 55905, USA. Tel: þ1-507-284-4741, Fax: þ1-507-266-4419, E-mail: [email protected]



Fig. 85.1. Example of split liver transplantation. (Reproduced from Wijdicks, 2009, with the permission of the Mayo Foundation for Medical Education and Research. All rights reserved.)

the major indications for liver transplantation. In pediatric transplantation, the most common indications are extrahepatic biliary atresia and total parenteral nutrition (TPN) cholestasis (Gridelli et al., 1994). In some of these children with TPN cholecystasis progression can be rapid and liver cirrhosis may develop in a few months. (These children have been treated with TPN for acute and chronic intestinal failure.) The initial liver transplantation was orthotopic, where the patient liver is removed and replaced by a whole or partial donor liver. Over the years changes in technique have occurred that included a split liver technique (Fig. 85.1). The donor liver is attached through anastomosis of the suprahepatic and intrahepatic inferior vena cava, hepatic artery, portal artery, and bile duct (Fig. 85.1). As expected, the immediate postoperative care is predominated by the care of a coagulopathy, ventilatory management, and management of blood pressure and fluid balance. Most patients may have a severe coagulopathy in the first postoperative days until clotting factors are produced by the new liver. The fluid status is unstable with episodes of hypervolemia associated with hypertension. All these changes with blood pressure, oxygenation, and clotting can cause neuronal injury, but it is surprising how many patients do well after this major surgical procedure. Infections are rare and probably a result of preemptive gut decontamination and antifungal prophylaxis. The most challenging category of patients is patients with fulminant hepatic failure. Fulminant hepatic failure can lead to rapid neurologic deterioration attributed to brain edema. At some point during the course of time, a metabolic derangement (hepatic encephalopathy) progresses toward a structural lesion (cerebral edema) that causes permanent brainstem injury. Brain edema is more common in patients who have a short interval between the onset of jaundice and signs of encephalopathy, when

there is an associated infection, need for vasopressors, or when there is associated renal failure. Increased arterial ammonia at presentation in fulminant hepatic failure is a strong predictor for more severe manifestations of cerebral edema. Over the years neurologic complications have decreased and most of the complications now are mostly postoperative agitation, encephalopathy, and seizures. Major structural brain lesions are incidental and may involve intracranial hemorrhage or a posterior reversible encephalopathy syndrome due to immunosuppressive drugs. More recent studies suggest neurologic complications may reach up to one in four patients. Only seizures have declined over the years and all other complications have remained quite prevalent (Table 85.1).

CLINICAL FEATURES Any neurologist evaluating a neurologic complication for liver transplantation is expected to have a good knowledge of the pretransplant setting, reasons for transplantation, perioperative complications, and most importantly, polypharmacy use in the postoperative setting. One should anticipate great difficulties with understanding the patient’s condition and the spectrum of neurologic complications varies widely. One could expect to see a mildly confused patient or a comatose patient, a single seizure or status epilepticus, a recovering compression neuropathy or a severe flaccid quadriplegia. Patients may do well initially only to deteriorate later in the early postoperative course and some may develop a neurologic manifestation years after liver transplantation. How the prevalence of complications has evolved over time is difficult to gather from the existing literature. Most series involve thousands of patients over many years with many significant changes in postoperative care. Most reported early neurologic complications after liver transplantation are altered



Table 85.1 Neurologic complications of liver transplantation over time


Time epoch






Peripheral nerve


Adams et al., 1987 Guarino et al., 1996 Vecino et al., 1999 Lewis and Howdle, 2003 Dhar et al., 2008

1982–1986 1986–1993 1996–1998 1990–2000 2000–2002

52 199 43 627 101

25% 6% 7% 6% 4%

8% 24% 16% 11% 28%

6% 3% 9% 4% 0

2% 0.5% 0 2% 0

0 4% 0 4% 0

2% 4% 2% 6% 0

*Ischemic and hemorrhagic combined. CPM, central pontine myelinolysis.

Table 85.2 Neurologic complications after transplantation: classification by neurologic signs and symptoms and common diagnostic considerations Sign or symptom


Failure to awaken

Hypoxic-ischemic encephalopathy, central pontine myelolysis, anesthetic agents, air embolism, acute graft failure Intracranial hemorrhage, seizures, drug toxicity Immunosuppressive toxicity, acute hypoglycemia, hyperglycemia, corticosteroids, fungal meningitis Ciclosporin or tacrolimus toxicity, intracranial hemorrhage, lymphoma, meningitis Ciclosporin or tacrolimus toxicity Cardiac arrest, ciclosporin toxicity, posterior reversible encephalopathy syndrome (PRES) Ischemic or hemorrhagic stroke, neoplasm, brain abscess Immunosuppressive drugs Hypoxic-ischemic encephalopathy, ketamine or cephalosporin intoxication Acute liver (rejection) disease Haloperidol overdose, malignant hyperthermia Acute critical illness polyneuropathy, polymyositis, corticosteroids, associated myopathy, neuromuscular blocking agents Fungal meningitis, muromonab-CD3 toxicity, ciclosporin or tacrolimus use, lymphoma, astrocytoma

Loss of consciousness Confusional state Seizures Mute or stuttering Cortical blindness Hemiparesis Tremors Myoclonus Asterixis Rigidity Muscle weakness Headaches

consciousness, seizures, agitation, and encephalopathy and, occasionally, acute neuromuscular weakness. Late complications may involve central nervous system (CNS) infections and de novo brain tumors. The most frequently seen neurologic complications and presumed causes are shown in Table 85.2.

ABNORMAL CONSCIOUS STATE Neurologists will have difficulty defining an abnormal conscious state in a liver transplant recipient. Even an acute confusional state might be difficult to define but can be considered if it lasts for several days and is associated with agitation, acute disorientation, and sometimes hallucinations. Acute confusional state after

a liver transplant can be due to alcoholic liver disease and in fact is quite common in these patients. In our study, confusion occurred as early as 3 days after transplantation for alcoholic liver disease and was associated with increased levels of serum ammonia and also brain atrophy on CT scan, all suggesting a predisposition (Buis et al., 2002). In some patients, a high dose of corticosteroids in the setting of an immunosuppressive regimen could lead to an agitated confusional state but this complication is rare in our experience. The use of calcineurin inhibitors is most likely the most common cause for abnormal level of consciousness (Freise et al., 1991). Ciclosporine and tacrolimus are usually part of a postoperative immunosuppressive regimen and neurologic symptoms often



occur during intravenous loading of these drugs (Small et al., 1996). Over the years there has been far more experience with titrating these drugs and therefore the incidence of severe neurotoxicity has declined substantially. In addition, newer drugs such as sirolimus are not associated with neurotoxicity. This is explained by a different mechanism of action – sirolimus blocks interleukin 2 and does not inhibit calcineurin. Immunosuppressive toxicity has a colorful display of symptoms and its clinical features are similar in any transplant recipient (de Groen et al., 1987; Wijdicks et al., 1999; Wijdicks, 2001). Most of the time patients start with a progressive position tremor that is then followed by visual hallucinations and development of a language or speech abnormality (Bird et al., 1990; Reyes et al., 1990). Mostly, articulation abnormalities are seen; in the past this has been called a “foreign accent syndrome.” Some patients become mute and develop a frontal syndrome with marked abulia (Valldeoriola et al., 1996; Laureno and Karp, 1997). When not recognized and calcineurin inhibitors are continued seizures appear and may become recurrent. Unusual manifestations of calcineurin inhibitors are visual hallucinations, grimacing, tongue protrusion, opsoclonus, and cortical blindness (Ghalie et al., 1990; Steg and Garcia, 1991; Marchiori et al., 2004). All these clinical features can be located to a specific area in the brain, predominantly the brainstem or occipital lobe. The challenge is to “prove” neurotoxicity in a liver transplant recipient and this is difficult because neurologic findings correlate poorly with serum levels of ciclosporin or tacrolimus. Even a marked increase in dose or level does not necessarily predispose the patient to toxicity and in fact, rapidly titrating towards increasing plasma levels is a crucial part of early postoperative management. Moreover MR imaging can be normal in a patient with neurotoxicity but in a patient with an abnormal level of consciousness and seizures, normal MR imaging makes neurotoxicity a much less likely possibility. If present, the MRI abnormalities can be profound and involve typical features known to occur in a posterior reversible encephalopathy syndrome (Truwit et al., 1991). There is abnormal signal in the subcortical white matter predominantly in the occipital regions bilaterally (Fig. 85.2), which may extend into the frontal regions and into the thalamus. There is typically no restricted diffusion or abnormal enhancement and the abnormalities fairly rapidly resolve after the immunosuppressive drug is replaced. Switching from one calcineurin inhibitor to another may also be successful (Emre et al., 2000; Jain et al., 2000). Currently there is a growing incentive to avoid calcineurin inhibiting agents and replace these drugs with sirolimus or CellCept (mycophenolate mofetil) (Maramattom and Wijdicks, 2004). However, sirolimus

Fig. 85.2. MRI image showing marked hyperintensities due to vasogenic edema associated with use of calcineurin inhibitor.

is not an innocuous drug having major problems with skin lesions (Montalbano et al., 2004). The mechanisms of ciclosporin and tacrolimus toxicity have not been resolved but breakdown of the blood–brain barrier is needed for ciclosporin to enter the brain. Ciclosporin is very lipophilic and therefore cannot cross the blood–brain barrier because of tight junctions. It has been speculated that impairment of the blood–brain barrier due to surgery associated with ischemic insult due to hypotension might have predisposed the patient in the postoperative phase; however, it is not a common occurrence. Most of the abnormalities are simply fluid extravasation and not neuronal destruction causing cytotoxic edema. There are no neuropathology studies in a series of patients that could explain the true nature of this disorder. A second common cause of altered consciousness is accumulation of sedation. Mostly drugs such as midazolam or propofol have been used and their pharmacokinetics might be difficult in any transplant patient. Midazolam is a complicated drug in a patient who has just received a liver graft because it is highly proteinbound and pre-existing protein levels may increase its sedative effect. Opioids can be used in the postoperative phase and also may cause a significant decrease in response, certainly when used in combination with

NEUROLOGIC COMPLICATIONS OF LIVER TRANSPLANTATION midazolam. Another cause of postoperative stupor after liver transplant is central pontine myelinolysis (CPM). This has been typically associated with rapid correction of hyponatremia but this relationship between hyponatremia and CPM after liver transplantation has never been definitively established. Fluid shifts from major compartments occur after liver transplantation but CPM is very uncommon with only a few cases seen in many thousands of liver transplant patients. The diagnosis may not be recognized if an MRI scan is not performed and the patient may present with stupor alone (Boon et al., 1991; Buis et al., 2002; Guo et al., 2006). Abnormal level of consciousness can also be due to graft failure and presents itself with liver function tests rapidly becoming abnormal and a patient who lapses into a higher clinical stage of encephalopathy. The patient may be drowsy with slowing immediately after surgery but then deteriorate into a state with less orientation, pronounced confusion, new development of asterixis and eventually, lapsing into an unresponsive comatose state. Finally, and most unfortunately, some patients might be brain dead after liver transplantation. This scenario is relatively uncommon in patients who have had an emergent liver transplantation for fulminant hepatic failure. The clinical scenario here is that patients developed a massively increased intracranial pressure (ICP) that required barbiturate treatment. Failure to obtain a reliable neurologic examination or any additional ancillary tests may have led to proceeding with liver transplantation leaving only a patient without demonstrable brain function in the postoperative phase. In some patients a marked ICP rise during transplantation may have tipped the balance and resulted in loss of all brainstem function. The evaluation of patients with an abnormal conscious state should also include consideration of anoxic-ischemic injury. In liver transplantation this is highly unusual but mostly seen if there has been an intraoperative cardiorespiratory arrest shortly after transplantation. Sudden loss of consciousness in the liver transplantation patient is typically due to catastrophic intracranial hemorrhage. Cerebral hematoma is particularly common in patients after liver transplantation with coagulopathy and bacterial sepsis syndrome, but fungal infections, such as an overwhelming Aspergillus fumigatus infection, may present with a massive intracranial hemorrhage. Coagulopathy plays a role but bacteremia or fungemia was found in a large proportion of our patients who presented with intracranial hemorrhage (Wijdicks et al., 1995a).

SEIZURES A new seizure in a transplant recipient should foretell a major medical or neurologic problem. Seizures have been reported frequently in a liver transplant recipient


and in some series may have been seen in up to 10–20% of patients (Wijdicks et al., 1994; Wijdicks et al., 1996a). In the early days of transplantation seizures were associated with neurotoxicity and this has remained a strong consideration in any patient with liver transplant. Other, less common causes are acute hyponatremia, hypomagnesemia, and hyperglycemia, but all published recent information is poorly detailed and seizures have been mostly linked to neurotoxicity. In any event, a new structural lesion should be documented or at least excluded and some cases may have an intracranial hemorrhage or a CNS infection. Seizures may also occur in patients with a rapidly evolving rejection recognized by increasing arterial ammonia. Management of seizures in a transplant recipient is typically an antiepileptic drug if there is a structural lesion. If antiepileptic drugs are considered, intravenous levetiracetam is probably the best agent to use and the least hepatotoxic. Failure rapidly to correct a metabolic cause, probability of drug toxicity, and whether electroencephalography (EEG) shows epileptiform abnormalities are also reasons to treat patients. Long-term management is rarely warranted.

BRAIN EDEMA The postoperative management of brain edema in patients who received a liver to replace an acutely necrotic liver is another major neurologic issue. Management has already begun in the pretransplantion phase but needs continuation in the days after transplantation (Daas et al., 1995; Auzinger and Wendon, 2008). Brain edema after fulminant hepatic failure is prominent in patients with stage III/IV hepatic encephalopathy (Fraser and Arieff, 1985) and in fact those are usually the patients who are acutely listed for transplantation (Emond et al., 1989; Russo et al., 2004; Khanna and Hemming, 2010). The potential mechanism for brain edema involves both a vasogenic and a cytotoxic component (Ritt et al., 1969; Blei, 2007, 2008). Current leading explanations are that there is an osmotic and oxidative stress neuronal damage. Glutamine has been the major responsible substance and a significant increase of glutamine in the brain precedes increase in brain water in many experimental models (Raabe, 1987; Albrecht and Norenberg, 2006). Ammonia diffuses through the bloodstream barrier, causes a rise in glutamine which attracts water due to its function as an osmolite (Bhatia et al., 2006; Bernal et al., 2007). Brain edema can be very rapid and cause a significant problem with management of increased ICP. A protocol for management is shown in Table 85.3. Placement of an intracranial pressure monitoring device is necessary to control ICP during the perioperative phase. There is an



Table 85.3 Treatment options for brain edema in fulminant hepatic failure Propofol infusion (start with 30 mg/kg per minute and may increase to 200 mg/kg per minute for brief periods of time) Moderate hypothermia (33–35 C) with cooling blankets, alcohol rubbings, and ice lavage Pentobarbital bolus of 3–5 mg/kg intravenously followed by 1–3 mg/kg per hour up to normalizing of intracranial pressure Mannitol, 0.5–1 g/kg every 6 hours if plasma osmolality is < 310 mOsm/L

understandable reluctance by neurosurgeons to place ICP monitors due to the associated coagulopathy with nearly absent liver function, but with the use of recombinant factor VIIa, coagulopathy can be controlled (Shami et al., 2003). The risk of a clinically relevant probe-associated hemorrhage is approximately 10–20%. On the other hand, losing a patient with rapid brain edema that could have been detected and controlled is equally problematic. Most experts in this field feel that ICP monitoring should be present in a patient lapsing into stupor necessitating intubation and mechanical ventilation. Monitoring ICP in fulminant hepatic failure remains essential to shepherd the patient through surgery (LeRoux et al., 1990; Brandsaeter et al., 2002). A sudden increase in ICP has been noted during transplantation and these surges of ICP do occur after reperfusion of the transplanted liver and may even extend through the first day after liver transplantation (Montalti et al., 2005). Table 85.3 shows options for treatment of brain edema. Propofol may be useful and in small doses has reduced intermittent increases in ICP. With a dosage of 1–3 mg/kg we were able to control ICP satisfactorily (Wijdicks and Nyberg, 2002). Treatment is typically the use of osmotic drugs (Raghaven and Marik, 2006; O’Grady, 2007). However, the use of hypertonic saline and mannitol may be initially problematic if the patient has developed a hepatorenal syndrome but not with continuous renal replacement therapy. There is a current interest in quickly using hypothermia (33–34 C) in combination with high-dose barbiturates (Stravitz et al., 2007). Further data are forthcoming as to whether hypothermia should be standard in the management of brain edema in fulminant hepatic failure. Monitoring EEG with pentobarbital may be useful but ICP may still be elevated in burst suppression patterns and it is better to be guided by the ICP tracing. What remains unclear is how many patients are able to be salvaged when frank edema and crowding of the basal cisterns appear on a

repeat CT scan (Wijdicks et al., 1995b; Lee and Wijdicks, 2008). In many of these patients transplantation may come too late. In these urgent situations a hepatic bridging device would be ideal, but it has long been a holy grail for hepatologists and transplant surgeons (Van de Kerkhove et al., 2004; Park and Lee, 2005).

CENTRAL NERVOUS SYSTEM INFECTIONS A patient with a recent organ transplantation and treated with immunosuppression is at increased risk of opportunistic infections, and they can rapidly become quite serious (Feltracco et al., 2010). In the early postoperative phase (less than 1 month) infections are usually systemic bacterial or fungal infections and the brain and spinal cord is mostly spared. Most of the neurologic infectious diseases cause substantial morbidity and mortality and it would require systemic autopsy studies to tabulate them accurately. When a CNS infection intervenes, parasitic infections (Hoare et al., 2006), viral infections, and fungal infections predominate. Most series of liver transplant patients will, fortunately, only have a few patients with devastating infections. Not infrequently, these infections occur in patients with a complicated postoperative clinical course and already long ICU stays. CNS infections present as a meningoencephalitis with treatment-refractory headache, behavior changes, and less commonly localizing signs such a hemiparesis. Intracerebral hemorrhage may be associated with fungal infections (Wijdicks et al., 1995a). The most frequently encountered pathogen is Aspergillus fumigatus and it may be rapidly invasive and fatal (Boon et al., 1990). The diagnosis is very difficult to make intra vitam and more commonly autopsy will be able to show the widely disseminated angioinvasive hyphae. In our experience we have seen only sporadic cases in liver transplant recipients, but when it occurred no patient survived the concomitant multiorgan involvement. Other causes are Cryptococcus neoformans and a variety of other fungal infections but mostly reported as anecdotes in the literature. MR imaging can be helpful in documenting multiple small abscesses, but there are no distinguishing features. CSF will invariably show a lymphocytic pleocytosis and a biopsy or immunodiffusion tests for the detection of antibodies. CSF India ink (with suspicion of Cryptococcus neoformans) is frequently positive and helpful clinically (Wu et al., 2002). Disseminated viral infections have also been described with very high mortality rates, but again no systemic studies have been reported. A viral encephalopathy that has emerged more recently is a human herpes virus 6 (HHV-6) (Seeley et al., 2007). This infection may be seen several weeks after transplantation and is often

NEUROLOGIC COMPLICATIONS OF LIVER TRANSPLANTATION 1263 unrecognized or initially misdiagnosed as a metabolic Meningeal involvement may produce headache. The derangement or neurotoxicity from immunosuppressive diagnosis can only be considered if the CT scan shows agents. A confusional state with disorientation may a new mass lesion in the periventricular region and with be the only clinical sign. Isolation by PCR is necessary a proportionally large amount of perilesional edema. A and no other tests have any key features. Mortality is biopsy might be necessary to find the lesion followed by high, with about 80% of the patients remaining comaaggressive treatment with radiation. Outcome, however, tose. Foscarnet has been tried in some cases but there remains very poor with ultimate demise in all patients. is as yet little experience. Another concern is the transmission of a primary high Another under-recognized infection is cytomegalovigrade CNS tumor of a donor to a liver recipient and multiple rus (CMV) encephalopathy. Approximately 80% of liver single cases have been reported. A recent study evaluated recipients have reactivation of a latent CMV that may the risk and found it to be very low (less than 3%). Nonetheoccur several weeks after transplantation. Again the less molecular chimera studies have proved malignant brain diagnosis of CMV encephalitis is notoriously difficult tumors came from the donor (Kashap et al., 2009). with a presentation that is baffling to most clinicians. Some patients present with focal findings such as dysarNEUROMUSCULAR COMPLICATIONS thria, spasticity and rigidity, and tremor, and others Liver transplantation should spare muscle and nerve. develop fever and neck stiffness. CMV chorioretinitis may be demonstrated, but CMV encephalitis may occur However, neuropathies may occur due to cannulation, without this manifestation. In all these opportunistic coagulation-induced compressive hematomas (Wijdicks infections recent availability of PCR technology has et al., 1996a; Campellone et al., 1998). The relationship increased recognition but there is as yet no evidence that between immunosuppressive agents and development early treatment improves outcome. of a neuromuscular disorder has never been established Progressive multifocal leukoencephalopathy caused and should be considered unlikely. Most neuropathies are due to stretch with surgery or by a JC virus is another unusual complication after transpositioning and possibly preventable. A brachial plexoplantation and only a few well-documented cases have been reported. Behavioral change and dementia are compathy can be due to a shoulder hyperabduction but axilmon due to demyelination of the frontal lobe. The MRI lary vein cannulation is less commonly used in liver scan shows characteristic increased signal in the white transplantation. Ulnar and radial neuropathies are matter and brain biopsy can demonstrate in situ hybriduncommon after liver transplant surgery and are noticed ization for JC virus. Cytarabine is used to temporize by the patient usually as significant hand muscle weakthe tumor growth but with little success and most ness and more often painful tingling. Bilateral peroneal palsies are far more common after liver transplantation patients have not survived more than a year after the due to prolonged immobility during surgery in patients diagnosis. already predisposed as a result of marked weight loss. All these neuropathies have a good outcome over time. CENTRAL NERVOUS SYSTEM In our series, we found coagulopathy-associated psoas MALIGNANT TUMORS hematomas causing a femoral hematoma but this may Any transplant recipient is at risk of developing B cell only be seen in the more severe cases with rejection after lymphomas or glioblastoma multiforme or progressive liver transplantation. Chronic inflammatory demyelinatmultifocal leukoencephalopathy (PML) (Schiff et al., ing polyneuropathy has been reported in patients after 2001). These disorders are extremely uncommon, but reduction of immunosuppressive drugs. The true incican present within weeks after transplantation. Most dence is not known, nor how an immunologic response notorious is the occurrence of CNS lymphoma several to multiple nerves emerges (Taylor et al., 1995). weeks after transplantation (occurrence may vary from Any patient that develops a postoperative sepsis is at a few weeks to more than two decades after transplanrisk of critical illness polyneuropathy and presents tation). Most post-transplantation lymphomas are with severe quadriplegia. Rhabdomyolysis is also a premonoclonal B cell lymphomas, but multiclonal B cell sentation of severe sepsis but is less commonly seen lymphomas or T cell lymphomas have been reported. after liver transplantation. In cases reported certain Epstein–Barr virus infection has been linked to B cell drugs may have contributed (i.e., combination of statins lymphoma. CNS lymphoma represent with both brain and antibiotics). Patients may have considerable weakand spinal cord involvement, but presentation is nonspeness and muscle pain. Muscles are tender to touch but cific with new behavioral changes, visual hallucinations, this may be an unreliable sign in a critically ill patient or focal signs such as hemiparesis. In most patients a who just underwent a major transplantation procedure. change in personality may be the only key sign. Rhabdomyolysis cannot be clinically differentiated from



critical illness myopathy, which is more common in patients with sepsis, use of neuromuscular blockade and prolonged bed rest, and from corticosteroid-induced necrotic myopathy. In both, EMG will show a myopathic pattern (short duration motor units and fibrillation potentials) and creatine phosphokinase (CPK) values can be elevated. Outcome is favorable and rapid and muscle biopsies are usually deferred. The outcome of patients with critical illness polyneuropathy after liver transplantation is not known but likely not different from other clinical situations. There is generally little concern with neuromuscular disorders in liver transplant recipients and they rarely impact on mobility or function.

CONCLUSIONS There are specific neurologic problems with liver transplant recipients. The most challenging are: (1) treatment of acute fulminant liver failure and cerebral edema; (2) treatment of recurrent seizures and recognition of immunosuppressive neurotoxicity; (3) treatment and evaluation of agitation and postoperative confusion; (4) CNS infections, which are uncommon in the postoperative phase but can occur later, and often cause fatality. Neurologic complications after liver transplantation have declined, mostly as a result of better postoperative titration of immunosuppressive agents, critical care management, and possibly better selection of patients undergoing liver transplantation. Moreover, the spectrum of neurologic complications may change over time with liver transplant surgeons now mostly concerned with postoperative confusion and agitation. Neurologists seeing patients in a transplant unit should be prepared to see critically ill patients with multiple medical problems, procedures, and polypharmacy. Neurologists may also provide specific management recommendations and even be closely involved with the day to day care.

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Neurologic complications of liver transplantation.

A new spectrum of neurologic complications has appeared with treatment of the organ transplant recipient. There are specific problems in liver recipie...
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