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 89

Neurologic aspects of multiple organ transplantation SASˇA A. ZˇIVKOVIC´* Neurology Service, Department of Veterans Affairs and Department of Neurology, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA

INTRODUCTION The field of organ transplantation remains one of the most dynamic areas in medicine, with ever changing protocols and improved outcomes (Linden, 2009a). Availability of more potent immunosuppressants and better understanding of pathogenesis of allograft rejection have facilitated the development of more effective immunosuppressive protocols and prophylactic regimens decrease the impact of opportunistic infections. Such improvements have established organ transplantation as a valid treatment option for patients with irreversible end-organ failure. Transplantations of kidney, heart, and liver have been well established for more than two decades, and more recently transplantation of intestine became accepted as a rescue treatment for patients with intestinal failure who failed parenteral nutrition (Grant et al., 2005; AbuElmagd, 2006; Abu-Elmagd et al., 2009a; Fishbein, 2009). Multisystemic medical conditions (e.g., amyloidosis, diabetes) may compromise the function, or even lead to failure of several different organs. Multiorgan failure requires complex multidisciplinary care and may necessitate simultaneous transplantation of several organs, including combinations of heart–lung allograft, heart–liver, kidney–pancreas, or multivisceral transplantation (Table 89.1). Additionally, combined hematopoietic stem cell and solid organ transplantations have been performed in an attempt to modulate the postoperative immunologic response and induce the tolerance of allograft with decreased immunosuppression needs (Starzl and Zinkernagel, 1998; Starzl, 2004). Postoperative clinical course after organ transplantation is frequently marred by various surgical and medical complications, and it has been estimated that up to 30–60% of patients may develop some type of

post-transplant neurologic complications (Patchell, 1994; Bronster et al., 2000; Lewis and Howdle, 2003; Zˇivkovic´ and Abdel-Hamid, 2010). Overall, neurologic complications associated with organ transplantation typically stem from (1) the transplant procedure, (2) metabolic insult created by the underlying primary disease, (3) opportunistic infections, and (4) neurotoxicity of immunosuppressive medications (Zˇivkovic´ and AbdelHamid, 2010). Most commonly, neurologic complications do not determine the outcome of transplantation except in some patients with opportunistic CNS infections. In more recent years, as transplantation outcomes and survival continued to improve, the spectrum of post-transplant neurologic complications started to shift from acute postoperative complications to chronic complications which are increasingly encountered in an outpatient setting. The most commonly reported neurologic complications after transplantation are still alterations of consciousness, seizures, and neuromuscular complications (Zˇivkovic´ and Abdel-Hamid, 2010).

MULTIVISCERAL TRANSPLANTATION Intestinal failure is frequently accompanied by dysfunction and failure of other abdominal organs requiring liver–intestine or multivisceral transplantation (Abu-Elmagd et al., 2009a; Fishbein, 2009). Intestinal failure is defined as an “inability to maintain proteinenergy, fluid, electrolyte, or micronutrient balance” as a result of obstruction, dysmotility, surgical resection, congenital defect, or disease-associated loss of absorption (O’Keefe et al., 2006). The most common cause of intestinal failure requiring transplantation is short bowel syndrome (SBS), present in more than 70% of allograft recipients, followed by functional intestinal problems (e.g., dysmotility) in 20%, and “other” causes

*Correspondence to: Sasˇa A. Zˇivkovic´, M.D., Ph.D., PUH F878, 200 Lothrop St, Pittsburgh, PA 15213, USA. Tel: þ1-412-647-1706, Fax: þ1-412-647-8398, E-mail: [email protected]

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Table 89.1

Table 89.2

Multiorgan transplantations in US in 2009

Neurologic manifestations of nutritional deficiencies

Kidney–heart Kidney–intestine Kidney–lung Liver–heart Liver–intestine Multivisceral and intestinal Liver–kidney–heart Liver–kidney–pancreas–intestine Liver–lung Liver–lung–heart Liver–pancreas–intestine Pancreas–kidney Pancreas–intestine Heart–lung

60 5 3 11 4 180 4 9 10 1 76 854 9 30

Copper Selenium Chromium Carnitine Vitamin B1 Vitamin B2 Vitamin B3 Vitamin B6 Vitamin B12

Vitamin D Vitamin E

(UNOS OPTN Annual Report, 2009)

in the remaining of 10% of recipients (Hanto et al., 2005). Loss of functioning bowel in SBS requires complex dietary and medical management needed to alleviate severe disability and failure to thrive (Matarese et al., 2005). Intestinal failure may precipitate nutritional deficiencies or affect absorption of medications (O’Keefe et al., 2006; Ward, 2010). Malnutrition and various dietary deficiencies can precipitate a wide spectrum of neurologic disorders (Table 89.2). In adult patients, SBS is most often caused by Crohn’s disease, mesenteric thrombosis, or volvulus (Table 89.3). More recently, complications of surgeries for treatment of obesity have been recognized as another iatrogenic cause of SBS. Management of intestinal failure is based on trying to maintain balance of fluid, electrolytes, and nutrients and most patients will require nutritional support with total parenteral nutrition (TPN), at least temporarily. It has been estimated that more than 10 000 patients in the US are currently treated with long-term TPN, and 15–20% are deemed potential candidates for intestinal or multivisceral transplantation (DiBaise and Scolapio, 2007). Chronic TPN use may precipitate cholestatic liver injury, or even hepatic failure, but the pathophysiology of liver injury is still not well understood. Liver injury related to TPN is indicative of a poor outcome and these patients may require liver replacement (Pironi et al., 2011). Other frequent complications of TPN include malnutrition (if not properly formulated) and recurrent infections complicating venous access. Patients on TPN need continuous dietary monitoring to avoid sequelae of inadequate nutritional support (Mikalunas et al., 2001). Recurrent bloodstream infections have been reported in two-thirds of patients with long-term TPN (Marra et al., 2007). Patients who can no longer be maintained on TPN will require intestinal transplantation as a

Myeloneuropathy/myelopathy Myopathy Neuropathy Myopathy Wernicke–Korsakoff syndrome, peripheral neuropathy Optic neuropathy Encephalopathy, peripheral neuropathy, optic neuropathy Sensory neuropathy,* infantile seizures Subacute combined degeneration, dementia, peripheral neuropathy, autonomic neuropathy, optic neuropathy Myopathy, muscle cramps Retinitis pigmentosa, peripheral neuropathy, spinocerebellar degeneration

*Pyridoxine neurotoxicity may also cause sensory neuropathy. (Heller and Friedman, 1983; Cuba Neuropathy Field Investigation Team, 1995; Verhage et al., 1996; Chariot and Bignani, 2003; Orssaud et al., 2007; Kumar, 2010)

Table 89.3 Primary illnesses causing intestinal failure in pediatric and adult patients Children

Adults

Gastroschisis Necrotizing enterocolitis Intestinal atresia Volvulus Aganglionopathy Pseudo-obstruction

Mesenteric ischemia Inflammatory bowel disease Abdominal neoplasms Radiation enteritis Trauma Volvulus Pseudo-obstruction

(Abu-Elmagd et al., 2009a; Nayyar et al., 2010)

rescue therapy (Abu-Elmagd, 2006). Transplantation of small intestine (jejunoileum) is performed as an isolated intestinal transplantation procedure, or in combination with transplantation of other abdominal organs. It may be combined with liver allograft, and it is also the essential part of multivisceral transplantation (Abu Elmagd, 2006; Fishbein, 2009). Multivisceral and intestinal (MVI) transplantations are usually grouped together when outcomes of transplantation are considered. Multivisceral transplantation (also used synonymously is the term multiorgan transplantation) is performed simultaneously in contrast to sequential transplantations in patients developing organ failures at different times after initial transplantation (e.g., kidney failure related to calcineurin inhibitor (CNI) toxicity). Multivisceral

NEUROLOGIC ASPECTS OF MULTIPLE ORGAN TRANSPLANTATION transplantation offers immunologic protection to the intestinal allograft and is associated with lower rejection rate when compared to isolated intestinal transplantation (de Vera et al., 2000). Surgical complexity and formidable immunologic challenges has precluded wider use of multivisceral transplantation since 1987, when Dr Starzl and his team performed the first successful multivisceral transplantation (Starzl et al., 1989). Soon thereafter, Drs. Goulet and Grant and their groups performed the first successful isolated intestine and small intestine–liver transplantations, respectively (Grant et al., 1990). Continued advances in surgical technique and immunosuppression strategies established the role of MVI transplantation as a viable option for patients with complex multiorgan failures (Abu-Elmagd et al., 2009a, b, 2012). Development of improved and more potent immunosuppressive protocols based on recipient pretreatment and reduced maintenance immunosuppression enabled improved survival and reduction of organ rejection and post-transplant complications (Abu-Elmagd et al., 2009a, b, 2012). In the last few years, post-transplant survival at 1 and 5 years has reached 92% and 70%, which is comparable to other types of solid organ allografts (Abu-Elmagd et al., 2009a). However, the complexities of surgery and postoperative care are still largely limiting these procedures to a small number of academic centers, and more than 80% of MVI transplantations in the US have been performed by only 10 transplant centers (Grant et al., 2005). Currently there are close to 200 intestinal and multivisceral transplantations performed annually in the US, compared to more than 6000 liver transplantations (UNOS OPTN Annual Report, 2009). In August of 2010, there had only been 1988 intestinal and multivisceral transplantations performed in the US since 1990 (UNOS OPTN Annual Report, 2009). Immunogenicity of transplanted abdominal organs necessitates intensive immunosuppressive therapy which is associated with significant risks of immunosuppressant toxicity and opportunistic infections (Abu-Elmagd et al., 2009a, b). More recently, conditioning and tolerogenic immunosuppression strategies have tried to circumvent the need for such aggressive approach and allow effective use of lower intensity immunosuppression (Starzl et al., 2003; Abu-Elmagd et al., 2009a, b). This approach has allowed the use of lower doses of corticosteroids and CNIs and reduction of their toxicity. While close monitoring of nutritional status is still needed, successful transplantation is followed by nutritional autonomy in 90% of survivors and significant improvement and quality of life (AbuElmagd et al., 2012). Candidates for MVI transplantation frequently have an extensive history of abdominal surgeries, including

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intestinal resection, and complex pretransplant morbidities. Most common primary diseases leading to underlying organ failure differ in children and adults (Table 89.3). In children the most common underlying conditions include gastroschisis, necrotizing enterocolitis, and intestinal atresia. In the adult population the most common causes are inflammatory bowel disease, mesenteric artery thrombosis caused by hypercoagulable state, and abdominal tumors. Complex pretransplant morbidities and metabolic disturbances present unique challenges in post-transplant care of these patients (Hopfner et al., 2013). There are very few reports of neurologic complications after intestinal and multivisceral transplantation, consisting of individual case reports and one larger retrospective study (Mendez et al., 2006; Zˇivkovic´ et al., 2010). The rate of neurologic complications after MVI transplantation was reported as 86%, which is higher than the 30–60% usually reported with liver, kidney, or other solid organ transplantations (Patchell, 1994; Zˇivkovic´ and Abdel-Hamid, 2010; Zˇivkovic´ et al., 2010). Autopsy series showed frequent brain atrophy in deceased MVI allograft recipients, explained by long-standing metabolic disturbances and nutritional deficiencies (Idoate et al., 1999). Most commonly reported post-transplant neurologic complications in MVI allograft recipients include alterations of consciousness, seizures, and cerebrovascular complications (Zˇivkovic´ et al., 2010). The rate of opportunistic CNS infections with MVI in early series was higher than with other types of transplantation (Fishman, 2007; Zˇivkovic´ et al., 2010). However, the use of less intense immunosuppression in recent years will probably reduce the frequency of neurologic complications in line with other types of allografts.

Multivisceral transplantation Multivisceral transplantation is usually described as en bloc transplantation of three or more abdominal organs, including stomach, but at this time there is still no consensus on the definition of multivisceral allograft (Fig. 89.1; Table 89.4). The graft is modified according to the individual patient’s need with inclusion or exclusion of one or more abdominal organs, including the liver and kidney. Inclusion of the small bowel (jejunoileum) is essential to consider the graft as multivisceral. A variant known as “cluster transplantation” includes only liver, pancreas, duodenum, and possibly stomach. Preservation of native pancreas may improve posttransplant glucose control, but its impact on neurologic complications is uncertain (Cruz et al., 2010). The posttransplant course after multivisceral transplantation does not differ significantly in its spectrum from the complications seen after isolated intestine or

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Gastrostomy tube

Duodenojejunal anastomosis PV Aorta Vascular graft, SMV

PV Jejunostomy tube Vascular graft, SMA

Aortic Condult

Chimney ileostomy

JPC

Ileocolic anastomosis Transplanted Native

A

B

C

Fig. 89.1. Intestinal and multivisceral allografts. The three main different types of intestinal transplantation are (1) isolated intestine; (2) combined liver–intestine; (3) multivisceral transplantation containing the stomach, duodenum, pancreas, small bowel, and liver. PV, portal vein; SMA, superior mesenteric artery; SMV, superior mesenteric vein. (Modified from Abu-Elmagd et al., 2009b.) Table 89.4 Definitions of multivisceral allograft Definition of multivisceral allograft

Source (Grant et al., 2005) (UNOS OPTN Annual Report, 2009) (Tzakis et al., 2005)

Includes stomach as part of composite visceral graft Includes liver, intestine and either pancreas or kidney Replacement of all organs dependent on the celiac and superior mesenteric arteries

liver–intestine transplantation, including neurologic complications (Abu-Elmagd et al., 2009a, b, 2012; Zˇivkovic´ et al., 2010; Hopfner et al., 2013).

Isolated intestine transplantation Intestine allograft transplantation is an integral part of multivisceral transplantation, but if function of other abdominal organs is preserved, some patients may undergo isolated intestine transplantation. This may be the preferred procedure for patients who need transplantation in the near future before multivisceral allograft

may become available (Fishbein, 2009). Isolated transplantation of the intestine is typically performed in patients that have (relatively) intact function of other abdominal organs or if the patient cannot wait for availability of compatible multivisceral allograft (Fishbein, 2009). When compared to multivisceral and liver– intestine allografts, there is an increase of risk of graft rejection and loss with isolated intestinal allograft (AbuElmagd et al., 2009a). As a result of improved surgical and immunosuppression protocols, intestinal transplantation is associated with improved survival rates compared to nontransplanted candidates (Pironi et al., 2008; Abu-Elmagd et al., 2009a, b). Most transplant recipients achieve TPN-independence after transplantation and improved quality of life (Rovera et al., 1998). Transplantation of isolated intestinal allograft is more commonly performed in adults than in children due to more frequent liver dysfunction in pediatric patients and a different spectrum of underlying primary diseases leading to intestinal failure.

Liver–intestine transplantation Combined liver–intestine transplantation is pursued in patients with intestinal failure and liver dysfunction. At this time there is no consensus on definition of the extent of liver dysfunction required for

NEUROLOGIC ASPECTS OF MULTIPLE ORGAN TRANSPLANTATION liver–intestine allograft transplantation (Fishbein, 2009). Liver–intestine transplantation is also considered in patients with liver failure and concurrent portomesenteric thrombosis. When compared to isolated small bowel transplantation, composite liver–intestine and multivisceral transplantation procedures are associated with improved allograft tolerance (de Vera et al., 2000; Abu-Elmagd et al., 2009a).

Pediatric intestinal and multivisceral transplantation Intestinal failure and SBS are relatively rare in children, but if present are associated with severe morbidity and a profound impact on growth and development. Intestinal failure in this population is defined as an inability to achieve adequate weight and growth without parenteral nutritional support. Medical management of pediatric intestinal failure may enable some patients to achieve enteral autonomy, but intestinal (or multivisceral) transplantation may be required in more than one-third of patients (Nucci et al., 2008). Early referral for transplantation is recommended to avoid more extensive morbidity which may also affect the outcome of transplantation. High morbidity associated with transplantation is countered frequently with abysmal prognosis of many nontransplanted patients. Almost a half of pediatric patients on long-term TPN develop liver disease, and in the presence of cirrhosis 1 year mortality may amount to 70–80% (Goulet et al., 2004). At this time transplantation pediatric allograft recipients comprise 55–60% of all MVI transplantations (UNOS OPTN Annual Report, 2009). Pediatric MVI transplantation differs from the same procedures in adult recipients in underlying etiologies of intestinal failure and its profound impact on and pre- and posttransplant morbidity and growth and development of allograft recipients (Kato et al., 2006; Mazariegos et al., 2008; Nayyar et al., 2010). Pediatric MVI transplant patients may present unique challenges in the acute postoperative phase or later, especially with multiple preexisting morbidities and late transplant referrals (Hauser et al., 2008). Outcome of MVI transplantation will directly affect the future growth and development of allograft recipients, and while most allograft recipients improve after transplantation, they may still not be able to catch up with their healthy age-matched controls (Sudan et al., 2000; Abu-Elmagd et al., 2009a). In recent years, protocols using lower doses of corticosteroids seemed to have improved post-transplant growth in pediatric intestinal transplant recipients (Ueno et al., 2006). Cognitive developmental delay and psychiatric disorders have been reported in up to 37% of pediatric MVI allograft

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recipients (Abu-Elmagd et al., 2012). Chronic malnutrition and lack of adequate social support in some patients may also contribute to developmental delays and challenges. Despite the high prevalence of psychiatric and developmental disorders in this population, almost one-third (31%) will later graduate from college and an additional 35% will finish an equivalent of high school (Abu-Elmagd et al., 2012). At this time there are no published systematic studies describing neurologic complications following intestinal and multivisceral transplantation in pediatric MVI allograft recipients.

NEUROLOGIC COMPLICATIONS OF MULTIVISCERAL AND INTESTINAL TRANSPLANTATION Neurologic complications of organ transplantation are a frequent cause of morbidity in early and late postoperative clinical course. Due to complex metabolic disturbances, nutritional insufficiencies, and high immunosuppression requirements the rate of neurologic complications after MVI transplantation is relatively high when compared to transplantations of liver, lung, or heart (Lewis and Howdle, 2003; Zierer et al., 2007; Zˇivkovic´ et al., 2010). The most commonly described complications include alterations of consciousness, headaches, and seizures (Table 89.5) (Zˇivkovic´ et al., 2010). While complex nutritional deficiencies in MVI transplant candidates invoke similarities with bariatric surgery patients, the observed spectrum of related neurologic complications is different (Thaisetthawatkul et al., 2004; Juhasz-Pocsine et al., 2007; Kazemi et al., 2010; Zˇivkovic´ et al., 2010). Half of adult MVI allograft recipients still receive vitamin D and B6 supplementation after successful surgery (Abu-Elmagd et al., 2012). Lack of reported complications attributable to malnutrition after MVI transplantation is also related to strict monitoring of nutritional parameters, similarly to the recommendations with bariatric surgery (Matarese et al., 2005, 2007; Thaisetthawatkul et al., Table 89.5 Neurologic complications after intestinal and multivisceral transplantation Altered consciousness Seizures Ischemic stroke Intracerebral hemorrhage CNS infection Peripheral neuropathy Headaches (Zivkovic et al., 2010)

43% 17% 4% 2% 7% 7% 50%

1310 S.A. ZˇIVKOVIC´ 2010). However, we also have to acknowledge that it consciousness and behavior (Small et al., 1996; would be difficult to compare bariatric procedures Bartynski et al., 2008). Neurotoxicity of other medicawith over 100 000 cases yearly with the 300 annual cases tions is less common. Antiviral medications and antibiof MVI transplantation. Additionally, as complications otics (e.g., aciclovir, cephalosporins) may also of bariatric surgery such as copper-deficiency precipitate toxic encephalopathy, especially in patients myeloneuropathy may manifest 9 years or longer after with hepatorenal dysfunction (Grill and Maganti, the gastric bypass, it will be essential to compare long2008). Opportunistic infections may precipitate alterterm surveillance results for meaningful comparison ations of consciousness via direct spreading to central of outcomes. nervous system or by triggering septic encephalopathy. Complexity of pretransplant morbidities and posttransplant complications may also help to explain high Alterations of consciousness and behavior levels of stress and frequent psychiatric disorders in Encephalopathy defined as an alteration of consciousMVI allograft recipients (Stenn et al., 1992; DiMartini ness or behavior is quite common in transplant recipiet al., 1996; Surman et al., 2009). ents, including multivisceral allograft recipients. Etiologies vary widely, from drug toxicities and metabolic abnormalities to opportunistic infections (with or Epilepsy without direct involvement of CNS) (Zˇivkovic´ et al., Epileptic seizures occur commonly in transplant recipi2010). Liver failure may also precipitate hepatic encephents and most frequent causes include toxic-metabolic alopathy, similar to that in liver transplant recipients disturbances, CNI neurotoxicity, and CNS infections (Guarino et al., 2006). Liver dysfunction in MVI trans(Estol et al., 1989; Wijdicks et al., 1996). In MVI recipiplant recipients is commonly related to cholestatic ents, seizures were reported in up to 17% of recipients TPN-related liver injury, but it is not the only possible (Zˇivkovic´ et al., 2010). Generalized tonic-clonic seizures cause of hyperammonemic encephalopathy. Etiology are most common. Nonconvulsive status epilepticus may of hyperammonemia may be quite complex and also be difficult to distinguish from toxic-metabolic encephrelated to: (1) hepatic allograft rejection, (2) liver cirrhoalopathy, even with careful review of video-EEG recordsis, (3) bacterial overgrowth, and (4) urea cycle enzyme ing (Brenner, 2005). Electroencephalographic findings abnormalities. Bacterial overgrowth in strictured bowel are frequently not specific, and repeated studies are with intestinal transplant-related portocaval shunt may often needed to demonstrate epileptiform changes on precipitate relapsing encephalopathy associated with EEG (Steg and Wszolek, 1996). Neurotoxicity of CNIs hyperammonemia (Shah et al., 2003). Partial urea cycle may precipitate seizures, with or without PRES. At this enzyme abnormalities may also, under stress conditions, time it remains unclear when it is safe to discontinue trigger hyperammonemia which may be difficult to antiepileptics after resolution of PRES, and recomtreat. Successful use of hemodialysis and nitrogen waste mended durations of treatment after clinical resolution agents has been reported in one patient with hyperammoof PRES vary from several weeks to several months. Seinemic coma after heart–lung transplantation (Berry zures associated with structural brain abnormalities et al., 1999). In addition to hyperammonemic encephacaused by PRES, ischemic stroke, or cerebral hemorlopathy, other toxic-metabolic encephalopathies may rhage may warrant long-term antiepileptic treatment. stem from hyper- or hypoglycemia, electrolyte disturTreatment of status epilepticus after MVI transplanbances, drug toxicity, and opportunistic infections. Clintation does not differ from standard treatment protoically it may be difficult to distinguish metabolic (or cols, but maintenance antiepileptic regimens have to toxic) encephalopathy from nonconvulsive status epileptake into consideration possible hepatic, renal, and/or ticus and the role of EEG in such settings cannot be overintestinal dysfunction, and also altered absorption of emphasized. However, caution is needed in the orally administered medications. Traditionally used antiinterpretation of EEG findings as electroencephaloepileptic medications phenytoin and carbamazepine may graphic patterns may be difficult to distinguish with ceraffect metabolism of CNIs and there is a risk of hepatotainty (Brenner, 2005). Neurotoxicity of calcineurin toxicity. The use of topiramate in this population is usuinhibitors (CNIs), tacrolimus and cyclosporine (CNI), ally precluded by its appetite-suppressing properties is particularly common in first 30 days after transplanwhich are problematic in such patients who are already tation when higher dosing is used (Zˇivkovic´ et al., at risk from nutritional deficiencies. As with other types 2010). Clinical manifestations of CNI neurotoxicity of transplants, levetiracetam is being used more freinclude altered mental status, tremor, and posterior quently, especially since it is now available in intravereversible encephalopathy syndrome (PRES), characternous preparation as well (Chabolla and Wszolek, 2006). ized by typical imaging findings and alterations of

NEUROLOGIC ASPECTS OF MULTIPLE ORGAN TRANSPLANTATION 1311 54 adult MVI allograft recipients at the University of Cerebrovascular complications Pittsburgh showed a prevalence of CNS opportunistic Post-transplant stroke is more common than in general infections of 7%, which is higher than with other types population and affects up to 2–4% of non-heart allograft of allografts (Fishman, 2007; Zˇivkovic´ et al., 2010). In recipients (Zˇivkovic´ and Abdel-Hamid, 2010; Zˇivkovic´ recent years, improvements in immunosuppressive reget al., 2010). Uncontrolled hyperlipidemia and hypertenimens and routine prophylactic therapy have reduced the sion, which may be aggravated by immunosuppressive prevalence of opportunistic CNS infections, down to medications, increase the risk of cardiovascular and 1–2% in recent reported series with other types of solid cerebrovascular disease. Post-transplant hypertension organ transplants (Lewis and Howdle, 2003; Zierer et al., has been reported in up to 51% of adult MVI allograft 2007). A similar reduction in CNS infections was recipients (Abu-Elmagd et al., 2012). Despite frequent observed in MVI allograft recipients more recently infections in this group, so far there have been no reports (author’s unpublished observation). of an increased rate of infective endocarditis. HypercoaChronic immunosuppression may diminish the gulability is relatively frequent in MVI allograft recipiinflammatory response, altering typical clinical signs ents and mesenteric artery thrombosis related to an or even radiologic features of an infection (Linden, underlying hypercoagulable condition is one of the more 2009b). Additionally, complex toxic-metabolic disturcommon indications for MVI transplantation. Common bances may also mask the signs of infection and delay causes of hypercoagulable state include antithrombin the diagnosis. The spectrum of infection causes also deficiency, factor V Leiden mutation, and protein C changes depending on time after transplantation, intenand S deficiencies (Giraldo et al., 2000). These patients sity of immunosuppression and exposures, with inclumay require lifelong anticoagulation, even after liver sion of opportunistic pathogens and atypical transplantation, and are at an increased risk of deep presentations (Fishman, 2007). Therefore, to prevent venous thrombosis and pulmonary embolism (Giraldo infections, different prophylactic protocols are routinely et al., 2000). Deep venous thrombosis may precipitate used in the treatment of transplant recipients and the use stroke via shunt (paradoxical embolism) through a patof individual medications will depend on specific expoent foramen ovale, which may be present in up to 25% sures and comorbidities. In the specific population of of the general population (Kent and Thaler, 2010). While intestinal and multivisceral allograft recipients, the proxclinical significance of hypercoagulable conditions in the imity of intestinal bacterial load and impaired defensive pathogenesis of arterial cerebrovascular thrombosis barriers due to inflammation and rejection create an remains somewhat controversial (Levine, 2005), ischeenvironment with a high risk of bacterial and fungal mic strokes might be more frequent in MVI allograft infections. Bacterial and fungal systemic infections recipients with underlying hypercoagulable conditions are very common, and increasing incidence was (Zˇivkovic´ et al., 2010). observed 3 months or longer after transplantation; this Cerebrovascular complications related to thrombotic pattern was explained by chronic intense immunosupmicroangiopathy have not been reported in this populapression (Kusne et al., 1994). Fatal infections have been tion. Thrombotic microangiopathy may present with a associated with graft failure in 11% of recipients, and stuttering clinical course and is usually considered as were most commonly bacterial (61%), followed by funsimilar to thrombotic thrombocytopenic purpura gal (31%) and viral infections (7%) (Abu-Elmagd et al., (TTP) (Dawson et al., 1991; Scully and Machin, 2009). 2009a). Bacterial CNS infections are overall uncommon Thrombotic microangiopathy may improve with in transplant recipients except with some specific enviwithdrawal of CNIs. ronmental exposures (e.g., unpasteurized dairy and listeHigh prevalence of hypercoagulable conditions, freriosis), and timely treatment will reduce the morbidity. quent infections, and dehydration (diarrhea) predisposes However, there is an increased risk of fungal opportumultivisceral and intestinal transplant recipients to nistic CNS infections which carry a high mortality even higher risk of venous blood clotting, including cerebral with an early diagnosis. The port of entry for fungal venous sinus thrombosis. However, so far there are only infections is usually the respiratory system, and most rare reports of cerebral venous sinus thrombosis in this patients have clinical signs of respiratory infection. population (Zˇivkovic´ et al., 2010). Infrequently, fungal sinusitis may go unnoticed and precipitate catastrophic CNS infection in transplant recipients (van de Beek et al., 2008). Fatal fungal and Opportunistic infections protozoal CNS infections were reported in MVI alloOpportunistic infections are a significant source of morgraft recipients, and reported frequency of opportunisbidity after MVI transplantation (Kusne et al., 1996; tic CNS infections is higher than observed with other Guaraldi et al., 2005). Retrospective study of the first types of allografts (Mendez et al., 2006; Fishman,

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2007). In reported series, CNS aspergillosis was the most commonly reported opportunistic CNS infection in MVI transplant recipients (Nishida et al., 2002; Zˇivkovic´ et al., 2010). Parasitic infections are also fortunately rare, but mortality is very high (Campbell et al., 2006; Mendez et al., 2006). The most common parasitic infection in transplant recipients is toxoplasmosis, while amebiasis and strongyloidosis are rare. Solid organ transplant recipients are also at risk of viral encephalitides most commonly caused by cytomegalovirus (CMV), varicella zoster (VZV) and herpes simplex (HSV) viruses (Fishman, 2007). EBV infection may be associated with post-transplant lymphoproliferative disorder (PTLD). In the early years of MVI transplantations, CMV infections had a significant negative impact on transplantation outcomes, but this was not related to associated CNS infections (Furukawa et al., 1996). In subsequent years, implemented surveillance and prophylactic measures diminished the impact of CMV infections (Abu-Elmagd et al., 2009a, b). Progressive multifocal leukoencephalopathy (PML) has a very high mortality, but it is fortunately rare in HIV-negative solid organ transplant recipients (Amend et al., 2010). PML is caused by JC virus, and the same virus was also implicated in the pathogenesis of chronic intestinal pseudo-obstruction, which may cause intestinal failure leading to transplantation (Selgrad et al., 2009). However, to date there have been no reports of MVI transplant recipients with a firmly established diagnosis of PML, although there is a report of a single patient with PML-like leukoencephalopathy improving after allograft was removed (Idoate et al., 1999). Rarely, back pain and weakness may be caused by infectious discitis or vertebral osteomyelitis caused by bacterial or fungal infections (Gerlach et al., 2009).

Headaches Migraines are very common in the population as a whole, including MVI transplant candidates, and allograft recipients will commonly report worsening of preexisting or new onset of migraines after transplantation, especially with the use of calcineurin inhibitors. New onset or worsening of headaches always present a diagnostic and treatment challenge in transplant patients. Post-transplant headaches significantly worsen the quality of life of one-third of affected allograft recipients (Uutela et al., 2009). Interestingly, a high frequency of headaches was reported in intestinal and multivisceral transplant recipients but the underlying pathophysiology remains unclear (Zˇivkovic´ et al., 2010). Possible explanations include chronic use of pain medications in many patients and higher doses of tacrolimus than used with other types of transplantation. Rarely, new onset of

headaches in transplant patients may signify the presence of a severe neurologic condition, including CNS infection, fungal sinusitis, or calcineurin-inhibitor toxicity, especially when accompanied by other neurologic symptoms (e.g., confusion, focal weakness, seizures) (Kiemeneij et al., 2003; Mendez et al., 2006). Early diagnosis of opportunistic CNS infections is an imperative to allow early diagnosis and prompt treatment. Treatment decisions in transplant patients with headaches are frequently guided by limitations imposed by the transplant status. Topiramate is frequently avoided in intestinal and multivisceral transplant recipients due to its potential weight-losing properties. Additionally, topiramateinduced kidney stones were observed in 1.5% of treated epilepsy patients (Shorvon, 1996). Valproate may interact with tacrolimus or cyclosporine and is potentially hepatotoxic. Other options for treatment of migraines include riboflavine (200 mg twice daily) and magnesium (Peikert et al., 1996; Stracciari et al., 2006). Magnesium is sometimes used for headache prevention and it is already typically included in standard maintenance regimens of many transplant recipients treated with tacrolimus or cyclosporine to prevent CNI-induced hypomagnesemia. A short course of corticosteroids may be used for abortive treatment of migraines. Acetaminophen/ paracetamol and nonsteroidal anti-inflammatory medications are usually avoided due to potential hepato- and nephrotoxicity. Other options include preventive use of tricyclic antidepressants and b-blockers, but we should always investigate possible drug–drug interactions or consequences of suboptimal liver and kidney function. Additionally, tricyclics may slow intestinal motility and careful dosing is needed. Triptans should be used cautiously for abortive treatment, and we also have to consider altered enteral absorption in patients with allograft rejection or chronic diarrhea. Continued use of opioid medications for chronic pain, frequently related to prior abdominal surgeries, may also complicate headache treatment.

Neuromuscular complications Complex metabolic and toxic disturbances following intestinal and multivisceral transplantation create an environment rich in risk factors for development of various neuromuscular disorders. Neuromuscular complications after bariatric surgery have been well described and attributed to nutritional deficiencies and metabolic imbalance (Thaisetthawatkul et al., 2004; Rudnicki, 2010). We could possibly expect a similar spectrum of neuromuscular complications following frequent long-standing nutritional imbalance in MVI allograft recipients. Somewhat surprisingly there is a

NEUROLOGIC ASPECTS OF MULTIPLE ORGAN TRANSPLANTATION low reported prevalence of neuromuscular complications in intestinal and multivisceral transplant recipients, amounting only to up to 7% (Zˇivkovic´ et al., 2010). A complicated post-transplant course requiring prolonged stay in intensive care units increases the risk of critical illness myopathy, similarly as in other transplant patients (Campellone et al., 1998). Critical illness myopathy is frequently accompanied by its neuropathic counterpart, critical illness polyneuropathy (Visser, 2006). Other more frequent causes of polyneuropathy include diabetic and uremic neuropathies, and toxic neuropathies related frequently to the use of neurotoxic antibiotics. Frequent bacterial infections may necessitate the use of potentially neurotoxic antibiotics (e.g., metronidazole, linezolid), and the risk may be increased with prolonged use. Despite frequent nutritional deficiencies, there are no published reports of neuropathy directly attributable to defined nutritional deficiency in this population. Posttransplant diabetes has been described in 11% of MVI allograft recipients increasing the risk of diabetic neuropathy (Abu-Elmagd et al., 2012).

Other complications Post-transplant lymphoproliferative disorder (PTLD) remains relatively common after intestinal transplantation, especially in pediatric patients and with multivisceral allografts (Grant et al., 2005; Abu-Elmagd et al., 2009c). It has been reported that overall, up to 13% of MVI graft recipients may develop PTLD, and nonlymphoid neoplasms have been reported in an additional 3% of patients (Abu-Elmagd et al., 2009c). In MVI recipients, PTLD is typically associated with EBV infection (Abu-Elmagd et al., 2009a). Overall, CNS involvement in PTLD has been reported in up to 15% of patients with various types of allografts, and is usually associated with a poor prognosis (Buell et al., 2005). However, some patients may recover with decreased immunosuppression (Castellano-Sanchez et al., 2004). Lymphoid content of intestinal allograft increases the risk of graft-versushost disease (GVHD), which is more common than with other types of solid organ allografts and has been reported in up to 9% of MVI allograft recipients compared to 1–2% with liver transplantation (Wu et al., 2011). The risk of GVHD seems to be higher with multivisceral allografts when compared to isolated intestine and liver-intestine transplantation (Abu-Elmagd et al., 2009a). There are no reports of GVHD involving peripheral or central nervous system in MVI transplant recipients, but other previously reported cases of GVHD with neurologic involvement ranged from myositis and vasculitic neuropathy to cerebral vasculitis (Parker et al., 1996; Ma et al., 2002).

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Movement disorders are usually not a significant source of morbidity in intestinal transplant patients. Tremor is frequent with the use of CNIs, but only rarely is it severe enough to consider modification of immunosuppression. Use of metoclopramide to promote motility may precipitate tardive dyskinesia which may be difficult to treat (Zˇivkovic´ et al., 2008).

HEART^LUNG TRANSPLANTATION Combined heart–lung transplantation is most commonly performed for the treatment of congenital heart disease, cystic fibrosis, and idiopathic pulmonary arterial hypertension (Christie et al., 2010). Outcomes are usually grouped together with lung transplantations, and the long-term mortality is mostly related to infections and bronchiolitis obliterans, as with lung transplantation. In the early post-transplant course, morbidity is higher than with lung transplantation and this may be somewhat attributable to pre-existing heart failure and complex technical aspects of surgery and postsurgical care. The number of combined heart–lung transplantations has decreased in recent years by 50% when compared to the earlier peak in the 1990s (Christie et al., 2010). It seems that combined transplantation of lungs and heart offers some immunologic benefits and onset of cardiac vasculopathy is typically delayed when compared to transplantation of the heart alone. In the first year after transplantation, PTLD is the most common malignancy, and CNS involvement has been reported in 13% of heart or lung allograft recipients (Buell et al., 2005). Long-term survivors are exposed to an increased risk of malignancies, which have been reported in up to 40% of heart–lung transplant recipients after 15 years (Deuse et al., 2010). There have been no systematic studies of neurologic complications following heart–lung transplantation, and the spectrum of neurologic complications largely overlaps post-transplant complications in lung and heart allograft recipients. Postoperative phrenic nerve injury seems to be more common than after lung transplantation and this may be attributed to the more extensive surgical procedure (Ferdinande et al., 2004).

KIDNEY^PANCREAS TRANSPLANTATION Combined kidney–pancreas transplantation is the most commonly performed multiorgan transplantation procedure. Typical indication is kidney failure caused by diabetic nephropathy with poorly controlled diabetes. Simultaneous kidney–pancreas has better outcomes than sequential transplantation of kidney and pancreas on two different occasions (Wiseman, 2010).

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There have been no systematic studies of neurologic complications following kidney–pancreas transplantation. However, the postoperative course is similar to the clinical course following kidney transplantation. Worsening of weakness was reported after kidney– pancreas transplantation and this was attributed to myopathy as there was no associated worsening of neuropathy (Dyck et al., 2001). Diabetic neuropathy usually gets better following kidney–pancreas transplantation as glycemic control improves, but the extent of improvement is variable in individual patients. Vascular complications are relatively common in patients with diabetes, including ischemic strokes. Slower progression of macrovascular disease, including cerebrovascular complications, was demonstrated in kidney–pancreas transplant recipients when compared to patients with only kidney allograft (Biesenbach et al., 2005). Nevertheless, cerebrovascular complications remain a significant source of morbidity after kidney–pancreas transplantation and were still reported as a cause of death in almost 2% of allograft recipients (Sollinger et al., 2009). Benefit of a successful combined kidney–pancreas transplant becomes more apparent after 5 years or longer post-transplantation. There are no published systematic reports on occurrence of PTLD after kidney–pancreas transplantation, but more frequent CNS involvement was reported for both pancreas (27%) and kidney (18%) allograft recipients with PTLD (Buell et al., 2005).

COMBINED SOLID ORGAN AND HEMATOPOIETIC STEM CELL TRANSPLANTATION Combination of solid organ and hematopoietic stem cell transplantation(HSCT) has been pursued to improve allograft tolerance and reduce immunosuppression after transplantation (Starzl, 2004). Experimental studies on laboratory animals demonstrated induction of tolerance of allograft when donors’ bone marrow transplant was combined with solid tumor transplantation (Gozzo et al., 1970). Subsequent clinical studies showed a decrease of the rate of rejection, lower immunosuppression requirements, and even complete immunosuppression withdrawal in some patients (Zeevi et al., 1997; Delis et al., 2006). However, longer follow-up will be needed to establish the magnitude of benefit and risks of complications. Combined solid organ and hematopoietic stem cell transplantation may be complicated by acute and chronic GVHD with a reaction of the donor’s immune system attacking the host’s organs. Most recent reports record a decrease in risk with improved HSCT protocols and only 2% of allogeneic hematopoietic stem cell transplant recipients develop severe acute GVHD

(Gooley et al., 2010). At this time it is still not known if the risk of GVHD is changed after combined HSCT and solid organ transplantation. So far, there are no reports of GVHD related to HSCT-augmented solid organ transplantation. There are also no published systematic studies of neurologic complications of HSCTaugmented solid organ transplantation.

ACKNOWLEDGEMENTS The authors take full responsibility for the contents of this article, which do not represent the views of the Department of Veterans Affairs or the United States Government.

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