Neurologic complications of pancreas and small bowel transplantation.

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 87

Neurologic complications of pancreas and small bowel transplantation MICHAEL JACEWICZ1* AND CHRISTOPHER R. MARINO2 Department of Neurology, University of Tennessee Health Science Center, Memphis, TN, USA

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Department of Medicine, University of Tennessee Health Science Center, Memphis, TN, USA

INTRODUCTION Neurologic complications can involve any part of the central or peripheral nervous system and appear in as many as 30% of patients undergoing organ transplantation (Patchell, 1994; Zivkovic and Abdel-Hamid, 2010; Pustavoitau et al., 2011). For small bowel transplantation, the complication rate may be even higher because of the need for higher levels of immune suppression. Many of these neurologic complications (e.g., hypoxic/ischemic encephalopathy, neurotoxicity of immunosuppressive medications, opportunistic infections) apply to all transplant procedures, including pancreas and small bowel transplantation. Such general transplant complications are discussed in greater detail elsewhere in this book but are briefly reviewed here before the neurologic issues specific to pancreas and small bowel transplantation are addressed in detail. Because transplantation of the pancreas is often combined with kidney transplantation, and small-bowel combined with liver transplantation, the neurologic complications associated with kidney and liver transplantation are quite relevant to pancreas and bowel transplantation, respectively. Finally, as transplantation and immunosuppression protocols have evolved, patient and graft survival have improved, and the focus of neurologic complications has shifted toward long-term complications (Meier-Kriesche et al., 2006; Pustavoitau et al., 2011).

PERIOD PRECEDING TRANSPLANTATION Neurologic symptoms may arise before surgery because of the organ failure that precedes transplantation (Coles, 2000; Senzolo et al., 2009; Gremizzi et al., 2010; Nayyar

et al., 2010). Candidates for pancreas transplantation typically have advanced diabetes mellitus and extensive end organ damage, including nephropathy, retinopathy, and neuropathy. Candidates for small bowel transplantation have prolonged intestinal failure. Their dependence on total parenteral nutrition (TPN) may cause complex nutritional deficiencies and metabolic changes resulting in neurologic symptoms. Those patients exhibiting hepatic encephalopathy from TPN-induced liver failure typically require combined liver–intestine transplantation.

PERIOPERATIVE NEUROLOGIC COMPLICATIONS Neurologic deficits may first appear in the immediate postoperative period. Although most transplant procedures proceed uneventfully, occasionally the surgery is complicated by excessive bleeding, cardiovascular instability, and/or anesthesia problems. An intraoperative arterial watershed ischemic stroke may result, especially if there is prolonged intraoperative hypotension in the context of an unsuspected carotid stenosis. When the compromise of blood flow to the brain is global, diffuse cerebral hypoxic/ischemic damage (anoxic encephalopathy) occurs and is typically manifested by the patient’s failure to awaken in the recovery room. There may be multifocal muscle twitching (myoclonus), intractable seizures, prolonged coma, and a poor neurologic outcome. Excessive pressure in body/limb positioning, retraction, diversion of arterial blood to the transplant, hematoma formation, and other technical problems can produce compressive and/or ischemic nerve injury in 2–6% of transplant recipients (Pustavoitau et al., 2011). The resulting type of focal neuropathy depends on the type of allograft received.

*Correspondence to: Michael Jacewicz, M.D., University of Tennessee Health Science Center, Department of Neurology, 855 Monroe Ave, Rm 415, Memphis, TN 38163, USA. Tel: þ1-901-448-6661, E-mail: [email protected]

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M. JACEWICZ AND C.R. MARINO

Because pancreas transplantation is often combined with kidney transplantation, and small bowel with liver, the focal nerve deficits in pancreas and small bowel transplantation patients may actually reflect technical problems with transplantation of the paired organ. Thus, femoral neuropathy and lumbosacral plexopathy associated with kidney transplantation can be seen in combined pancreas–kidney transplantation. Brachial plexopathy is seen with liver transplantation and can complicate small bowel–liver transplants. Perineal neuropathy complicates all types of organ transplantations. Importantly, diabetes and nutritional deficiencies predispose the patient to entrapment neuropathies in the perioperative period, so special care in patient positioning must be taken to avoid applying pressure on peripheral nerves for prolonged periods of time.

FIRST POSTOPERATIVE MONTH ●

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Metabolic encephalopathy. In the intensive care unit (ICU), impairment of consciousness may be observed in the early postoperative period (less than 1 month). This may reflect anoxic encephalopathy, metabolic disturbances, immunosuppressive drug toxicity, adverse effects of other drugs (e.g., opioid and benzodiazepine sedation, metronidazole), and infection (Adair and Gilmore, 1994; Graves et al., 2009). As a perioperative complication, metabolic encephalopathy is especially common in liver transplants and is therefore pertinent to small bowel–liver transplantation. Immunosuppressive drugs, hypoxemia, alterations in blood chemistries (e.g., hypoglycemia and hyponatremia), volume depletion, sepsis, and other factors can contribute to the frequently multiple etiologies underlying the encephalopathy. An infection prior to transplantation, if inadequately treated, may produce a hyperacute infection and sepsis immediately after surgery with changes in mental status even though the organism never breaches the cerebrospinal fluid (CSF) space. Seizures. These may be overt or subtle (e.g., nonconvulsive status) and arise from anoxic brain damage, electrolyte abnormalities, high doses of immunosuppressants (e.g., cyclosporine, OKT3) and other drugs (e.g., meperidine, imipenem, ciprofloxacin).

After 1 month, these etiologies remain important reasons for alterations in mental status, but opportunistic infections become an increasing concern because of prolonged immune-suppression.

FIRST 6 MONTHS AFTER TRANSPLANTATION ●

Headache. Headache is not uncommon after transplantation and is usually found to be benign. It may

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involve a worsening of a prior migraine disorder. More worrisome is the onset of a new or different kind of headache in the context of suppressed immunity because the headache may be the initial manifestation of an opportunistic central nervous system (CNS) infection. A new headache in a transplant patient warrants very careful assessment that typically includes neuroimaging and CSF analysis. The headache occasionally arises from fungal sinusitis or toxicity from immunosuppressive drugs (van de Beek et al., 2008). Immunosuppressive drug neurotoxicity. Early after transplantation, immunosuppressive drugs (e.g., cyclosporine, tacrolimus) are administered at higher doses, increasing their risk for causing neurotoxicity (Wijdicks, 2001). This is especially relevant to small bowel allografts that typically require stronger immunosuppression than other organs. Overall, however, the use of calcineurin inhibitors, including tacrolimus and cyclosporine, has become safer over time with reductions in dosage and optimization in plasma levels (Smith et al., 2003; Burke et al., 2004). Adverse effects of immunosuppressive medications include: ● Headache ● Tremor ● Seizures ● Aseptic meningitis causing headache and neck stiffness ● Posterior reversible encephalopathy syndrome (PRES) causing cortical blindness, visual hallucinations, encephalopathy, seizures, and coma (Singh et al., 2000; Lee et al., 2008; Pustavoitau et al., 2011). PRES can be triggered by the calcineurin inhibitors tacrolimus and cyclosporine. It is less commonly associated with sirolimus or everolimus. White matter edema is typically detected on magnetic resonance imaging (MRI) or computed tomography (CT) in the posterior parietal and occipital lobes but other CNS structures can also be involved. The incidence may reach 6.0%. PRES is typically a late complication of renal transplantation (after 1 year) and appears in the setting of poorly controlled hypertension and typically shows less extensive brain edema. In contrast, liver transplant recipients typically develop PRES within 2 months of transplantation and exhibit extensive brain edema (Bartynski et al., 2008). These observations may be relevant to individuals with combined pancreas–kidney and intestine–liver transplants. ● Reversible internuclear ophthalmoplegia has been attributed to tacrolimus neurotoxicity (Oliverio et al., 2000; Lai et al., 2004).

NEUROLOGIC COMPLICATIONS OF PANCREAS AND SMALL BOWEL TRANSPLANTATION 1279 Opsoclonus has been described with cyclosportransplants. Stroke has been attributed to the high ine (Marchiori et al., 2004). Importantly, neuroburden of hypertension, atherosclerosis, and diabetoxicity usually subsides when the offending tes in patients requiring dialysis (Adams et al., drug is substituted with another immunosup1986; Ponticelli and Campise, 2005; Yardimci pressant (e.g., sirolimus or tacrolimus). et al., 2008). ● Antithymocyte globulin (ATG) and OKT3, a ● Intracranial hemorrhage. This may complicate up to monoclonal antibody directed against CD3 7% of liver transplant recipients and may apply to adhesion molecule, have been associated with small bowel–liver recipients. As mentioned above, aseptic meningitis, seizures, and rarely akinetic Aspergillus can invade the cerebral vasculature mutism (Doney et al., 1987; Martin et al., 1988; and cause hemorrhagic infarction. Adair et al., 1991). ● Critical illness myopathy-polyneuropathy. With a ● Corticosteroids administered in high doses prolonged ICU stay, the patient may develop critical can trigger a psychotic reaction (i.e., steroid psyillness myopathy and/or polyneuropathy. This neuchosis), mood swings (e.g., mania, depression), romuscular disorder is typically associated with steroid myopathy and critical illness myopathyuse of bolus steroids, sepsis, and prolonged neuropolyneuropathy. muscular junction blockade for mechanical ventilaCNS infections. Infectious pathogens are responsition. When recipients of pancreas transplants ble for up to 29% of structural lesions observed with develop a postoperative worsening of weakness, it neuroimaging of the brain of transplant recipients is more likely due to critical illness myopathy than and the mortality is high (Singh and Husain, to an aggravation of diabetic neuropathy. 2000). Bacterial infections predominate in the early ● Central pontine myelinolysis (CPM). In the setting post-transplant period after which viruses, opportuof overly rapid correction of hyponatremia, nistic and atypical organisms occur with increasing patients may develop quadriplegia, lethargy, pseufrequency (Pustavoitau et al., 2011). Nocardia may dobulbar palsy, and dysphagia. CPM is more cominfect up to 6% of immunocompromised individmon after liver transplantation and therefore a uals. The most common etiology of meningoencephpotential complication of small bowel–liver alitis in transplant patients is human herpes virus 6 transplantation. (HHV-6), typically appearing 2–6 weeks after trans● Graft rejection. Graft rejection often requires plantation. Progressive multifocal leukoencephalogreater immune suppression, creating increased risk pathy (PML) is relatively rare but tends to appear for drug neurotoxicity (e.g., tacrolimus, cyclospormonths to years after transplantation (Mateen ine, OKT3, steroids) and opportunistic infection. et al., 2011). The risk of PML is increased with rituxAt the same time, the declining function of the imab administration for immunosuppression. It is rejected allograft may trigger a metabolic encephapotentially reversible if diagnosed early and immulopathy or cause other neurologic complications nosuppression is lowered. Fungal brain abscesses (Zivkovic and Abdel-Hamid, 2010). tend to appear 1–5 months after transplantation. ● CNS malignancies. Primary brain lymphoma due to Aspergillus is the most prevalent abscess organism Epstein–Barr virus (EBV) is seen in the first 2 years and typically occurs in the setting of increasing (Snanoudj et al., 2003). Lymphoma not associated immunosuppression and organ rejection. Because with EBV occurs later and mostly in older patients of its angioinvasive properties, Aspergillus may (Penn and Porat, 1995). Lymphoproliferative disorcause focal cerebral infarcts and hemorrhagic ders are more common in small bowel–liver recipilesions. Candida causes meningitis and small cereents in whom the incidence may reach 5%. bral abscesses in the context of fungemia and neutropenia. Cryptococcal meningitis usually appears PANCREAS TRANSPLANTATION late. CNS infections with the less familiar dematiaceous fungi are appearing with increasing frequency Type 1 diabetes mellitus arises from autoimmune months to years after transplantation. Toxoplasmodestruction of pancreatic b cells leading to a state sis appears more often in heart recipients than with of chronic insulin deficiency. Poor glycemic control other organ transplants. with exogenous insulin often results in multiple diabetic Ischemic infarction appears in a setting of hypercomplications, including retinopathy, neuropathy, vastension, diabetes, cardiac arrythmias, coagulopathy, culopathy, and nephropathy. Whole pancreas transplaninfective endocarditis, and valvular heart disease. It tation restores normoglycemia and provides many has been seen in 5–10% of renal transplant recipients benefits: freedom from insulin injections, less stringent and therefore may be relevant to kidney–pancreas dietary restrictions and less frequent testing of blood ●

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glucose. More importantly, it stabilizes or even reverses some of the diabetic microvascular and macrovascular changes underlying the retinopathy, neuropathy, vasculopathy, and nephropathy, thereby improving mortality and morbidity (Abendroth et al., 1991; Dean et al., 2008; Richter et al., 2011; Robertson, 2013). The tradeoffs include operative risk and the hazards of chronic immunosuppression (Lerner, 2008). According to the International Pancreas Transplant Registry, more than 24 000 pancreas transplantations have been performed in the US and more than 35 000 worldwide as of December, 2010 (Gruessner, 2011). Pancreas transplantation is reserved mostly for individuals who now require or have previously undergone renal transplantation for end-stage renal disease. Other indications include rapidly advancing retinopathy and highly labile fluctuations in blood glucose. The majority of pancreas transplants involve simultaneous pancreas–kidney transplants. No other regimen of insulin delivery or renal therapy can achieve the level of physiologic regulation brought about by pancreas and kidney transplantation. While most transplants have been aimed at type 1 diabetics, type 2 diabetics may show comparable benefit (Light and Barhyte, 2005; Knight et al., 2010; Orlando et al., 2011). Currently, about 75% of pancreas transplants are completed simultaneously with a kidney transplant, 18% after a previous kidney transplantation (18%), and 7% are transplanted alone (Gruessner, 2011). Between 1987 and 2010, the recipient age at transplantation increased significantly (now includes patients in their 40s) and transplant indications have been extended to type 2 diabetics. The routine pretransplant screening of graft recipients for antidonor antibodies has made hyperacute rejection rare. Surgical techniques have evolved over time so that enteric drainage of the pancreas is now preferred in combination with systemic drainage of the venous effluent of the pancreas graft (Lam et al., 2010; Gruessner, 2011). Immunosuppression protocols now favor antibody induction therapy with tacrolimus and maintenance therapy with mycophenolate mofetil (MMF). The rate of steroid avoidance has increased over time. All these changes have led to improved patient and graft survival. Patient survival now reaches over 95% at 1 year post-transplant and over 83% after 5 years (Gruessner, 2011). Another potential indication for pancreas transplantation is cystic fibrosis. Pancreatic failure, including diabetes and exocrine insufficiency, contribute to morbidity and mortality in these patients. Simultaneous lung and pancreas transplantation in one patient achieved no further need for supplemental oxygen, insulin, or pancreatic enzyme replacement 1 year after transplantation (Fridell et al., 2008).

Pancreatic islet transplantation Pancreatic islet transplantation offers a less invasive alternative to whole pancreas transplantation (Lee et al., 2005; Remuzzi et al., 2009; Vantyghem et al., 2011). Pancreatic islets must first be isolated enzymatically from a donor pancreas, then infused into the recipient’s portal vein for engrafting in the liver. Despite increasing success of the procedure in the past decade, it still needs refinement and is considered experimental. Neurologic benefit to the patient has been observed (Lee et al., 2006), but neurologic complications from islet transplantation per se have yet to be reported. Given the relatively minimal invasiveness of the procedure, one might expect neurologic complications to be associated with subsequent immunosuppression and/or longstanding diabetes and not so much from the procedure itself.

Neurologic complications of diabetes Since this topic is covered elsewhere, only a brief description is provided here. Diabetes is a major risk factor for stroke and peripheral neuropathy. Patients may develop a peripheral neuropathy that is insidious and can precede overt loss of glycemic regulation. The neuropathy may be painful (burning feet) and cause considerable morbidity. Individual nerves can also undergo focal ischemic infarction (mononeuritis multiplex). Examples include diabetic (pupil-sparing) oculomotor paresis and femoral nerve infarction (diabetic amyotrophy). Diabetic disturbances of the autonomic nervous system can produce impotence, orthostatic hypotension with syncope, and reduced gastroenteric motility (gastroparesis). Because diabetic gastroparesis is often treated with metoclopramide (Patterson et al., 1999), patients may be at increased risk for tardive dyskinesia and a variety of movement disorders associated with that drug (Zivkovic et al., 2008; Rao and Camilleri, 2010). Gastroparesis also affects the bioavailability of medications and nutrients, which has broad implications for the diabetic control and immunosuppression.

Neurologic complications of pancreas transplantation The largest case series features a review of 15 patients (Kiok, 1988). In this study, there were 11 men and four women ranging in age from 24 to 44 years (average 31 years). Diabetes was diagnosed at a mean age of 11 (range 8 months to 25 years) and its duration prior to transplantation averaged 20 years (range 12–30 years). All suffered from nephropathy, with end-stage renal disease affecting 80%. Of the 20% (three patients) without end-stage renal disease, one had markedly labile glucose fluctuations and had suffered several bouts of diabetic ketoacidosis.

NEUROLOGIC COMPLICATIONS OF PANCREAS AND SMALL BOWEL TRANSPLANTATION Another developed end-stage renal disease after the pancreas transplant, ultimately requiring dialysis and a kidney transplant within 6 months. A third patient had mild renal failure and no need for dialysis. Fourteen patients also underwent renal transplantation, nine prior to pancreas transplantation, four combined with pancreas transplantation and one 6 months later. Fourteen patients demonstrated clinical signs and symptoms of peripheral neuropathy including autonomic neuropathy in six (diarrhea, gastroparesis, orthostatic hypotension). All had diabetic retinopathy. Patients were followed for up to 5 years. Three patients (20%) died within 1 year and a fourth died shortly afterwards. Nine patients (60%) developed neurologic complications after pancreas transplantation. None involved the pancreas transplant surgery itself. The neurologic complications following pancreas transplantation are shown in Table 87.1. Global cerebral ischemia posed the greatest neurologic risk to patients with pancreas transplants, affecting a third of the patients. To explain this risk, the author suggested that longstanding diabetes is associated with advanced atherosclerosis and the development of autonomic neuropathy. Both can predispose the patient to cardiovascular instability when subjected to the additional stresses of surgery, immunosuppression, infection, hemorrhage, and metabolic derangements. Toxic and infectious complications associated with immune suppression occurred in four patients (27%). These consisted of visual hallucinations attributed to cyclosporine in one patient, aseptic meningitis due to OKT3 monoclonal antibody therapy in a second patient, and two patients with herpes zoster neuritis. No CNS infections were observed but the number of patients in the case series was low. Among the 15 patients, peripheral nervous system complications developed in three. Herpes zoster affected the trigeminal nerve 77 days post-transplant in one patient

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and involved the T11–12 thoracic root 12 days posttransplant in another patient. The third patient suffered multiple compressive neuropathies seven days posttransplant during an operation to drain a pancreatic abscess. The neuropathies involved the median, ulnar, and radial nerves bilaterally and were attributed to blood pressure cuff compression. The main lesson from the patient who developed multiple compressive neuropathies is that patients with chronic metabolic and nutritional disorders, especially with a pre-existing peripheral neuropathy, are at much higher risk for compressive neuropathy, so suitable precautions should be taken.

Central nervous system infections The precise incidence of CNS infections in pancreas transplant recipients is unknown. Case reports in kidney and pancreas transplant recipients include toxoplasmosis (Hommann et al., 2002; Nasser et al., 2004) and aspergillosis. The latter may be heralded by an insidious sinusitis causing headache (van de Beek et al., 2008). West Nile encephalomyelitis has a clinical presentation in transplant recipients that initially appears indistinguishable from that of individuals with normal immunity, but the neurologic deficits continue to increase in severity and can prove lethal (Kleinschmidt-DeMasters et al., 2004; Rosenberg, 2004).

Immunosuppressive drug neurotoxicity Tacrolimus neurotoxicity has been reported to affect as many as 21% of pancreas transplant recipients (Gruessner, 1997). Neurotoxicity necessitating a change in immunosuppressive drugs, however, appears less frequent. Among 247 patients undergoing simultaneous kidney–pancreas transplantation or solitary pancreas transplantation, 33 individuals were switched from tacrolimus or other immunosuppressive agents to

Table 87.1 Central nervous system complications following pancreas transplantation CNS complication

Number

Global cerebral ischemia Postanoxic encephalopathy Terminal anoxia Cerebral infarction Spinal cord infarction Seizures Generalized tonic-clonic Partial motor Metabolic encephalopathy Aseptic meningitis

5 (33%) 3 (20%) 2 (13%) 1 (7%) 1 (7%) 2 (13%) 1 (7%) 1 (7%) 1 (7%) 1 (7%)

(Adapted with permission from Kiok, 1988.)

Interval after transplantation

2–11 months 17–22 days 6 months 6 months 2 months 11 months 4 days 1 month

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sirolimus because of adverse drug effects that included nephrotoxicity (24 patients), recurrent graft rejection (seven patients), hyperglycemia (four patients) and neurotoxicity (one patient) (Matias et al., 2008). The latter developed CNS leukoencephalopathy 17 months after transplantation, and switching from tacrolimus to sirolimus resulted in clinical improvement. A cystic fibrosis patient undergoing a combined lung–pancreas transplant also suffered CNS leukoencephalopathy (indistinguishable from PRES) at 11 months post-transplantation (Fridell et al., 2008); it too reversed in several days once tacrolimus was replaced by sirolimus. cyclosporine has been reported to cause irreversible retinal blindness in a pancreas–kidney transplant recipient (Esterl et al., 1996) but that complication is rare compared to the reversible visual loss associated with PRES. As an alternative immunosuppressive drug, sirolimus has been found to be relatively free of neurotoxic effects in heart transplants (van de Beek et al., 2009).

Orthostatic hypotension Orthostatic hypotension is common after kidney– pancreas transplant and occurs with much higher frequency than in isolated kidney transplant patients (Khurana et al., 2008). It typically appears 1–3 weeks after transplantation and may take several weeks to 9 months to resolve. Its occurrence shows no correlation with a preoperative history of orthostasis, gastroparesis, or peripheral neuropathy. The pathogenesis of postoperative orthostasis is unknown but may involve hyperinsulinemia after transplant or neuropeptides involved in the regenerative process (Khurana et al., 2008).

Lymphoproliferative disorders Post-transplant lymphoproliferative disorder (PTLD) is uncommon. PTLD is even rarer when isolated to the CNS (lymphoma), occurring in fewer than 1% of recipients, but it is potentially fatal. Thus, among 3105 renal transplants at one center, 10 patients developed CNS PTLD including two who had undergone simultaneous kidney–pancreas transplantation (Nabors et al., 2009). One had a complete response to methotrexate and the other succumbed to progressive PTLD despite therapy. Among 1357 pancreas transplants at another center, 18 patients developed PTLD, three of whom had CNS involvement, received radiotherapy and none survived (Paraskevas et al., 2005). In another study of 212 pancreas transplants, PTLD was found in 13 patients, including four with CNS involvement (Issa et al., 2009). Unlike the other reports, PTLD was successfully treated by withdrawal of immunosuppression (except for prednisone) and the addition of rituximab, an antilymphoma monoclonal antibody that permitted graft survival in the four CNS cases. One of the four later died of a

non-PTLD-related cause but only after a prolonged remission. The authors also observed that the incidence of PTLD in pancreas transplant patients appeared greater than for kidney transplants but comparable to liver and heart transplant recipients. Since the pancreas recipients developed EBV seropositivity and PTLD within 8 months of transplantation, they concluded that EBV was acquired from the donor organ. They recommended that pancreas transplant recipients undergo PTLD surveillance and be considered for PTLD prevention strategies (Issa et al., 2009).

Neuromuscular complications Compressive neuropathy can complicate pancreas transplantation surgery and has been reported for bilateral radial, median, and ulnar nerves (Kiok, 1988) and for carpal tunnel (Wadstrom et al., 1995). While pancreas transplantation can stabilize and even improve diabetic neuropathy, muscle weakness may actually worsen in the months after transplantation (Dyck et al., 2001). In a study of 85 type 1 diabetics who underwent simultaneous pancreas–kidney transplantations or pancreas after kidney transplantation, sequential clinical and EMG evaluations before, at 3 months, and yearly after transplantation uncovered muscle weakness that was independent of the overall severity of polyneuropathy. In fact, the neuropathy significantly improved over time, and patients reported improvement in their quality of life. The authors attributed the weakness to development of a myopathy that they speculated could be related to graft rejection, immunosuppression, sepsis, and/or intercurrent infections (Dyck et al., 2001). Diabetic muscle infarction has also been reported in the months following pancreas transplantation but it is a rare complication (Delis et al., 2002; Theodoropoulou et al., 2006). It is usually associated with poorly controlled diabetes (typically type 1) and occurs on the background of concomitant nephropathy, neuropathy, and retinopathy. The etiology is uncertain but has been attributed to diabetic microangiopathy and hypercoagulability. Despite restoration of normoglycemia after kidney–pancreas transplantation, diabetic muscle infarction may reflect prior tissue damage and fragility of small vessels arising from the long-term poor blood glucose control and hypertension. The pathogenesis could also involve the procoagulant effects of the calcineurin inhibitors and the use of steroids for immunosuppression (Delis et al., 2002).

Neurologic benefit of pancreas transplantation Multiple studies have demonstrated stabilization and/or improvement in peripheral and autonomic diabetic neuropathy following pancreas transplantation, usually

NEUROLOGIC COMPLICATIONS OF PANCREAS AND SMALL BOWEL TRANSPLANTATION performed in combination with kidney transplantation (Kennedy et al., 1990; Navarro et al., 1990; Comi et al. 1991; Gaber et al., 1991; Allen et al., 1997; Navarro et al. , 1997; Comi and Corbo, 1998).

PERIPHERAL NEUROPATHY One early study compared 61 type 1 diabetic patients who underwent pancreas transplantation to 48 comparable diabetics who did not (Kennedy et al., 1990). The patients periodically underwent neurologic examination, nerve conduction studies, and autonomic function tests for up to 42 months after transplantation. Patients managed without transplantation showed clinical and electrophysiologic worsening of their peripheral neuropathy over the first year of the study, but not much additional change over the ensuing 30 months. In contrast, patients with successful pancreas transplants showed a trend for the neuropathy to improve at 1 year and in the succeeding months. In another study, 18 type1 diabetics with polyneuropathy underwent simultaneous pancreatic–kidney transplantation and repeat testing of peripheral nerve and autonomic function over the next 4 years (Solders et al., 1991, 1992). Eighteen diabetics with only a kidney graft served as controls. After initial improvement of nerve conduction in both groups, attributed to the elimination of uremia, further improvement was seen only in the pancreas transplant recipients. Improvement in autonomic (parasympathetic) function was mild after 4 years and comparable in both groups (Solders et al., 1992). In another study, 53 diabetics with simultaneous pancreas–kidney transplants were followed for over 3 years (Muller-Felber et al., 1991, 1993). Their symptoms of polyneuropathy (e.g., pain, paresthesias, cramps, and restless legs) improved. Nerve conduction velocities increased but there was little change in clinical signs (e.g., sensation, muscle strength, tendon reflexes). In patients who developed kidney graft rejection, there was a slight decrease of nerve conduction velocity during the first year. After a pancreas graft rejection, no change of nerve conduction velocity occurred in the first year but a statistically significant decrease of 6.5 m/s was observed by the end of the study (Muller-Felber et al., 1991). In a study with a 10 year follow-up, 115 patients with a functioning pancreas transplant were compared to 92 controls treated with insulin. Patients underwent repeat neurologic examinations and serial studies of sensory nerve conduction, motor nerve conduction, and cardiorespiratory reflex over a period of up to 10 years (Navarro et al., 1997). The neuropathy progressively worsened in the control population treated with insulin. Their clinical examination score and composite indices for abnormal motor and sensory nerve conduction

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worsened throughout the study period. Autonomic function indices also worsened, but not until 1 year had elapsed. In contrast, patients with a successful pancreas transplant showed stabilization or improvement in their neuropathy. Motor and sensory nerve conduction indices rose significantly at all intervals tested after transplantation; clinical examination and autonomic testing showed mild improvement or no worsening. The contrast in improvement versus deterioration was most prominent 10 years out. Improvement was comparable whether individuals received a pancreas transplant alone, a pancreas transplant after a kidney transplant, or combined pancreas–kidney transplantation (Fig. 87.1). Another long-term prospective study of neuropathy compared 44 patients who underwent successful simultaneous pancreas–kidney transplantation to nine pancreas–kidney recipients in whom the pancreas had failed but the kidney remained functional (Allen et al., 1997). Electrophysiologic studies using a standardized protocol were carried out before transplantation and afterwards for up to 8 years. Two distinct patterns of neurologic improvement emerged in successfully transplanted patients: (1) nerve conduction velocity improved in a biphasic pattern with a rapid initial recovery followed by stabilization, and (2) nerve conduction amplitude exhibited a monophasic recovery that continued to improve throughout the observation period. Motor and sensory amplitude scores are more sensitive for axonal loss assessment and the results would suggest axonal regeneration. A similar trend toward improvement was observed in another study that did not quite reach statistical significance perhaps because follow-up was only up to 4 years and patient numbers were low (Vial et al., 1991). Six months after pancreas–kidney transplantation, corneal sensitivity increases and evidence for small nerve fiber regeneration can be detected by corneal confocal microscopy (Mehra et al., 2007). On the other hand, direct histologic evidence for nerve regeneration has been difficult to demonstrate in skin biopsies 2–3 years following simultaneous pancreas–kidney transplantation, perhaps because longer periods of normoglycemia are needed to permit nerve regeneration (Boucek et al., 2008).

AUTONOMIC NEUROPATHY Autonomic neuropathy, a common complication of diabetes, frequently accompanies peripheral neuropathy and failure of other organ systems in diabetes (Vinik et al., 2003). However, it may also be an isolated finding, preceding the appearance of other complications. Patients may exhibit resting tachycardia, exercise intolerance, orthostatic hypotension, constipation, gastroparesis, erectile dysfunction, sudomotor dysfunction, impaired neurovascular function, “brittle diabetes,”

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Fig. 87.1. Variations in the neurologic exam and indices of motor, sensory, and autonomic neuropathy in patients with pancreas transplant (N ¼ 10, open circles) versus insulintreated controls (N ¼ 13, filled circles) over 10 years. p < 0.01 for study versus control for neurological exam (NEx), motor nerve conduction (MNC) index and sensory nerve conduction (SNC) index. CRR, cardiorespiratory reflex. The steady deterioration in the insulin-treated controls contrasts with the gradual improvement or maintenance in the pancreas transplant group. (Adapted from Navarro et al., 1997, with permission.)

and failure to generate a response to hypoglycemic conditions. Gastrointestinal disturbances include esophageal enteropathy, gastroparesis, constipation, diarrhea, and fecal incontinence. Neurovascular dysfunction

contributes to erectile dysfunction, loss of skin integrity, and abnormal vascular reflexes. A series of studies compared the changes in autonomic and gastrointestinal function following pancreas–kidney versus kidney alone transplantation to determine how autonomic function influences quality of life and how transplantation alters that quality of life 1 year later (Gaber et al., 1991; Hathaway et al., 1993, 1994). Tests were conducted on vasomotor function (total capillary pulse amplitude, capillary vasoconstriction response to cold, capillary response to postural adjustments), cardiac function (R-R interval variation, valsalva ratio), overall autonomic function (total autonomic score, autonomic index), gastric function (cutaneous electrogastrography, gastric emptying, total gastrointestinal symptoms score), and quality of life (sickness impact profile). Kidney recipients showed significant improvement in total symptom score but little improvement in autonomic function. In contrast, pancreas–kidney recipients demonstrated significant improvement in postural adjustment ratio, valsalva ratio, electrogastography as well as total symptom score. Improvement or stabilization of gastric function occurred in 52% of pancreas–kidney recipients versus 42% of kidney alone recipients (Hathaway et al., 1994). In another study, autonomic symptoms of the gastrointestinal and thermoregulatory systems improved more in pancreas transplant recipients than in kidney transplant recipients, while hypoglycemia unawareness worsened in the kidney recipients, demonstrating that successful pancreatic grafting was able to halt the progression of autonomic dysfunction (Nusser et al., 1991). Cardiac autonomic neuropathy is a complication of uremia and diabetes, with severe dysfunction seen when these conditions coexist. As a measure of a deteriorating cardiovascular autonomic function, reduced heart rate variability is associated with an increased risk of myocardial ischemia and mortality (Vinik et al., 2003). The magnitude of the reduction is related to age and the severity of diabetes (Faulkner et al., 2001). Both kidney and kidney–pancreas transplantation lead to a substantial improvement in heart rate variability and cardiac autonomic function (Cashion et al., 1999). A successful pancreas transplant has produced longer survival times in patients with cardiac autonomic neuropathy when compared to nontransplanted patients (Navarro et al., 1991, 1996). A lack of symptomatic response to hypoglycemia occurs in individuals with long-standing type 1 diabetes and autonomic neuropathy due to impaired glucagon and epinephrine secretion. This hypoglycemia unawareness can prove fatal. Pancreas transplantation restores the glucagon response, improves the epinephrine response, and normalizes a subject’s recognition

NEUROLOGIC COMPLICATIONS OF PANCREAS AND SMALL BOWEL TRANSPLANTATION 1285 of hypoglycemic symptoms with the improvement susfor the early noninvasive detection of rejection. It is tained for up to two decades after transplantation likely that a combination of technologies will allow (Kendall et al., 1997; Paty et al., 2001). immunosuppression to be tailored to each recipient. Pancreas transplantation has also resulted in the Development of these approaches to immunosuppresrestoration of near-normal sexual function (Salonia sion is necessary to predict graft dysfunction ahead of et al., 2011). irreversible graft injury and allow adjustment in immuIn summary, the most common neurologic complicanosuppression regimens before the onset of rejection. tions of pancreas and kidney–pancreas transplantation Small bowel transplantation continues to be indicated are global cerebral ischemia, immunosuppressive mediprimarily in situations where all other therapeutic modalcation toxicities (aseptic meningitis, seizures, PRES), ities have failed. No randomized trials have compared immunocompromised infections (viral, fungal, protosmall bowel transplantation to long-term parental nutrizoan), and compressive peripheral neuropathy. In gention to establish guidelines for timely surgical referral. eral, both peripheral neuropathy and autonomic Late referral remains a major problem, with a great numfunction improve following pancreas transplantation. ber of patients requiring simultaneous liver transplantation at the time of intestinal transplantation (Chungfat et al., 2007). Early referral for isolated small bowel SMALL BOWEL TRANSPLANTATION transplantation should reduce the need for simultaneous Intestinal transplantation has shown exceptional growth multiorgan transplants and increase the number of residand remarkable progress over the past 20 years (Grant ual organs available for liver transplantation (Vianna et al., 2005; Matarese et al., 2007; O’Keefe et al., et al., 2008b). 2007; Fryer, 2008; Vianna et al., 2008a; Nayyar et al., Small bowel transplantation is not as commonly per2010; Sudan, 2010). As with other solid organ transplant formed as other organ transplants. Morbidity and mortalprocedures, small bowel transplantation has moved out ity associated with the procedure have improved in the of the experimental realm to become the standard of past decade but remain relatively high when compared care for many patients with intestinal failure. Intestinal to other organ transplantations. That has limited widetransplantation may soon be extended routinely to spread use of the procedure (Abu-Elmagd, 2006; Wolfe patients who, although not strictly meeting the criteria et al., 2010; Zivkovic et al., 2010). One year patient survival for intestinal failure, may benefit from intestinal transrates were 89% for intestine only and 63% for liver– plantation, such as patients who have nonresectable intestine transplantation in 2006–2007 (Wolfe et al., indolent tumors or diffuse thrombosis of the portome2010). In contrast, 1 year patient survival rates were senteric system. As clinical experience with intestinal 98% for pancreas only and 96% for kidney–pancreas transplantation increases, outcomes improve. Currently, transplants for the same time period (Wolfe et al., 1 year graft and patient survival following small bowel 2010). After 5 years, the patient survival rate fell to transplantation is 80%, which approaches that of other 58% for intestine only and 58% for liver–intestine transsolid abdominal organ transplants. Unfortunately, most plantation (Wolfe et al., 2010). In contrast, the 5 year of the gains in survival are seen in the first postoperative patient survival was 89% after pancreas only and 87% year, with long-term survival remaining basically after combined kidney–pancreas transplantation (Wolfe unchanged since the early 1990s. With improved outet al., 2010). Nonetheless, the number of patients on the comes, more centers have entered into the intestinal waiting list for small bowel transplantation doubled transplant arena. In the US alone, 20 centers performed between 1999 and 2008. About one-third to half of the at least one small bowel transplant in 2007. Improved 120–170 patients on the waiting list are transplanted each access to small bowel transplantation and more wideyear. For the year 2008, approximately three-quarters of spread awareness of this option should increase the numthe individuals waiting for an intestinal transplant were ber of transplants in the future. children, yet half of all small bowel transplantations were Immunosuppressive regimens continue to evolve, performed in adults (Wolfe et al., 2010). with induction therapy being the major target of change The most common condition leading to small bowel in the past 5 years. Although rejection rates in the first transplantation is short bowel syndrome following year after transplantation have been reduced by inducextensive intestinal resection(s). The causes of extensive tion therapy, long-term side-effects of heavy immunointestinal resection are multiple. Among adults, the most suppression continue to negatively impact transplant common causes are mesenteric vascular thrombosis, outcomes. The future for immunosuppression lies in Crohn’s disease, trauma, and locally invasive tumors. two areas: (1) individual monitoring of the immunosupIn children, gastroschisis, intestinal atresia, necrotizing pression level for each individual patient (Sindhi et al., enterocolitis, and volvulus are common conditions lead2010); (2) development of serum and tissue markers ing to extensive resection and/or transplantation.

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Neurologic complications of short bowel syndrome Extensive loss of intestinal mucosa decreases the absorptive surface for nutrients, electrolytes, and vitamins. This can result not only in malnutrition, but in specific vitamin deficiencies and their accompanying neurologic signs and symptoms. Cobalamin (vitamin B12) is largely absorbed in the distal small bowel, so deficiency is commonly seen with extensive ileal resection. Folate (vitamin B9), iron, and calcium are primarily absorbed in the proximal small bowel so deficiencies in these nutrients are seen with extensive duodenal and jejunal resections. Knowing the location of previous bowel resections alerts the clinician to predictable vitamin deficiency states and preemptive monitoring and replacement. ●

● ● ●

● ● ●

● ●

Cobalamin (B12) deficiency can lead to subacute combined degeneration of the spinal cord with paresthesias of the extremities and spastic weakness and incoordination of the limbs. Neuropsychiatric changes, encephalopathy, and visual impairment may also complicate vitamin B12 deficiency. Folate (B9) deficiency can lead to peripheral neuropathy and mental confusion. Biotin (B7) deficiency can produce peripheral neuropathy and seizures. Panthothenic acid (B5) deficiency can cause a peripheral neuropathy with numbness, paresthesias, burning feet, and generalized motor weakness. Thiamine (B1) deficiency can cause Wernicke’s encephalopathy and peripheral neuropathy. Vitamin A deficiency can impair vision in dim light (night blindness). Vitamin E deficiency can produce a spinocerebellar degenerative disorder with weakness, ataxia, and loss of proprioception. Hyporeflexia, dysphagia, dysarthria, ophthalmoplegia, and dementia can complicate the advanced stages of vitamin E deficiency. Vitamin D deficiency can result in a proximal myopathy. Malabsorption of calcium and magnesium can result in tetany (manifested by the Trousseau sign and Chvostek sign), encephalopathy and seizures. After transplantation, low magnesium levels (e.g., poor absorption due to organ rejection or any reason) may aggravate the neurotoxicity of calcineurin inhibitors such as cyclosporine (Thompson et al., 1984).

Neurologic complications of total parenteral nutrition Long-term total parental nutrition (TPN) is the treatment of choice for short bowel syndrome (Quigley, 1996; Matarese et al., 2005). The neurologic complications

of TPN typically include alterations in consciousness and metabolic encephalopathy due to a variety of causes, including catheter-related sepsis, poor glucose control, electrolyte abnormalities, and/or liver failure. The alterations in mental status typically occur without focal neurologic deficits. The mental changes are nonspecific but can progress to coma if untreated. ●

●

●

●

●

Hyperglycemia may occur with inadequate blood glucose monitoring and failure to accurately adjust the insulin dose in the TPN solution and/or administer subcutaneous insulin in a timely manner. Hypoglycemia may occur if the continuous infusion of TPN and its concentrated dextrose solution is suddenly stopped. Uncommonly, the metabolic encephalopathy is associated with focal neurologic deficits due to unmasking a previously compensated structural brain lesion or due to a stroke-like presentation in the case of hypoglycemia. Cholestatic hepatic failure is common in TPN patients, and when severe, it can cause a hepatic encephalopathy with confusion, lethargy, asterixis (negative myoclonus), tremor, and multifocal myoclonus. Hyperammonemia in infants can result in lethargy, twitching, and generalized seizures. Large fluctuations in serum electrolytes may predispose to encephalopathy and seizures. An adverse reaction to lipid emulsions may occur early in TPN, especially if there is associated kidney and liver failure. Dizziness, back pain, and headache may accompany nausea, dyspnea, sweating, and a cutaneous allergic reaction. Vitamin and mineral deficiencies as described above can arise but are rare when TPN solutions are correctly prepared.

Not everyone tolerates TPN. Some individuals develop potentially life-threatening TPN-related complications that are best managed by small bowel or multivisceral transplantation. Complications include recurrent episodes of catheter-associated sepsis, catheter-associated vascular thrombosis, and TPN-induced cholestatic liver failure. When liver function is preserved, an isolated small bowel transplant suffices. In contrast, individuals with cholestatic TPN-induced liver failure require transplantation of both intestine and liver. Multivisceral transplants are reserved for patients who have short bowel syndrome, TPN-induced liver failure and a history of surgery, abdominal trauma, motility disorders, tumors, or other abdominal problems.

Perioperative neurologic complications in small bowel transplantation Technical problems with surgery or anesthesia can result in neurologic complications that are not specific to

NEUROLOGIC COMPLICATIONS OF PANCREAS AND SMALL BOWEL TRANSPLANTATION transplantation of the small bowel. These are discussed above in the introduction. Brachial plexopathy occasionally complicates liver transplantation and therefore presents a small additional risk for intestine–liver transplant recipients. Perineal entrapment neuropathy can be seen with all types of surgery, including organ transplantations. For patients undergoing combined small bowel and liver transplantation, the presence of hepatic encephalopathy prior to surgery may be the strongest predictor of perioperative neurologic complications, primarily encephalopathy, and to a lesser degree, seizures (Dhar et al., 2008).

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organ transplants (40–60%) (Patchell, 1994; Pless and Zivkovic, 2002). The higher prevalence of complications was attributed to the complex metabolic disturbances in the pre- and post-transplant periods (Tyden et al., 1988) and to the aggressive immune suppression necessitated by the increased immunogenicity of the intestine (AbuElmagd et al., 2001; Sindhi et al., 2010). The frequency of neurologic complications was similar for all three types of allografts: isolated intestinal, liver–intestine, and multivisceral (Table 87.2). ●

Neurologic complications following perioperative period for small bowel transplantation As of August, 2011, only one sizeable study existed that directly addressed the different neurologic disorders of small bowel and multivisceral transplantation (Zivkovic et al., 2010). It was a retrospective review of adult patients who underwent intestinal transplantation at the University of Pittsburgh Medical Center between 1990 and 1998. The study period overlapped with the early use of heavy immunosuppression as adjuvant pretreatment and posttreatment therapy (Abu-Elmagd et al., 2001). Twentyeight patients received an isolated small bowel transplant, 17 received a composite liver–intestine transplant, and nine received multivisceral allografts. The spectrum of neurologic complications in their intestinal transplant recipients was similar to that of other solid organ transplant recipients (Patchell, 1994; Wijdicks, 1999; Zivkovic and Abdel-Hamid, 2010; Pustavoitau et al., 2011). However, the overall rate of neurologic complications was higher (85%) than with other transplanted solid

●

●

Headache was the most common neurologic complaint, affecting half of all patients in the study. The frequency of 50% was an order of magnitude higher than the 5% frequency associated with liver transplantation (Lewis and Howdle, 2003; Zivkovic et al., 2010). The discrepancy could be attributed to higher dosages of tacrolimus and pain medications used for chronic abdominal pain (due to previous abdominal operations) that might have triggered rebound headaches in this population. Encephalopathy and impaired consciousness were common in the post-transplant period, affecting 43% of the patients. There were multiple potential contributing factors underlying the metabolic encephalopathy but none were unique to intestinal transplantation (Wijdicks, 1999; Zivkovic and Abdel-Hamid, 2010; Zivkovic et al., 2010). Seizures occurred in 17% of cases, and these were attributed to metabolic disturbances and structural brain lesions found postmortem in intestinal transplant patients (Idoate et al., 1999). As previously described in liver transplant recipients, seizures did not herald a catastrophic event and only two patients had recurrent seizures (Wijdicks et al., 1996).

Table 87.2 Prevalence of neurologic complications in intestinal allograft recipients Type of allograft Complicationa

IS (n ¼ 28)

LI (n ¼ 17)

MV (n ¼ 9)

Total (N ¼ 54)

Headache Encephalopathy Seizures CNS infection Neuromuscular complications Stroke No. of patients with neurologic complications

13 9 5 2 2 0 23

11 10 3 1 1 0 16

3 4 1 1 1 2 7

27 (50%) 23 (43%) 9 (17%) 4 (7%) 4 (7%) 2 (4%) 46 (85%)

IS, isolated intestinal; LI, liver/intestine; MV, multivisceral. a Patients may have had more than one complication. (Adapted with permission from Zivkovic et al., 2010.

1288 M. JACEWICZ AND C.R. MARINO ● CNS infections were much more common when have significantly reduced PTLD morbidity and morcompared to liver and heart transplants: 7% versus tality, with patient survival now 91% at 1 year and 75% 3% and 1.2%, respectively (Lewis and Howdle, at 5 years (Abu-Elmagd et al., 2009). 2003). Aggressive immunosuppression after intestinal transplantation combined with rejection and/or In summary, the Zivkovic study attributed most neurosepsis may compromise normal intestinal barriers logic complications in small bowel transplantation to and facilitate bacterial translocation and permit disdirect neurotoxicity by immunosuppressive agents and semination to the CNS and elsewhere (Cicalese et al., to opportunistic infections arising from aggressive 2001). There were three CNS infection cases, all preimmunosuppression at the time of the study. The specsenting within 7 months of transplantation. The only trum of neurologic complications resembled those assofatal neurologic complication involved a CNS infecciated with other solid organ transplants. The recent tion with Aspergillus. CNS aspergillosis is known to development of immune suppression protocols with complicate the early post-transplant period, often in lower doses of immunosuppressants should reduce the the setting of organ rejection and increased immune risk of neurologic complications (Flynn et al., 2005). suppression (Pustavoitau et al., 2011). Fatal CNS Additional prospective studies are needed to characterinfections with toxoplasmosis and Acanthamoeba ize the neurologic complications and their risk factors have also been reported following intestinal and as immunosuppression protocols continue to evolve. multivisceral transplantation (Campbell et al., Among 20 pediatric patients with combined liver– 2006; Mendez et al., 2006). Cryptococcal meningitis small bowel transplantation at one center, neurologic has been reported in a small bowel transplant patient complications were reported in five (25%), consisting among other adult solid organ transplants (Vilchez of two seizures, two with peripheral neuropathy, and et al., 2003). If the donor intestine contains intestinal one transient blurring of vision (probable PRES) protozoa such as Echinococcus and Strongyloides, (Fernandez et al., 2010). In comparison, neurologic probtheir transfer into an immune-suppressed host could lems occurred in 26 of 107 (24%) children receiving isoproduce disease including CNS involvement but lated liver transplants (Fernandez et al., 2010). actual cases are rare (Kotton and Lattes, 2009). Immigrants and other world travelers unaware of Neuropathology their infectious status are often accepted for organ donations without evaluation for parasitic diseases Among patients awaiting small bowel transplantation, that are common in their country of origin (Kotton death is usually due to liver failure associated with TPN and Lattes, 2009; Kotton, 2011). (Idoate et al., 1999). Following small bowel transplantation, ● Tacrolimus neurotoxicity was most common in the the cause of death and most observed neuropathologic early post-transplantation period, attributable to changes result from complications of anesthesia, the surgihigher immunosuppression requirements to prevent cal procedure, postoperative medical management, graft rejection, particularly with composite liver–intestine rejection and/or the adverse effects of immunosuppresand multivisceral allografts. sion, including CNS infections (Idoate et al., 1999). ● Ischemic brain infarcts occurred exclusively in A variety of neuropathologic abnormalities are seen patients with hypercoagulable conditions. Hypercoain patients with intestinal failure, both before and after gulable conditions are a frequent cause of short bowel transplantation (Table 87.3). In this series, survival after syndrome related to mesenteric thrombosis, and transplantation varied from 19 days to 523 days. The intestinal allograft recipients with hypercoagulable most common neuropathologic observation was an syndromes require lifelong anticoagulation to preincrease in Alzheimer type 2 astrocytes in both transvent recurrent vascular thromboses that may occur planted and nontransplanted patients. This finding even with normalized levels of coagulation factors. reflects the brain changes induced by chronic liver fail● Post-transplant lymphoproliferative disorders ure complicating prolonged TPN therapy. (PTLD) used to complicate about 20% of small bowel The next most common neuropathologic observations transplant cases (Nalesnik et al., 2000) but now occur were vascular complications from cardiac arrest, ischemic far less frequently, in about 5% of combined liver– infarction, cerebral edema, or intracranial hemorrhage. In bowel transplants (Abu-Elmagd et al., 2009; the vast majority of patients, the acute vascular changes Pustavoitau et al., 2011). To minimize PTLD and were the cause of death. Of note, cerebral atrophy was improve outcome, innovative management strategies observed in all pediatric patients but not in adult patients. have been devised. At one center, pretransplant lymThis was postulated to arise from nutritional inadequacy phoid depletion, preemptive antiviral therapy, and of TPN and/or some developmental anomaly in the pediminimization of post-transplant immunosuppression atric patients.

NEUROLOGIC COMPLICATIONS OF PANCREAS AND SMALL BOWEL TRANSPLANTATION

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Table 87.3 Neuropathology of small bowel transplantation Transplanted patients (n ¼ 13) Neuropathological changes

Total (%)

Children (n ¼ 8)

Adults (n ¼5)

Non-transplanted patients (n ¼ 4)

A. Metabolic: Astrocytosis (Alzheimer type II) Central pontine and extrapontine myelinolysis B. Vascular: Global brain ischemia Brain infarcts Intracranial hemorrhage Cerebral edema C. Infections: Aspergillosis Cytomegalovirus Leukoeneeplialopathy PML-like Candida albicans Phagocytic nodules D. EBV-related PTLD E. Brain atrophy and hydrocephalus ex-vacuo

10 (77)

6 5 1 7 5 4 4 3 2 0 1 0 0 2 2 7

4 4 0 2 2 1 0 1 2 1 1 1 0 0 0 0

4 4 0 4 2 3 1 3 1 0 0 0 1 1 0 4

9 (69)

4 (31)

2 (15) 7 (54)

(Adapted from Idoate et al., 1999, with permission.)

Diagnostic evaluation Given the wide spectrum of neurologic complications in small bowel transplant recipients, how does one reach an accurate diagnosis? Success depends on addressing several key elements. The physician must: ● ● ● ●

● ●

identify any pretransplant neurologic dysfunction and its relationship to organ failure consider the type of organ transplant and its predilection for specific neurologic complications characterize the time course of symptoms, classifying neurologic complications as either early or late consider the type and intensity of immune suppression and the protocol’s profile for potential neurotoxicity identify any additional risk factors for opportunistic pathogens apart from immunosuppression consider graft rejection as a predisposition to certain neurologic complications.

Diagnostic testing includes basic blood work such as blood count, electrolytes (especially sodium, calcium, and magnesium), and a comprehensive metabolic panel. Specialized testing includes blood levels for immunosuppressive drugs, tests for infectious organisms, and comprehensive CSF analysis including PCR and immune analyses for viruses and other pathogens. EEG may show generalized or focal slowing and disclose epileptogenic foci. EMG can help identify the nature of a

neuromuscular disorder. CT and MRI play key roles in identifying structural lesions responsible for neurologic deficits. However, clinical signs and symptoms and the lesions found by neuroimaging often lack specificity, making biopsy the ultimate diagnostic study in some cases.

Treatment Two important generalizations can be made regarding the approach to treatment of neurologic complications in small bowel transplant patients. First, therapy must be directed at specific etiologies identified in the diagnostic evaluation. For example, vitamin deficiencies can be treated orally (e.g., vitamins A, D, E) and/or parenterally (e.g., B12, thiamine); electrolyte deficiencies with replacement therapy; opportunistic infections with antibiotics (e.g., ampicillin or trimethoprim/sulfamethoxazole for Listeria; ganciclovir or foscarnet for HHV-6); seizures with anticonvulsants; neoplasms with chemotherapy and/or radiation. TPN may need to be restarted with graft rejection. The reader is referred to pages be 82–86, and 88–89 for a more detailed discussion on how the generic complications of organ transplantation are treated. Second, neurologic complications often require changes in immunosuppressive therapy, either dosage or type. To minimize further neurologic injury, the physician must carefully consider the benefits and toxicities

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of specific immunosuppressive drugs when making such changes. For example, when a calcineurin inhibitor (e.g., tacrolimus) is suspected of causing severe neurotoxicity, it should be replaced with mycophenolate mofetil or one of the FKBP12 ligands (sirolimus or everolimus) since they are less toxic (Pustavoitau et al., 2011).

CONCLUSIONS Recipients of pancreas and small bowel transplants suffer many of the same neurologic complications observed in other organ transplant recipients, including metabolic encephalopathy, seizures, headache, drug toxicities, CNS infections, stroke, neuromuscular disorders, CPM and secondary CNS malignancies. Certain neurologic complications are more frequent depending on the organ type, choice of immunosuppressant therapy, and duration of transplantation. While transplantation medicine and surgical techniques are rapidly advancing, relatively little has been written on the neurologic complications of pancreas and gastrointestinal transplantation, and much of what is available is dated. It is a field that clearly needs additional research.

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Infectious complications after human small bowel transplantation.

Liver, pancreas and small bowel transplantation: current ethical issues.

Neurologic complications of intestinal transplantation.

Neurologic complications of cardiac transplantation.

Neurologic complications of liver transplantation.

Neurologic complications in renal transplantation.

Neurologic complications of bone marrow transplantation.

Short bowel syndrome and small bowel transplantation.

Cadaveric small bowel and small bowel-liver transplantation in humans.

Nutrition and Small Bowel Transplantation.

Nutrition and small bowel transplantation.

Small bowel transplantation.

liver transplantation.

Posttransplant lymphoproliferative disorder presenting as a small bowel obstruction in a patient with pancreas transplantation alone.

Advances in small bowel transplantation.

Major complications of small bowel diverticula.

Comprehensive risk assessment for early neurologic complications after liver transplantation.

Small bowel transplantation: past, present and future.

Neurologic Complications and Treatment.

Neurologic complications of vaccinations.

Imaging in pediatric small bowel transplantation.

Endoscopic monitoring in small bowel transplantation.

Successful small bowel transplantation in an infant.

Neurologic complications of alcoholism.