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 86
Neurologic complications of intestinal transplantation ANDREA STRACCIARI* AND MARIA GUARINO Neurology Unit, S. Orsola-Malpighi University Hospital, Bologna, Italy
INTRODUCTION The first attempts at intestine transplantation (ITx) in humans were made during the 1960s, but intestinal transplants were not successful until the 1990s, when potent immunosuppressive drugs became available along with improved methods to prevent infections. In particular, the introduction of FK506 (tacrolimus) led to a consistent improvement in ITx outcome, significantly lengthening patient and graft survival, due also to the refinement of surgical techniques and better clinical management. Notwithstanding, ITx remains a difficult procedure and the results are still inferior to those of other organ transplants, especially in terms of long-term outcome and multivisceral transplants, due to a high risk of immunologic complications, and the subsequent need for profound immunosuppression with its attending sideeffects such as malignancies, infections, and drug toxicity. After ITx, patients may experience various medical and surgical complications, the commonest including infections, rejection, intestinal ischemia, and leaks from the anastomoses. There are treatment options for all of these complications, but in some cases they result in graft loss or even the death of the patient. Among ITx complications, neurologic problems have received little attention to date, especially when compared to those occurring after other solid organ transplantations. Prior to a detailed analysis, a short survey of the general aspects of ITx may be useful.
GENERAL REMARKS Indications and contraindications for intestinal transplantation ITx is indicated in patients with chronic, irreversible intestinal failure associated with failure or severe complications of parenteral nutrition. Intestinal failure
may result from a variety of anatomic and functional conditions, the leading cause being the short bowel syndrome, which results from inadequate bowel length due to the primary disease or surgical resections. The functional condition results from inadequate bowel function due to neuromuscular or mucosal disease, although bowel length may be completely preserved. A list of common indications for ITx is presented in Table 86.1. As with other solid abdominal organ transplants (Steinman et al., 2001), absolute contraindications to ITx include life-threatening and other irreversible disease not related to the digestive system such as severe cardiopulmonary disease, severe systemic infections with multiple organ failure, aggressive malignancy, profound neurologic disabilities, and importantly, insufficient vascular patency to guarantee vascular access for up to 6 months after transplant (Caicedo and Iyer, 2005; Braun et al., 2007; Vianna et al., 2008; Millar et al., 2009). A relative contraindication may be excessive narcotic dependency and usage in children with chronic intestinal pseudo-obstruction (CIPO) (Millar et al., 2009), a heterogeneous group of rare disorders presenting with symptoms and signs of intestinal obstruction, but without a mechanical basis.
Surgical procedures and complications Three different approaches are currently adopted for ITx: (1) isolated intestinal transplant – to date estimated at 30% (Berg et al., 2009) – for those patients presenting only intestinal failure; (2) combined liver and intestine transplant, when intestinal and end-stage liver failure coexist; (3) multivisceral transplant, when multiorgan failure requires transplantation of at least three organs, including the intestine. Surgical complications are common, occurring in 50% of transplanted patients, but rarely hampering the
*Correspondence to: Dr. Andrea Stracciari, Unita` Operativa di Neurologia, Policlinico S. Orsola-Malpighi, via Albertoni 15, 40138 Bologna, Italy. Phone: þ39-051-636-2643, Fax: þ39-051-636-2640, E-mail: [email protected]
1268
A. STRACCIARI AND M. GUARINO
Table 86.1 Causes of intestinal failure requiring intestine transplantation Children
Adults
Gastroschisis Volvulus Necrotizing enterocolitis Intestinal atresia Pseudo-obstruction Microvillus inclusion disease Intestinal polyposis Aganglionosis/Hirschsprung disease Trauma Tufting enteropathy
Superior mesenteric artery and venous thrombosis Crohn disease Intestinal dysmotility Trauma Volvulus Desmoid tumor Familial polyposis Gastrinoma Budd–Chiari disease Intestinal adhesions Pseudo-obstruction Inflammatory bowel disease Radiation enteritis
transplant success. The main complications are postsurgery anastomotic haemorrhage, vascular occlusion, and biliary loss or obstruction, whereas intestinal perforations, wound dehiscence, and wound infections are less common (Guaraldi et al., 2005; Braun et al., 2007; Millar et al., 2009). Most adult intestine recipients have had multiple abdominal surgeries before reaching ITx and have developed dense adhesions, which may result in significant blood loss and hemodynamic instability at the time of transplant. In addition, intestinal transplant recipients may have a poor nutritional status, which directly impacts on wound and anastomotic healing. The post-transplant clinical course is frequently complicated by extensive metabolic, toxic, and infectious disorders related to previous dependence on total parenteral nutrition, frequent severe hepatic cholestasis, and the strong immunosuppression required to prevent and/or control rejection. The intestine is more difficult to transplant than other solid organs, some of the reasons possibly being the large number of white cells in the bowel which provides a strong stimulus for rejection, and the large number of bacteria in the gut, which increases the risk of infection after transplantation. Because of the degree of immunosuppression used, typical and atypical postoperative infections are likely to occur after ITx (Kusne et al., 1996; Guaraldi et al., 2005; Fryer, 2008), and sepsis/multiorgan failure continues to be the leading cause of death (Fryer, 2008). Approximately half of the deaths in intestinal transplant patients have been clearly attributed to sepsis, while another quarter have been attributed to multiorgan failure to which sepsis was likely a contributing factor (Fryer, 2008). The most common locations of infections
are the bloodstream, central venous catheters (CVC), respiratory tract, wound and intra-abdominal cavity (Guaraldi et al., 2005; Tzakis et al., 2005; Oltean et al., 2006; Kimura et al., 2009). Another common post ITx complication is rejection (Grant et al., 2005; Fryer, 2008; Mazariegos et al., 2010), which can lead to graft failure and death. Some forms of acute rejection occur in up to 90% of intestinal transplant recipients. Acute cellular allograft rejection can occur at any time but is most common in the first year. Chronic rejection, demonstrated in 10–13% of intestine-only transplants (Fryer, 2008), consists of the sum of persistent episodes of acute rejection, presenting with diarrhea, weight loss, intermittent fever, abdominal pain, and gastrointestinal hemorrhage.
Immunosuppression ITx presents a greater immunologic challenge than other solid organs transplants (Pirenne and Kawai, 2009), being still characterized by a higher incidence of rejection due to the susceptibility of the intestinal graft, a large amount of donor lymphoid tissue, and the colonization of bacteria which can translocate into the circulation once the integrity of the intestinal mucosal barrier is disrupted. This is why ITx patients usually need more profound immunosuppression than other solid organ transplant recipients. The immunosuppressive history of successful ITx began with the clinical introduction of tacrolimus, which still represents the core immunosuppression used for maintenance therapy. Subsequently, induction therapy combined with immune modulation became the standard protocol. To date, induction therapy has been adjusted to minimize the dosage of immunosuppression, and consists of monoclonal (e.g., muromonab (OKT3)) or polyclonal antibody preparations, or antilymphocyte agents. Steroids are usually also included in most postoperative immunosuppressive regimens. Sirolimus has been used in combination with tacrolimus and may help prevent chronic rejection (Fishbein et al., 2002; Fryer, 2008) and reduce the dependence on tacrolimus and steroids. The risk of complications associated with immunosuppressive agents, especially tacrolimus, is not negligible. Chronic renal damage is particularly frequent and dangerous. In general, average serum levels for this drug are maintained at higher levels in intestinal transplant recipients compared with levels for other solid organ recipients, thereby explaining why a decline in renal function is more common and precipitous after ITx (Kato et al., 2006; Watson et al., 2008).
NEUROLOGIC COMPLICATIONS Unlike other types of solid organ transplantation, the literature on neurologic complications after ITx is scant.
NEUROLOGIC COMPLICATIONS OF INTESTINAL TRANSPLANTATION 1269 A review updated to December 2010 found few case Etiology reports and only three case series, all retrospective. Of As for other organ transplants, the etiology of neurothese, one is autoptic (Idoate et al., 1999), another conlogic complications appears to be heterogeneous, often cerns a population of children who received liver and multifactorial, and varies depending on the phase liver plus small bowel transplant (Fernandez et al., considered. 2010), with data presented all together for both types During the organ transplant procedure neurologic of transplantation, thereby concealing the complications problems may occur due to the pre-existing conditions strictly related to ITx. The only informative study on of the patient as well as the long duration and complexity clinical neurologic complications after ITx is that by of the operation, and are more frequent in multivisceral Zivkovic´ et al. (2010). transplantation. Patients may experience increased intracranial pressure, with a severely compromised cerebral Epidemiology perfusion pressure. Hypovolemia and hypercarbia may complicate surgery, with a further reduction in The few available data seem to indicate that the neurocerebral blood flow. Hypotension may develop, leading logic complications of ITx are more common than those to a hypoxic-ischemic event. For these reasons, surgeryaffecting other solid organ transplant recipients. In their related neurologic complications mostly affect the sample, including 23 isolated ITx, 16 with liver plus intescentral nervous system (CNS), mainly causing cerebrotine transplantation, and seven multivisceral transplants, vascular injury. Peripheral nervous system (PNS) damexamined retrospectively with a median follow-up of 25 age may also occur, presenting with mononeuropathies months, Zivkovic´ et al. (2010) found that 46 of 54 recipcaused by stretching, compression, or direct injury, espeients (85%) developed one or more neurologic complicacially in the case of prolonged and complex surgery, such tions. This overall rate of neurologic complications is as multivisceral transplants. consistently higher than that reported with other transIn the early postsurgical phase (
Chapter 86
Neurologic complications of intestinal transplantation ANDREA STRACCIARI* AND MARIA GUARINO Neurology Unit, S. Orsola-Malpighi University Hospital, Bologna, Italy
INTRODUCTION The first attempts at intestine transplantation (ITx) in humans were made during the 1960s, but intestinal transplants were not successful until the 1990s, when potent immunosuppressive drugs became available along with improved methods to prevent infections. In particular, the introduction of FK506 (tacrolimus) led to a consistent improvement in ITx outcome, significantly lengthening patient and graft survival, due also to the refinement of surgical techniques and better clinical management. Notwithstanding, ITx remains a difficult procedure and the results are still inferior to those of other organ transplants, especially in terms of long-term outcome and multivisceral transplants, due to a high risk of immunologic complications, and the subsequent need for profound immunosuppression with its attending sideeffects such as malignancies, infections, and drug toxicity. After ITx, patients may experience various medical and surgical complications, the commonest including infections, rejection, intestinal ischemia, and leaks from the anastomoses. There are treatment options for all of these complications, but in some cases they result in graft loss or even the death of the patient. Among ITx complications, neurologic problems have received little attention to date, especially when compared to those occurring after other solid organ transplantations. Prior to a detailed analysis, a short survey of the general aspects of ITx may be useful.
GENERAL REMARKS Indications and contraindications for intestinal transplantation ITx is indicated in patients with chronic, irreversible intestinal failure associated with failure or severe complications of parenteral nutrition. Intestinal failure
may result from a variety of anatomic and functional conditions, the leading cause being the short bowel syndrome, which results from inadequate bowel length due to the primary disease or surgical resections. The functional condition results from inadequate bowel function due to neuromuscular or mucosal disease, although bowel length may be completely preserved. A list of common indications for ITx is presented in Table 86.1. As with other solid abdominal organ transplants (Steinman et al., 2001), absolute contraindications to ITx include life-threatening and other irreversible disease not related to the digestive system such as severe cardiopulmonary disease, severe systemic infections with multiple organ failure, aggressive malignancy, profound neurologic disabilities, and importantly, insufficient vascular patency to guarantee vascular access for up to 6 months after transplant (Caicedo and Iyer, 2005; Braun et al., 2007; Vianna et al., 2008; Millar et al., 2009). A relative contraindication may be excessive narcotic dependency and usage in children with chronic intestinal pseudo-obstruction (CIPO) (Millar et al., 2009), a heterogeneous group of rare disorders presenting with symptoms and signs of intestinal obstruction, but without a mechanical basis.
Surgical procedures and complications Three different approaches are currently adopted for ITx: (1) isolated intestinal transplant – to date estimated at 30% (Berg et al., 2009) – for those patients presenting only intestinal failure; (2) combined liver and intestine transplant, when intestinal and end-stage liver failure coexist; (3) multivisceral transplant, when multiorgan failure requires transplantation of at least three organs, including the intestine. Surgical complications are common, occurring in 50% of transplanted patients, but rarely hampering the
*Correspondence to: Dr. Andrea Stracciari, Unita` Operativa di Neurologia, Policlinico S. Orsola-Malpighi, via Albertoni 15, 40138 Bologna, Italy. Phone: þ39-051-636-2643, Fax: þ39-051-636-2640, E-mail: [email protected]
1268
A. STRACCIARI AND M. GUARINO
Table 86.1 Causes of intestinal failure requiring intestine transplantation Children
Adults
Gastroschisis Volvulus Necrotizing enterocolitis Intestinal atresia Pseudo-obstruction Microvillus inclusion disease Intestinal polyposis Aganglionosis/Hirschsprung disease Trauma Tufting enteropathy
Superior mesenteric artery and venous thrombosis Crohn disease Intestinal dysmotility Trauma Volvulus Desmoid tumor Familial polyposis Gastrinoma Budd–Chiari disease Intestinal adhesions Pseudo-obstruction Inflammatory bowel disease Radiation enteritis
transplant success. The main complications are postsurgery anastomotic haemorrhage, vascular occlusion, and biliary loss or obstruction, whereas intestinal perforations, wound dehiscence, and wound infections are less common (Guaraldi et al., 2005; Braun et al., 2007; Millar et al., 2009). Most adult intestine recipients have had multiple abdominal surgeries before reaching ITx and have developed dense adhesions, which may result in significant blood loss and hemodynamic instability at the time of transplant. In addition, intestinal transplant recipients may have a poor nutritional status, which directly impacts on wound and anastomotic healing. The post-transplant clinical course is frequently complicated by extensive metabolic, toxic, and infectious disorders related to previous dependence on total parenteral nutrition, frequent severe hepatic cholestasis, and the strong immunosuppression required to prevent and/or control rejection. The intestine is more difficult to transplant than other solid organs, some of the reasons possibly being the large number of white cells in the bowel which provides a strong stimulus for rejection, and the large number of bacteria in the gut, which increases the risk of infection after transplantation. Because of the degree of immunosuppression used, typical and atypical postoperative infections are likely to occur after ITx (Kusne et al., 1996; Guaraldi et al., 2005; Fryer, 2008), and sepsis/multiorgan failure continues to be the leading cause of death (Fryer, 2008). Approximately half of the deaths in intestinal transplant patients have been clearly attributed to sepsis, while another quarter have been attributed to multiorgan failure to which sepsis was likely a contributing factor (Fryer, 2008). The most common locations of infections
are the bloodstream, central venous catheters (CVC), respiratory tract, wound and intra-abdominal cavity (Guaraldi et al., 2005; Tzakis et al., 2005; Oltean et al., 2006; Kimura et al., 2009). Another common post ITx complication is rejection (Grant et al., 2005; Fryer, 2008; Mazariegos et al., 2010), which can lead to graft failure and death. Some forms of acute rejection occur in up to 90% of intestinal transplant recipients. Acute cellular allograft rejection can occur at any time but is most common in the first year. Chronic rejection, demonstrated in 10–13% of intestine-only transplants (Fryer, 2008), consists of the sum of persistent episodes of acute rejection, presenting with diarrhea, weight loss, intermittent fever, abdominal pain, and gastrointestinal hemorrhage.
Immunosuppression ITx presents a greater immunologic challenge than other solid organs transplants (Pirenne and Kawai, 2009), being still characterized by a higher incidence of rejection due to the susceptibility of the intestinal graft, a large amount of donor lymphoid tissue, and the colonization of bacteria which can translocate into the circulation once the integrity of the intestinal mucosal barrier is disrupted. This is why ITx patients usually need more profound immunosuppression than other solid organ transplant recipients. The immunosuppressive history of successful ITx began with the clinical introduction of tacrolimus, which still represents the core immunosuppression used for maintenance therapy. Subsequently, induction therapy combined with immune modulation became the standard protocol. To date, induction therapy has been adjusted to minimize the dosage of immunosuppression, and consists of monoclonal (e.g., muromonab (OKT3)) or polyclonal antibody preparations, or antilymphocyte agents. Steroids are usually also included in most postoperative immunosuppressive regimens. Sirolimus has been used in combination with tacrolimus and may help prevent chronic rejection (Fishbein et al., 2002; Fryer, 2008) and reduce the dependence on tacrolimus and steroids. The risk of complications associated with immunosuppressive agents, especially tacrolimus, is not negligible. Chronic renal damage is particularly frequent and dangerous. In general, average serum levels for this drug are maintained at higher levels in intestinal transplant recipients compared with levels for other solid organ recipients, thereby explaining why a decline in renal function is more common and precipitous after ITx (Kato et al., 2006; Watson et al., 2008).
NEUROLOGIC COMPLICATIONS Unlike other types of solid organ transplantation, the literature on neurologic complications after ITx is scant.
NEUROLOGIC COMPLICATIONS OF INTESTINAL TRANSPLANTATION 1269 A review updated to December 2010 found few case Etiology reports and only three case series, all retrospective. Of As for other organ transplants, the etiology of neurothese, one is autoptic (Idoate et al., 1999), another conlogic complications appears to be heterogeneous, often cerns a population of children who received liver and multifactorial, and varies depending on the phase liver plus small bowel transplant (Fernandez et al., considered. 2010), with data presented all together for both types During the organ transplant procedure neurologic of transplantation, thereby concealing the complications problems may occur due to the pre-existing conditions strictly related to ITx. The only informative study on of the patient as well as the long duration and complexity clinical neurologic complications after ITx is that by of the operation, and are more frequent in multivisceral Zivkovic´ et al. (2010). transplantation. Patients may experience increased intracranial pressure, with a severely compromised cerebral Epidemiology perfusion pressure. Hypovolemia and hypercarbia may complicate surgery, with a further reduction in The few available data seem to indicate that the neurocerebral blood flow. Hypotension may develop, leading logic complications of ITx are more common than those to a hypoxic-ischemic event. For these reasons, surgeryaffecting other solid organ transplant recipients. In their related neurologic complications mostly affect the sample, including 23 isolated ITx, 16 with liver plus intescentral nervous system (CNS), mainly causing cerebrotine transplantation, and seven multivisceral transplants, vascular injury. Peripheral nervous system (PNS) damexamined retrospectively with a median follow-up of 25 age may also occur, presenting with mononeuropathies months, Zivkovic´ et al. (2010) found that 46 of 54 recipcaused by stretching, compression, or direct injury, espeients (85%) developed one or more neurologic complicacially in the case of prolonged and complex surgery, such tions. This overall rate of neurologic complications is as multivisceral transplants. consistently higher than that reported with other transIn the early postsurgical phase (
