- Email: [email protected]
Neurologic Complications of Solid Organ Transplantation
N e u ro l o g i c C o m p l i c a t i o n s of Solid Organ Tra n s p l a n t a t i o n Michael Pizzi,
DO, PhD
a
, Lauren Ng,
MD, MPH
b,
*
KEYWORDS Neurologic complications Solid organ transplantation Seizures Cerebrovascular events Opportunistic infections Encephalopathy Drug toxicity KEY POINTS Among patients receiving solid organ transplants, approximately one-third will develop neurologic symptoms. Most of these neurologic symptoms will occur within 30 days of their transplantation. These neurologic symptoms include neurotoxicity of immunosuppressive agents, seizures, encephalopathy, cerebrovascular events, opportunistic infections, posttransplant lymphoproliferative disorder, and central pontine myelinosis. Some neurologic complications are seen more frequently in specific organ transplant recipients.
Among patients receiving solid organ transplants, approximately one-third will develop neurologic symptoms. Most of these neurologic symptoms will occur within 30 days of their transplantation.1 The most common neurologic complications are specific to the type of organ transplanted. For example, ischemic stroke is seen frequently in patients with heart and kidney transplant compared with other solid organ transplant recipients.2 Lung and pancreas transplant recipients tend to have a higher occurrence of hypoxic-ischemic encephalopathy, whereas liver recipients have higher occurrence of central pontine myelinolysis (CPM), and intestinal transplant patients have higher occurrence of Wernicke encephalopathy.3 The most common neurologic complications seen after solid organ transplantation are discussed in the following article and include neurotoxicity of immunosuppressive agents, seizures, encephalopathy, cerebrovascular events, opportunistic infections, and CPM.
Disclosure Statement: The authors have nothing to disclose. a Neuroscience Intensive Care Unit, University of Florida Health, Jacksonville, FL 32209, USA; b Departments of Critical Care Medicine, Neurology and Neurosurgery, Mayo Clinic, 4500 San Pablo Road, Jacksonville, FL 32224, USA * Corresponding author. E-mail address: [email protected] Neurol Clin 35 (2017) 809–823 http://dx.doi.org/10.1016/j.ncl.2017.06.013 0733-8619/17/ª 2017 Elsevier Inc. All rights reserved.
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NEUROTOXICITY OF IMMUNOSUPPRESSIVE AGENTS
Immunosuppressive agents are classified into induction or maintenance agents. Induction medications are administered to deplete the recipient’s reactive lymphocytes in order to mitigate acute rejection. The most common maintenance medications include corticosteroids, mycophenolate mofetil (MMF), calcineurin inhibitors, and noncalcineurin inhibitors. Corticosteroids produce various immunomodulating effects, such as inhibiting expression of proinflammatory proteins.4 Neurologic complications of corticosteroids often involve neurocognitive symptoms, such as delirium, insomnia, depression, and difficulty concentrating. MMF decreases lymphocyte proliferation because of decreasing de novo guanosine synthesis.5 MMF does not have significant neurologic side effects, but can cause headaches. Cyclosporine and tacrolimus are both calcineurin inhibitors. Calcineurin is a phosphatase that regulates various cytokines, such as interleukin-2 (IL-2) and transforming growth factor b. Inhibition of calcineurin by cyclosporine and tacrolimus ultimately decreases activation of T lymphocytes. As a neuronal phosphatase, calcineurin plays a role in the regulation of proteins associated with synaptic transmission, synaptic plasticity, and ultimately, learning and memory.6 Calcineurin is expressed in multiple areas of the central nervous system (CNS), such as cerebral cortex, cerebellum, hippocampus, striatum, and substantia nigra.7 The main manifestations of neurotoxicity from calcineurin inhibitors are posterior reversible encephalopathy syndrome (PRES), encephalopathy, akinetic mutism, and seizures. Risk factors for neurotoxicity include hypocholesterolemia, hypertension, hypomagnesemia, uremia, concomitant highdose steroids, and beta-lactam antibiotics.8,9 PRES can present with encephalopathy, seizure, headache, visual disturbances, focal neurologic deficits, and status epilepticus.10 Radiographically, the typical findings of PRES on MRI are hyperintensities on T2 or fluid attenuated inversion recovery sequences in the occipital and parietal regions. It is theorized that the posterior brain regions are susceptible to vasogenic edema associated with PRES because of the relative lack of sympathetic innervations in the posterior fossa. These areas of hyperintensity are often bilateral, but asymmetrical.11 However, in a study of various transplant patients receiving calcineurin inhibitors, approximately two-thirds of PRES cases involved the frontal region on radiographic imaging.12 That study also demonstrated that PRES does not correlate with supratherapeutic serum levels of calcineurin inhibitors and is often associated with levels in the therapeutic range. The proposed pathophysiology of PRES would involve damage and alteration of the endothelium, breakdown of the blood-brain barrier, and vasoconstriction. Endothelin-1 is a potent vasoconstrictor in addition to modulating leukocyte adhesion to endothelial cells. Cyclosporine has been associated with increases in blood pressure as well as concurrent increase in serum levels of endothelin-1 in renal transplant patients.13 PRES may present in transplant patients taking a calcineurin inhibitor who have hypomagnesemia, even in the absence of hypertension.14 Encephalopathy often presents as an alteration in awareness, arousal, and confusion that is typically seen within the first 30 days after transplantation and is attributed to initiation and supratherapeutic serum levels of calcineurin inhibitors.3,15 In the absence of radiologic evidence of PRES, other causes of encephalopathy must be evaluated, such as organ failure/rejection, cerebrovascular events (infarction or hemorrhage), hypoxic/ischemic injury, infections of the CNS, CPM, Wernicke encephalopathy, and nonconvulsive seizures/nonconvulsive status epilepticus.3
Complications of Solid Organ Transplantation
Akinetic mutism is diagnosed when the patient is unable to voluntarily generate speech or motor movements in the setting of retained awareness. Akinetic mutism can be seen with calcineurin inhibitors, in particular with tacrolimus.16,17 Holding the calcineurin inhibitor tends to resolve the symptoms. Seizures due to calcineurin inhibitors often present generalized and can be preceded by behavioral changes. Serum levels of calcineurin inhibitors are often within the therapeutic range.18 Monitoring with electroencephalography (EEG) is necessary to exclude nonconvulsive seizures or nonconvulsive status epilepticus after clinical seizure activity has ceased. Peripheral neurotoxicity such as axonal or demyelinating neuropathy is typically seen weeks to months after starting a calcineurin inhibitor. A demyelinating polyneuropathy resembling chronic inflammatory demyelinating polyneuropathy has been associated with tacrolimus, with subsequent improvement of symptoms after discontinuation of tacrolimus19 or after treatment with plasmapheresis or intravenous immunoglobulin.20 The noncalcineurin inhibitors sirolimus and everolimus inhibit the mammalian target of rapamycin (mTOR). Inhibiting mTOR effectively blocks IL-2 signaling via CD25 on activated T cells, thereby decreasing T-cell signaling and proliferation. Sirolimus and everolimus do not inhibit calcineurin and therefore do not have the same neurologic complications as cyclosporine and tacrolimus.21 Neurologic complications of sirolimus and everolimus are tremor, confusion, paresthesia, and hypoesthesia.22 Table 1 summarizes the neurologic complications associated with immunosuppressive medications. Several biological agents are also used as part of induction regimens. The monoclonal antibodies against IL-2 receptor a basiliximab and daclizumab are both approved by the US Food and Drug Administration for induction after renal transplantation. Muromonab-CD3 (Orthoklone OKT3) blocks T-cell activation by binding to the CD3 epsilon component.23 Antithymocyte globulin consists of polyclonal antithymocyte antibodies that deplete T cells as well as some B cells, dendritic cells, and natural killer cells.24 The most common neurologic side effects of these biological agents are aseptic meningitis, encephalopathy, headaches, and seizures.22 SEIZURES AFTER ORGAN TRANSPLANTATION
Seizures can be divided into generalized and focal seizures (with and without alterations in awareness). In organ transplant patients with no prior history of seizures,
Table 1 Neurologic complications associated with immunosuppressive medications Medication
Neurologic Complications
Monoclonal antibodies
Aseptic meningitis, encephalopathy, headache, seizures
Steroids
Delirium, insomnia, depression, difficulty concentrating, tremor, myopathy
MMF
Headache, psychiatric
Calcineurin inhibitors Tacrolimus Cyclosporine
PRES, encephalopathy, seizures, akinetic mutism, peripheral neurotoxicity
Noncalcineurin inhibitors Sirolimus Everolimus
Tremor, confusion, paresthesia, hypoesthesia, headache
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2% to 24% of these recipients will have a seizure after transplantation.2 Most seizures after transplantation are due to drug toxicity and present clinically as generalized seizures.25 Generalized seizures can also be due to metabolic derangements, most notably hyponatremia, hypomagnesemia, hypoglycemia, and hyperammonemia. Focal seizures are often due to focal structural abnormalities such as intracranial hemorrhage, abscess (Aspergillus and Nocardia), meningitis (Listeria and Cryptococcus), encephalitis, malignancy such as posttransplantation lymphoproliferative disorder (PTLD), and PRES. Cerebrospinal fluid (CSF) analysis should be conducted if there are signs of infection associated with seizures. If no provoking factors can be identified and corrected, then seizures should be treated to established algorithms. First-line treatment is a benzodiazepine (most often intravenous lorazepam with maximum dose of 0.1 mg/kg). Brain imaging (MRI being preferable) and EEG monitoring should also be done to evaluate for structural causes and to monitor for nonconvulsive seizures/nonconvulsive status epilepticus in the poorly responsive or encephalopathic patient. If seizures are recurrent, an intracranial structural abnormality is identified, or if the EEG demonstrates potentially epileptogenic abnormalities, then an antiepileptic drug (AED) should be started. AED therapy should be tailored to the patient’s organ function associated with that particular medication’s metabolism. Phenytoin, valproic acid, phenobarbital, and carbamazepine are AED medications that undergo hepatic metabolism and affect the metabolism of other medications. Given the adverse effects of these older AEDs, levetiracetam has become the drug of choice for posttransplant seizures.26 Tremors and myoclonus can be mistaken for seizures and are often due to metabolic derangements and medication side effects, such as propofol.27 ENCEPHALOPATHY
Encephalopathy can present with symptoms of altered mental status, such as confusion, changes in alertness and awareness, delirium, headache, changes in vision, hallucinations, tremor, chorea, or seizures. Encephalopathy usually occurs within the first 30 days after transplantation and can be attributed to medication toxicity (especially calcineurin inhibitors), metabolic derangements (hypoglycemia, hyponatremia or hypernatremia, hyperammonemia, hypercalcemia, or hypermagnesemia), infections of the CNS or systemic infections, PRES, and stroke.2 Among the metabolic derangements, hyperammonemia is frequently associated with hepatic transplantation1 and very rarely associated with lung transplantation.28–32 Hyperammonemia can cause encephalopathy because of various mechanisms such as cerebral edema from the accumulation of glutamine from glutamate in astrocytes,33 changes to the blood-brain barrier,34 and alteration of neuronal excitability because of interactions of ammonium ion with potassium and NMDA channels,35,36 which could also lead to seizures. In the lung transplant population, hyperammonemia often leads to coma, seizures, and death with a mortality of 67% to 75%.30,37 The threshold for obtaining an EEG in encephalopathic patients after organ transplantation should be very low in order to evaluate for possible nonconvulsive seizures or nonconvulsive status epilepticus.38 Treatment of hyperammonemia involves varying combinations of protein restriction, bowel decontamination, amino acids, dialysis, and nitrogen scavengers. Pharmaceutical treatment of hyperammonemia include lactulose, rifaximin, metronidazole, levocarnitine, argninine, sodium phenylacetate, sodium benzoate, and zinc, which is a cofactor for various enzymes in the urea cycle (Table 2).30,36,37,39–41 In addition, if ureaplasma infection is suspected as an inciting factor for hyperammonemia, fluoroquinolones and macrolides are recommended.29
Complications of Solid Organ Transplantation
Table 2 Treatment modalities for hyperammonemia Nondrug therapy
Protein restriction Dialysis, CVVH or IHD
Bowel decontamination
Lactulose Rifaximin Metronidazole
Amino acids
Levocarnitine Arginine
Nitrogen scavengers
Sodium phenylacetate Sodium benzoate
Enzyme cofactor
Zinc
Ureaplasma treatment
Fluoroquinolones Macrolides
Abbreviations: CVVH, continuous veno-venous hemofiltration; IHD, hemodialysis.
CEREBROVASCULAR EVENTS
Cerebrovascular events occur most commonly in the heart and kidney transplant population because of concomitant risk factors of hypertension, diabetes, and hyperlipidemia.42 In addition, age, previous stroke, arrhythmias, corticosteroid use, and hypercoagulable states increase the risk of stroke after heart or renal transplant.42 The incidence of stroke after heart transplant is 2% to 10%, 5% to 10% after kidney transplant, 2% to 3% after lung transplant, and 0% to 3% after liver transplant.9 Twenty percent of cerebrovascular events in heart transplant recipients occur in the first 2 weeks after transplant, and 60% of the events are ischemic strokes, 28% are transient ischemic attacks, and 12% are intracerebral hemorrhages (ICHs).43 Perioperative stroke after heart transplant is associated with a higher 1-year mortality compared with postoperative delirium, encephalopathy, peripheral neuropathy and myopathy, and seizures.44 In addition, ICH can also occur after solid organ transplantation, mainly liver and kidney transplant, with an incidence of 1% to 7% and 0.5% to 2%, respectively.9 Polycystic kidney disease in renal transplant patients has been associated with a 10-fold higher risk of ICH because of the presence of berry aneurysms in the anterior circulation.45,46 Other risk factors include poorly controlled hypertension, diabetes, and left ventricular hypertrophy.46,47 Mortality associated with ICH in renal transplant can be as high as 48%.47 With regards to liver transplant, in one review of 22 autopsies, 23.6% were noted to have ICH, and these were likely related to severe coagulopathy associated with severe hepatic failure and/or infectious causes, such as aspergillus and bacterial endocarditis.48 Overall, cerebrovascular events after transplant can lead to significant morbidity and mortality. CENTRAL NERVOUS SYSTEM INFECTIONS
CNS infections are frequent and can increase mortality significantly after solid organ transplant with 44% to 77% of CNS infections leading to death.8 In addition, CNS fungal infections have a mortality greater than 90%.49 However, because of improvements in immunosuppressive therapy and routine surveillance, the prevalence of these infections has dropped to 1% to 2% from 7%.44,50 Unfortunately, because of an impaired inflammatory response because of immunosuppression, the clinical manifestations of CNS infections can be blunted, and patients may only present with fever
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and headache.49 Therefore, it is important to be mindful of CNS infections in the setting of fever, headache, and altered mental status even in the absence of other manifestations. CNS infections can be stratified by time course after transplantation and then further into bacterial, fungal, viral, and protozoal (Tables 3 and 4). In the first month after transplant, CNS infections are rare; however, when they do occur, they are usually related to donor-transmitted infections, nosocomial pathogens, or infections already present before transplantation.8,51 The second to sixth month posttransplant period is when patients are at the greatest risk for infection, predominately viral and opportunistic pathogens.52 Varicella zoster (VZV), Epstein-Barr (EBV), and cytomegalovirus (CMV) are the main viral pathogens, whereas herpes simplex virus 1 and 2 (HSV) and human herpes virus 6 (HHV-6) are rarely encountered.8,51,52 Opportunistic infections can be caused by nocardia, aspergillus, toxoplasma, listeria, and Cryptococcus, and out of these, aspergillus, listeria, and Cryptococcus account for 80% of CNS infections seen in this population.8 After 6 months, infections are stratified into 1 of 3 categories: reactivation of previous infections, opportunistic infections secondary to chronic high immunosuppression, and community-acquired infections, also seen in nonimmunocompromised patients.8,51,52 Bacterial Infections
Opportunistic bacterial CNS infections are rare and mainly due to nocardia, listeria, and mycobacterium. Systemic nocardia affects 0.7% to 6% of solid organ transplant recipients; CNS is the most frequent secondary site of infection and is involved in onethird of patients with systemic nocardiosis.9,51 The primary entry point for nocardia is pulmonary, and 18% to 40% spread hematogeneously.53 Historically, heart transplant recipients had the highest risk of nocardiosis, which decreased with the use of trimethoprim-sulfamethoxaxole.53 Listeria can be caused by unpasteurized dairy, leading to meningitis and rhomboencephalitis with an associated mortality of 50%, especially if diagnosis is delayed.9,51 Mycobacterium tuberculosis is an extremely rare cause of basilar meningitis and abscess or tuberculoma in the transplant population with an incidence of 0.3% to 1% in liver transplant recipients and 2% to 3% in renal transplant recipients.9,51 Viral Infections
As mentioned above, viral CNS infections are seen in months 1 to 6 after transplant and comprise EBV, CMV, VZV, HSV, HHV-6, and JC virus. Most of these viruses will cause meningitis or encephalitis except EBV, which rarely causes encephalitis
Table 3 Common central nervous system infections by time course posttransplant Time Course
Infections
First 30 d
Pretransplant colonization Nosocomial infections (Methicillin-resistant Staphylococcus aureus, candida, Aspergillus) Donor-derived transmission
30 d to 6 mo
Viral infections (HSV, EBV, CMV) Opportunistic infections (Nocardia, Toxoplasma, Listeria)
>6 mo
Opportunistic infections (Cryptococcus, listeria, Nocardia, Aspergillus) Community-acquired infections Reactivation of previous infections
Complications of Solid Organ Transplantation
Table 4 Common central nervous system infections by pathogen Type
Organism
Clinical Presentation
Treatment
Bacterial
Nocardia
Meningitis, cerebritis, mass lesion Rhomboencephalitis, meningitis Basilar meningitis, tuberculoma
Trimethoprim-sulfamethaxole
Shingles, GuillainBarre syndrome Encephalitis Encephalitis, GuillainBarre syndrome Limbic encephalitis Encephalitis PML
Acyclovir, VZV immunoglobulin
Listeria Mycobacterium Viral
VZV EBV CMV HHV-6 HSV-1/HSV-2 JC virus
Fungal
Aspergillus
Brain abscess, cerebral hemorrhage Cryptococcus Meningitis, mass lesion, increased intracranial pressure Mucormycosis Rhinocerebral infection Candida Meningitis, abscess Coccidiomycosis Basilar meningitis Histoplasma Meningitis
Protozoal Toxoplasmosis
Space-occupying lesion
Ampicillin gentamicin Rifampin 1 isoniazid 1 pyrazinamide 1 ethambutol 1 pyridoxine
Acyclovir, ganciclovir Ganciclovir, foscarnet, CMV immunoglobulin Ganciclovir, foscarnet Acyclovir None Voriconazole or amphotericin 1 flucytosine Amphotericin flucytosine
Amphotericin Amphotericin fluconazole Amphotericin fluconazole Amphotericin itraconazole Pyrimethamine 1 sulfadiazine 1 folinic acid
Data from Conti DJ, Rubin RH. Infection of the central nervous system in organ transplant recipients. Neurol Clin 1988;6(2):241–60; and Pless M, Zivkovic SA. Neurologic complications of transplantation. Neurologist 2002;8(2):107–20.
but is associated with PTLD.49,51 The manifestations of PTLD resemble primary CNS lymphoma, with tumors arising deep in the brain in perivascular spaces and 25% of patients experiencing spread to the leptomeninges.8 In PTLD, the B-cell proliferation contains EBV DNA and expresses EBV gene products, and it is thought to start from an EBV infection or reactivation of a latent infection.8 EBV will infect the B lymphocytes leading to proliferation, which goes unchecked because of abnormal cellular and humoral immune mechanisms.8 In turn, this leads to the formation of a malignant clone, which then proliferates, producing a lymphoma. Treatment involves lowering immunosuppression, antiviral therapy, and chemotherapy and radiation.8 Despite treatment, survival is only 31% in patients who develop PTLD.8 JC virus also does not cause meningitis or encephalitis but instead leads to progressive multifocal leukoencephalopathy (PML), a demyelinating disorder that occurs late in the posttransplant course.53 Clinical signs include personality changes, seizures, headaches, aphasia, gait disturbances, and visual disturbances, with a classic pattern of subcortical white matter lesions with no contrast enhancement or edema.51,53 Unfortunately, PML has a very poor prognosis and typically becomes fatal within 4 to 6 months despite lowering immunosuppression.53,54 No medical therapy has demonstrated clinical benefit in treating PML.55 HHV-6 is increasingly being recognized as a cause for encephalitis in the transplant population and is the most neuroinvasive of the herpesviruses.51,53 Median time of
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onset is about 45 days and manifests as altered mental status, seizures, headaches, and speech disturbance.51,53 Amnesia may also be present because of its predilection for the hippocampus and limbic system.51,53 Ganciclovir and Foscarnet are treatment options, but mortality is still reported to be 58%.53 Fungal Infections
Cryptococcus is the most common cause of CNS meningitis in the posttransplant population, with the highest risk after heart and intestinal transplant leading to mortalities as high as 31% to 66%.51,53 It can lead to elevated intracranial pressure in the absence of a mass lesion or hydrocephalus because of basilar arachnoiditis, blocking the passage of CSF, and patients often need CSF diversion through serial lumbar punctures, external ventricular drains, lumbar drains, and even ventriculoperitoneal shunts in addition to treatment with amphotericin B and flucytosine.51,53 Aspergillus causes abscess formation in the frontoparietal lobe, basal ganglia, cerebellum, and brainstem with radiographic findings of single or multiple nonenhancing, low-density lesions.56 Mortality is high at 65% to 100% despite treatment with voriconazole or amphotericin B.54 It occurs on average 24 days after transplant in all solid organ transplant recipients and, similar to nocardia, is usually spread from the lung.57 Protozoal Infections
Toxoplasmosis has the highest incidence in heart transplant patients because cardiac tissue is a site of latency for the cysts.51,53 Clinical signs include altered mental status, seizures, and focal neurologic findings, and median time to presentation is on average 3 months after transplant.51,53 Typical radiographic findings are multiple, ring-enhancing lesions in the periventricular space. Toxoplasmosis can also involve heart and lungs and is associated with high mortality (65%–92%) if it is disseminated.13 Prevalence has decreased because of the use of trimethoprimsulfamethoxazole for prophylaxis, whereas treatment involves the use of pyrimethamine and sulfadiazine.51,53 CENTRAL PONTINE MYELINOLYSIS
CPM is a serious neurologic complication that characteristically affects liver transplant recipients in the first 1 to 2 weeks after transplant. Incidence is 17% after liver transplant with mortality greater than 50%.58,59 CPM was first described in alcoholic patients after rapid correction of hyponatremia; however, there is no direct link between hyponatremia and the development of CPM in liver transplant patients, and its cause and pathophysiology in these cases remain unknown. Two proposed mechanisms for CPM after liver transplant are a chronic hypoosmolar state leading to oligodendroglial dehydration, resulting in separation of axon from myelin with myelinosis and necrosis, and rapid restoration and maintenance of an intracellular osmolar state provoking high-energy demand with inadequate energy supply and leading to oligodenroglial apoptosis.58 A retrospective study of 1378 liver transplant patients found that severe and very severe hyponatremia, transfusion of greater than 4 platelet units, transfusion of greater than 12 fresh frozen plasma units, hemorrhagic complications, and increasing the sodium more than 12 mmol in the postoperative course were all risk factors for developing CPM.60 In another study of 997 adult liver transplant patients, risk factors for pontine or extrapontine myelinolysis included higher perioperative sodium variation, higher perioperative maximum serum sodium peak, and higher mean perioperative osmolality.61 A retrospective study in China also showed an association between
Complications of Solid Organ Transplantation
CPM and hyponatremia, rapid increase of serum sodium perioperatively, plasma osmolality increase postoperatively, duration of operation, and high cyclosporine levels.62 Other risk factors include electrolyte imbalances, diabetes mellitus, malnutrition, chronic hyponatremia, and cyclosporine use.58,59 Clinical signs and symptoms include progressive confusion and altered mental status, dysarthria, dysphagia, pseudobulbar palsy, ophthalmoplegia, and quadriplegia; tremor, catatonia, ataxia, mutism, and myoclonus can also be seen with extrapontine involvement.63 MRI is the imaging modality of choice and demonstrates T2 hyperintensities in the pons and often in various extrapontine locations. There is no treatment available. COMMON NEUROLOGIC COMPLICATIONS AFTER HEART TRANSPLANTATION
Neurologic complications are the most common adverse events after heart transplantation with rates of occurrence of 50% to 70%, and up to 20% mortality in these patients.44,64,65 Stroke is the most common neurologic complication associated with heart transplant, with a 3% to 10% incidence in these patients.66 Most strokes are due to ischemic infarctions, but hemorrhagic strokes can also occur in 0.6% to 2.5% of heart transplant recipients.67,68 Cardiovascular risk factors for ischemic stroke are found in many heart transplant patients, including hypertension, hyperlipidemia, atrial fibrillation, and diabetes mellitus. Technical and surgical complications of heart transplantation, such as preoperative use of intraaortic balloon pump or left ventricular assist device, prolonged cardiopulmonary bypass, intraoperative hypotension, or perioperative hemodynamic instability, can all contribute to increase the risk of cerebral infarction.69 In a retrospective review of 313 heart transplant patients, perioperative stroke occurred in 5% of patients and was associated with greater than 1-year mortality.64 Hemorrhagic stroke and vasogenic edema, possibly leading to PRES, can be associated with a hyperperfusion state during cardiopulmonary bypass.70 Unilateral vasogenic edema can be seen due to cardiopulmonary cannulation producing a unilateral hyperperfusion syndrome.71 Strict postoperative blood pressure control is essential in these cases, with possible improvement of symptoms over days to weeks. COMMON NEUROLOGIC COMPLICATIONS AFTER LUNG TRANSPLANTATION
Lung transplant patients have the highest mortality of any solid organ transplant recipients with 3-month survival rate of 88%, 5-year survival rate of 53%, and 10-year survival of 30%.72 In a 20-year retrospective review of lung transplants at a single center, 92% of recipients had neurologic complications within 10 years of transplantation.73 Severe encephalopathy was the most common neurologic complication (30% of lung recipients), followed by cerebrovascular events (12.6%). A separate retrospective analysis of 759 lung transplant patients demonstrated early (within 2 weeks of lung transplant) neurologic complications in 9.2% of patients. Forty-one percent of these patients had stroke, followed by encephalopathy (37%) that was attributed to calcineurin inhibitor toxicity in more than half of the cases.74 Severe hyperammonemia was seen in 4 patients (6%) after lung transplant, and despite maximum medical treatment, 3 of the 4 patients died within 30 days from lung transplant. Five-year survival was lower in patients with neurologic complications (51.1%) compared with recipients without neurologic complications (62.1%). It is theorized that lung transplant recipients are susceptible to neurologic complications because of decreased brain “reserve” from chronic hypoxia.75,76 Chronic hypoxia would make these patients more susceptible to hemodynamic instability in the perioperative period, neurotoxicity
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due to calcineurin inhibitors, and proinflammatory molecules that are upregulated in the perioperative period.74 COMMON NEUROLOGIC COMPLICATIONS AFTER LIVER TRANSPLANTATION
The incidence of neurologic complications after liver transplantation varies across studies depending on their definition and the duration of follow-up, ranging from 4 to 75.2,77–79 Most neurologic complications after liver transplant are categorized as encephalopathy and occur most often within 30 days of transplantation. In a retrospective study of 791 liver transplant patients, neurologic complications occurred in 8.2% over a 10-year observation period with nearly half (46.2%) of these neurologic complications occurring within 30 days of transplant.80 The most common neurologic complication over those 10 years of follow-up was cerebrovascular, including ischemic infarction (63%) and ICH (37%). Of the ischemic events, some were noted to span more than one vascular territory, suggesting a venous infarction, which was diagnosed in 5 of 17 ischemic stroke patients. During the initial 30 days after transplantation, metabolic encephalopathy was the most common neurologic complication; causes included calcineurin inhibitors, hyponatremia, and CPM. Seizures are also common after liver transplantation, with an incidence of 16% to 45%,79,81 and therefore, EEG is essential to evaluate for nonconvulsive seizures/nonconvulsive status epilepticus in liver transplant patients with encephalopathy. A prospective study of 136 liver transplant patients at a single institution demonstrated that 32.8% of patients developed neurologic complications and that 27.6% of these patients were diagnosed with metabolic encephalopathy. Independent predictors of metabolic encephalopathy were acute or chronic liver failure, primary sclerosing cholangitis, and number of subsequent surgeries.82 In a prospective study of 84 patients, encephalopathy before liver transplantation was shown to be an independent risk factor for developing a neurologic complication after transplantation.83 Infections of the CNS after liver transplantation have an incidence of approximately 5% and are commonly due to Listeria monocytogenes, Aspergillus fumigates, Cryptococcus neoformans, HSV, and CMV.53 Furthermore, with prolonged immunosuppression, PML caused by the JC virus should be on the differential diagnosis of the liver transplant patient with rapid progressive neurologic decline. There have been 8 case reports of PML in liver transplant patients, with the reason for liver transplant due to hepatitis C virus–related liver cirrhosis.84 COMMON NEUROLOGIC COMPLICATIONS AFTER RENAL TRANSPLANT
Kidneys are the most commonly transplanted solid organ and also have the highest rate of neurologic complications, with reported rates of 10% to 21%.54 The most common neurologic complications after renal transplant are cerebrovascular events, with a prevalence of 8%.54 As mentioned above, this is due to advanced atherosclerosis from preexisting conditions, such as diabetes and hypertension, that often lead to end-stage renal disease (ESRD). Hyperlipidemia is also a risk factor for cerebrovascular events and is commonly found in ESRD. Mechanisms for hyperlipidemia include depressed activity of lipoprotein lipase in uremia combined with the high proportion of lipids in the diet to compensate for protein restriction.42 Renal transplant recipients are also thought to be hypercoagulable because of decreased fibrinolytic activity and overcorrection of platelet aggregation and thrombin generation associated with uremia, which occurs in the first 3 weeks after transplantation.42 Systemic lupus erythematosus and vasculopathies, such as polyarteritis nodosa, Fabry disease, and granulomatosis and polyarteritis, can also lead to cerebrovascular events in this
Complications of Solid Organ Transplantation
population.42 Cerebral hemorrhage is also seen in renal transplant patients because of risk factors of hypertension and polycystic kidney disease. Other common neurologic complications include infections, femoral neuropathy, and immunosuppressive drug toxicities. Infectious complications comprise the infections listed above.85 Femoral neuropathy affects 2% of renal transplant recipients because of compression of the femoral nerve during surgery.85 Tacrolimus and steroids are the most commonly used immunosuppressant drugs in renal transplantation.54 Thus, it is important to keep in mind the various neurotoxicities associated with these medications (see Table 1). COMMON NEUROLOGIC COMPLICATIONS AFTER PANCREAS TRANSPLANT
Pancreas transplantations are performed primarily for the patient with diabetes mellitus and are often done in conjunction with renal transplantation. Another indication for pancreatic transplantation is cystic fibrosis, in which a combined pancreas-lung transplant is done. In a small case series done at the University of Pittsburgh in 1988, 33% of the patients who underwent pancreatic transplantation developed global cerebral ischemia, followed by 13% who developed seizures.86 Other complications documented were cerebral infarction, spinal cord infarction, metabolic encephalopathy, and aseptic meningitis related to immunosuppression, herpes zoster, and compressive neuropathy.86 Most cerebrovascular and ischemic events are due to underlying severe diabetes mellitus with end-organ involvement and advanced atherosclerosis. Another major complication is tacrolimus neurotoxicity, which affects as many as 21% of pancreatic transplantation patients.87 Conversely, pancreatic transplant can actually improve peripheral and autonomic diabetic neuropathy particularly when done in conjunction with renal transplantation.87 SUMMARY
Neurologic complications cause significant morbidity and mortality in solid organ transplant patients. These complications include encephalopathy, seizures, drug toxicities, infections, and cerebrovascular events. Many of the infectious complications have devastating effects, and thus, any patient with fever or altered mental status or headache after transplant should undergo a thorough evaluation, including brain imaging and CSF analysis. REFERENCES
1. Shah M. Inpatient neurologic consultation in solid organ transplant patients. Semin Neurol 2015;35(6):699–707. 2. Senzolo M, Ferronato C, Burra P. Neurologic complications after solid organ transplantation. Transpl Int 2009;22(3):269–78. 3. Dhar R, Human T. Central nervous system complications after transplantation. Neurol Clin 2011;29(4):943–72. 4. Vacca A, Felli MP, Farina AR, et al. Glucocorticoid receptor-mediated suppression of the interleukin 2 gene expression through impairment of the cooperativity between nuclear factor of activated T cells and AP-1 enhancer elements. J Exp Med 1992;175(3):637–46. 5. Hartono C, Muthukumar T, Suthanthiran M. Immunosuppressive drug therapy. Cold Spring Harb Perspect Med 2013;3(9):a015487. 6. Baumgartel K, Mansuy IM. Neural functions of calcineurin in synaptic plasticity and memory. Learn Mem 2012;19(9):375–84.
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7. Asai A, Qiu J, Narita Y, et al. High level calcineurin activity predisposes neuronal cells to apoptosis. J Biol Chem 1999;274(48):34450–8. 8. Patchell RA. Neurological complications of organ transplantation. Ann Neurol 1994;36(5):688–703. 9. Pustavoitau A, Bhardwaj A, Stevens R. Neurological complications of transplantation. J Intensive Care Med 2011;26(4):209–22. 10. Fugate JE, Rabinstein AA. Posterior reversible encephalopathy syndrome: clinical and radiological manifestations, pathophysiology, and outstanding questions. Lancet Neurol 2015;14(9):914–25. 11. Bartynski WS, Boardman JF. Distinct imaging patterns and lesion distribution in posterior reversible encephalopathy syndrome. AJNR Am J Neuroradiol 2007; 28(7):1320–7. 12. Burnett MM, Hess CP, Roberts JP, et al. Presentation of reversible posterior leukoencephalopathy syndrome in patients on calcineurin inhibitors. Clin Neurol Neurosurg 2010;112(10):886–91. 13. Cauduro RL, Costa C, Lhulier F, et al. Endothelin-1 plasma levels and hypertension in cyclosporine-treated renal transplant patients. Clin Transplant 2005;19(4): 470–4. 14. Osorio JM, Bravo J, Perez A, et al. Magnesemia in renal transplant recipients: relation with immunosuppression and posttransplant diabetes. Transplant Proc 2010;42(8):2910–3. 15. Bronster DJ, Emre S, Boccagni P, et al. Central nervous system complications in liver transplant recipients–incidence, timing, and long-term follow-up. Clin Transplant 2000;14(1):1–7. 16. Sierra-Hidalgo F, Martinez-Salio A, Moreno-Garcia S, et al. Akinetic mutism induced by tacrolimus. Clin Neuropharmacol 2009;32(5):293–4. 17. Garrido SM, Chauncey TR. Neuroleptic malignant syndrome following autologous peripheral blood stem cell transplantation. Bone Marrow Transplant 1998;21(4): 427–8. 18. Wijdicks EF, Wiesner RH, Krom RA. Neurotoxicity in liver transplant recipients with cyclosporine immunosuppression. Neurology 1995;45(11):1962–4. 19. Labate A, Morelli M, Palamara G, et al. Tacrolimus-induced polyneuropathy after heart transplantation. Clin Neuropharmacol 2010;33(3):161–2. 20. Wilson JR, Conwit RA, Eidelman BH, et al. Sensorimotor neuropathy resembling CIDP in patients receiving FK506. Muscle Nerve 1994;17(5):528–32. 21. Rompianesi G, Montalti R, Cautero N, et al. Neurological complications after liver transplantation as a consequence of immunosuppression: univariate and multivariate analysis of risk factors. Transpl Int 2015;28(7):864–9. 22. Anghel D, Tanasescu R, Campeanu A, et al. Neurotoxicity of immunosuppressive therapies in organ transplantation. Maedica (Buchar) 2013;8(2):170–5. 23. Taylor AL, Watson CJ, Bradley JA. Immunosuppressive agents in solid organ transplantation: mechanisms of action and therapeutic efficacy. Crit Rev Oncol Hematol 2005;56(1):23–46. 24. Mueller T. Mechanisms of action of thymoglobulin. Transplantation 2007;84: S5–10. 25. Wijdicks EF, Plevak DJ, Wiesner RH, et al. Causes and outcome of seizures in liver transplant recipients. Neurology 1996;47(6):1523–5. 26. Shepard PW, St Louis EK. Seizure treatment in transplant patients. Curr Treat Options Neurol 2012;14(4):332–47. 27. Walder B, Tramer MR, Seeck M. Seizure-like phenomena and propofol: a systematic review. Neurology 2002;58(9):1327–32.
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28. Anwar S, Gupta D, Ashraf MA, et al. Symptomatic hyperammonemia after lung transplantation: lessons learnt. Hemodial Int 2014;18(1):185–91. 29. Bharat A, Cunningham SA, Scott Budinger GR, et al. Disseminated ureaplasma infection as a cause of fatal hyperammonemia in humans. Sci Transl Med 2015;7(284):284re3. 30. Chen C, Bain KB, Iuppa JA, et al. Hyperammonemia syndrome after lung transplantation: a single center experience. Transplantation 2016;100(3):678–84. 31. Hocker S, Rabinstein AA, Wijdicks EF. Pearls & oy-sters: status epilepticus from hyperammonemia after lung transplant. Neurology 2011;77(10):e54–6. 32. Lichtenstein GR, Kaiser LR, Tuchman M, et al. Fatal hyperammonemia following orthotopic lung transplantation. Gastroenterology 1997;112(1):236–40. 33. Gropman AL, Summar M, Leonard JV. Neurological implications of urea cycle disorders. J Inherit Metab Dis 2007;30(6):865–79. 34. Walker V. Ammonia toxicity and its prevention in inherited defects of the urea cycle. Diabetes Obes Metab 2009;11(9):823–35. 35. Braissant O, McLin VA, Cudalbu C. Ammonia toxicity to the brain. J Inherit Metab Dis 2013;36(4):595–612. 36. Tapper EB, Jiang ZG, Patwardhan VR. Refining the ammonia hypothesis: a physiology-driven approach to the treatment of hepatic encephalopathy. Mayo Clin Proc 2015;90(5):646–58. 37. Lichtenstein GR, Yang YX, Nunes FA, et al. Fatal hyperammonemia after orthotopic lung transplantation. Ann Intern Med 2000;132(4):283–7. 38. Hocker SE. Status epilepticus. Continuum (Minneap Minn) 2015;21(5 Neurocritical Care):1362–83. 39. Teperman LW. Impact of pretransplant hepatic encephalopathy on liver posttransplantation outcomes. Int J Hepatol 2013;2013:952828. 40. Berry GT, Bridges ND, Nathanson KL, et al. Successful use of alternate waste nitrogen agents and hemodialysis in a patient with hyperammonemic coma after heart-lung transplantation. Arch Neurol 1999;56(4):481–4. 41. Rueda JF, Caldwell C, Brennan DC. Successful treatment of hyperammonemia after lung transplantation. Ann Intern Med 1998;128(11):956–7. 42. Bruno A, Adams HP Jr. Neurologic problems in renal transplant recipients. Neurol Clin 1988;6(2):305–25. 43. Alejaldre A, Delgado-Mederos R, Santos MA, et al. Cerebrovascular complications after heart transplantation. Curr Cardiol Rev 2010;6(3):214–7. 44. Heroux A, Pamboukian SV. Neurologic aspects of heart transplantation. Handb Clin Neurol 2014;121:1229–36. 45. Zivkovic SA, Abdel-Hamid H. Neurologic manifestations of transplant complications. Neurol Clin 2010;28(1):235–51. 46. Wijdicks EF, Torres VE, Schievink WI, et al. Cerebral hemorrhage in recipients of renal transplantation. Mayo Clin Proc 1999;74(11):1111–2. 47. Mour G, Wu C. Neurologic complications after kidney transplantation. Semin Nephrol 2015;35(4):323–34. 48. Bronster DJ, Emre S, Mor E, et al. Neurologic complications of orthotopic liver transplantation. Mt Sinai J Med 1994;61(1):63–9. 49. Conti DJ, Rubin RH. Infection of the central nervous system in organ transplant recipients. Neurol Clin 1988;6(2):241–60. 50. Zivkovic SA. Neurologic aspects of multiple organ transplantation. Handb Clin Neurol 2014;121:1305–17. 51. Avila JD, Zivkovic S. The neurology of solid organ transplantation. Curr Neurol Neurosci Rep 2015;15(7):38.
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52. Pless M, Zivkovic SA. Neurologic complications of transplantation. Neurologist 2002;8(2):107–20. 53. Singh N, Husain S. Infections of the central nervous system in transplant recipients. Transpl Infect Dis 2000;2(3):101–11. 54. Potluri K, Holt D, Hou S. Neurologic complications in renal transplantation. Handb Clin Neurol 2014;121:1245–55. 55. Tan CS, Koralnik IJ. Progressive multifocal leukoencephalopathy and other disorders caused by JC virus: clinical features and pathogenesis. Lancet Neurol 2010; 9(4):425–37. 56. Baddley JW, Salzman D, Pappas PG. Fungal brain abscess in transplant recipients: epidemiologic, microbiologic, and clinical features. Clin Transplant 2002; 16(6):419–24. 57. Hotson JR, Pedley TA. The neurological complications of cardiac transplantation. Brain 1976;99(4):673–94. 58. Fukazawa K, Nishida S, Aguina L, et al. Central pontine myelinolysis (CPM) associated with tacrolimus (FK506) after liver transplantation. Ann Transplant 2011; 16(3):139–42. 59. Fryer JP, Fortier MV, Metrakos P, et al. Central pontine myelinolysis and cyclosporine neurotoxicity following liver transplantation. Transplantation 1996;61(4): 658–61. 60. Morard I, Gasche Y, Kneteman M, et al. Identifying risk factors for central pontine and extrapontine myelinolysis after liver transplantation: a case-control study. Neurocrit Care 2014;20(2):287–95. 61. Crivellin C, Cagnin A, Manara R, et al. Risk factors for central pontine and extrapontine myelinolysis after liver transplantation: a single-center study. Transplantation 2015;99(6):1257–64. 62. Yu J, Zheng SS, Liang TB, et al. Possible causes of central pontine myelinolysis after liver transplantation. World J Gastroenterol 2004;10(17):2540–3. 63. Cascales Campos P, Ramirez P, Gonzalez R, et al. Central pontine and extrapontine myelinolysis: a rare and fatal complication after liver transplantation. Transplant Proc 2011;43(6):2237–8. 64. van de Beek D, Kremers W, Daly RC, et al. Effect of neurologic complications on outcome after heart transplant. Arch Neurol 2008;65(2):226–31. 65. Perez-Miralles F, Sanchez-Manso JC, Almenar-Bonet L, et al. Incidence of and risk factors for neurologic complications after heart transplantation. Transplant Proc 2005;37(9):4067–70. 66. Zierer A, Melby SJ, Voeller RK, et al. Significance of neurologic complications in the modern era of cardiac transplantation. Ann Thorac Surg 2007;83(5):1684–90. 67. Cemilla´n CA, Alonso-Pulpon L, Burgos-Lazaro R, et al. Neurological complications in a series of 205 orthotopic heart transplant patients. Rev Neurol 2004; 38(10):906–12 [in Spanish]. 68. Guillon B, Wiertlewski S, Trochu JN, et al. Late cerebrovascular complications of cardiac transplantation. Rev Neurol (Paris) 2000;156(3):264–9 [in French]. 69. Acampa M, Lazzerini PE, Guideri F, et al. Ischemic stroke after heart transplantation. J Stroke 2016;18(2):157–68. 70. Belvis R, Marti-Fabregas J, Cocho D, et al. Cerebrovascular disease as a complication of cardiac transplantation. Cerebrovasc Dis 2005;19(4):267–71. 71. Wijdicks EF, Campeau N, Sundt T. Reversible unilateral brain edema presenting with major neurologic deficit after valve repair. Ann Thorac Surg 2008;86(2): 634–7.
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72. Christie JD, Edwards LB, Kucheryavaya AY, et al. The registry of the International Society for Heart and Lung Transplantation: twenty-eighth adult lung and heartlung transplant report–2011. J Heart Lung Transplant 2011;30(10):1104–22. 73. Mateen FJ, Dierkhising RA, Rabinstein AA, et al. Neurological complications following adult lung transplantation. Am J Transplant 2010;10(4):908–14. 74. Shigemura N, Sclabassi RJ, Bhama JK, et al. Early major neurologic complications after lung transplantation: incidence, risk factors, and outcome. Transplantation 2013;95(6):866–71. 75. Liao D, Higgins M, Bryan NR, et al. Lower pulmonary function and cerebral subclinical abnormalities detected by MRI: the atherosclerosis risk in communities study. Chest 1999;116(1):150–6. 76. Pierson DJ. Pathophysiology and clinical effects of chronic hypoxia. Respir Care 2000;45(1):39–51 [discussion: 51–3]. 77. Ghaus N, Bohlega S, Rezeig M. Neurological complications in liver transplantation. J Neurol 2001;248(12):1042–8. 78. Lewis MB, Howdle PD. Neurologic complications of liver transplantation in adults. Neurology 2003;61(9):1174–8. 79. Saner FH, Sotiropoulos GC, Gu Y, et al. Severe neurological events following liver transplantation. Arch Med Res 2007;38(1):75–9. 80. Kim JM, Jung KH, Lee ST, et al. Central nervous system complications after liver transplantation. J Clin Neurosci 2015;22(8):1355–9. 81. Derle E, Kibaroglu S, Ocal R, et al. Seizure as a neurologic complication after liver transplant. Exp Clin Transplant 2015;13(Suppl 1):323–6. 82. Bernhardt M, Pflugrad H, Goldbecker A, et al. Central nervous system complications after liver transplantation: common but mostly transient phenomena. Liver Transpl 2015;21(2):224–32. 83. Pujol A, Graus F, Rimola A, et al. Predictive factors of in-hospital CNS complications following liver transplantation. Neurology 1994;44(7):1226–30. 84. Verhelst X, Vanhooren G, Vanopdenbosch L, et al. Progressive multifocal leukoencephalopathy in liver transplant recipients: a case report and review of the literature. Transpl Int 2011;24(4):e30–4. 85. Ponticelli C, Campise MR. Neurological complications in kidney transplant recipients. J Nephrol 2005;18(5):521–8. 86. Kiok MC. Neurologic complications of pancreas transplants. Neurol Clin 1988; 6(2):367–76. 87. Jacewicz M, Marino CR. Neurologic complications of pancreas and small bowel transplantation. Handb Clin Neurol 2014;121:1277–93.
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DO, PhD
a
, Lauren Ng,
MD, MPH
b,
*
KEYWORDS Neurologic complications Solid organ transplantation Seizures Cerebrovascular events Opportunistic infections Encephalopathy Drug toxicity KEY POINTS Among patients receiving solid organ transplants, approximately one-third will develop neurologic symptoms. Most of these neurologic symptoms will occur within 30 days of their transplantation. These neurologic symptoms include neurotoxicity of immunosuppressive agents, seizures, encephalopathy, cerebrovascular events, opportunistic infections, posttransplant lymphoproliferative disorder, and central pontine myelinosis. Some neurologic complications are seen more frequently in specific organ transplant recipients.
Among patients receiving solid organ transplants, approximately one-third will develop neurologic symptoms. Most of these neurologic symptoms will occur within 30 days of their transplantation.1 The most common neurologic complications are specific to the type of organ transplanted. For example, ischemic stroke is seen frequently in patients with heart and kidney transplant compared with other solid organ transplant recipients.2 Lung and pancreas transplant recipients tend to have a higher occurrence of hypoxic-ischemic encephalopathy, whereas liver recipients have higher occurrence of central pontine myelinolysis (CPM), and intestinal transplant patients have higher occurrence of Wernicke encephalopathy.3 The most common neurologic complications seen after solid organ transplantation are discussed in the following article and include neurotoxicity of immunosuppressive agents, seizures, encephalopathy, cerebrovascular events, opportunistic infections, and CPM.
Disclosure Statement: The authors have nothing to disclose. a Neuroscience Intensive Care Unit, University of Florida Health, Jacksonville, FL 32209, USA; b Departments of Critical Care Medicine, Neurology and Neurosurgery, Mayo Clinic, 4500 San Pablo Road, Jacksonville, FL 32224, USA * Corresponding author. E-mail address: [email protected] Neurol Clin 35 (2017) 809–823 http://dx.doi.org/10.1016/j.ncl.2017.06.013 0733-8619/17/ª 2017 Elsevier Inc. All rights reserved.
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NEUROTOXICITY OF IMMUNOSUPPRESSIVE AGENTS
Immunosuppressive agents are classified into induction or maintenance agents. Induction medications are administered to deplete the recipient’s reactive lymphocytes in order to mitigate acute rejection. The most common maintenance medications include corticosteroids, mycophenolate mofetil (MMF), calcineurin inhibitors, and noncalcineurin inhibitors. Corticosteroids produce various immunomodulating effects, such as inhibiting expression of proinflammatory proteins.4 Neurologic complications of corticosteroids often involve neurocognitive symptoms, such as delirium, insomnia, depression, and difficulty concentrating. MMF decreases lymphocyte proliferation because of decreasing de novo guanosine synthesis.5 MMF does not have significant neurologic side effects, but can cause headaches. Cyclosporine and tacrolimus are both calcineurin inhibitors. Calcineurin is a phosphatase that regulates various cytokines, such as interleukin-2 (IL-2) and transforming growth factor b. Inhibition of calcineurin by cyclosporine and tacrolimus ultimately decreases activation of T lymphocytes. As a neuronal phosphatase, calcineurin plays a role in the regulation of proteins associated with synaptic transmission, synaptic plasticity, and ultimately, learning and memory.6 Calcineurin is expressed in multiple areas of the central nervous system (CNS), such as cerebral cortex, cerebellum, hippocampus, striatum, and substantia nigra.7 The main manifestations of neurotoxicity from calcineurin inhibitors are posterior reversible encephalopathy syndrome (PRES), encephalopathy, akinetic mutism, and seizures. Risk factors for neurotoxicity include hypocholesterolemia, hypertension, hypomagnesemia, uremia, concomitant highdose steroids, and beta-lactam antibiotics.8,9 PRES can present with encephalopathy, seizure, headache, visual disturbances, focal neurologic deficits, and status epilepticus.10 Radiographically, the typical findings of PRES on MRI are hyperintensities on T2 or fluid attenuated inversion recovery sequences in the occipital and parietal regions. It is theorized that the posterior brain regions are susceptible to vasogenic edema associated with PRES because of the relative lack of sympathetic innervations in the posterior fossa. These areas of hyperintensity are often bilateral, but asymmetrical.11 However, in a study of various transplant patients receiving calcineurin inhibitors, approximately two-thirds of PRES cases involved the frontal region on radiographic imaging.12 That study also demonstrated that PRES does not correlate with supratherapeutic serum levels of calcineurin inhibitors and is often associated with levels in the therapeutic range. The proposed pathophysiology of PRES would involve damage and alteration of the endothelium, breakdown of the blood-brain barrier, and vasoconstriction. Endothelin-1 is a potent vasoconstrictor in addition to modulating leukocyte adhesion to endothelial cells. Cyclosporine has been associated with increases in blood pressure as well as concurrent increase in serum levels of endothelin-1 in renal transplant patients.13 PRES may present in transplant patients taking a calcineurin inhibitor who have hypomagnesemia, even in the absence of hypertension.14 Encephalopathy often presents as an alteration in awareness, arousal, and confusion that is typically seen within the first 30 days after transplantation and is attributed to initiation and supratherapeutic serum levels of calcineurin inhibitors.3,15 In the absence of radiologic evidence of PRES, other causes of encephalopathy must be evaluated, such as organ failure/rejection, cerebrovascular events (infarction or hemorrhage), hypoxic/ischemic injury, infections of the CNS, CPM, Wernicke encephalopathy, and nonconvulsive seizures/nonconvulsive status epilepticus.3
Complications of Solid Organ Transplantation
Akinetic mutism is diagnosed when the patient is unable to voluntarily generate speech or motor movements in the setting of retained awareness. Akinetic mutism can be seen with calcineurin inhibitors, in particular with tacrolimus.16,17 Holding the calcineurin inhibitor tends to resolve the symptoms. Seizures due to calcineurin inhibitors often present generalized and can be preceded by behavioral changes. Serum levels of calcineurin inhibitors are often within the therapeutic range.18 Monitoring with electroencephalography (EEG) is necessary to exclude nonconvulsive seizures or nonconvulsive status epilepticus after clinical seizure activity has ceased. Peripheral neurotoxicity such as axonal or demyelinating neuropathy is typically seen weeks to months after starting a calcineurin inhibitor. A demyelinating polyneuropathy resembling chronic inflammatory demyelinating polyneuropathy has been associated with tacrolimus, with subsequent improvement of symptoms after discontinuation of tacrolimus19 or after treatment with plasmapheresis or intravenous immunoglobulin.20 The noncalcineurin inhibitors sirolimus and everolimus inhibit the mammalian target of rapamycin (mTOR). Inhibiting mTOR effectively blocks IL-2 signaling via CD25 on activated T cells, thereby decreasing T-cell signaling and proliferation. Sirolimus and everolimus do not inhibit calcineurin and therefore do not have the same neurologic complications as cyclosporine and tacrolimus.21 Neurologic complications of sirolimus and everolimus are tremor, confusion, paresthesia, and hypoesthesia.22 Table 1 summarizes the neurologic complications associated with immunosuppressive medications. Several biological agents are also used as part of induction regimens. The monoclonal antibodies against IL-2 receptor a basiliximab and daclizumab are both approved by the US Food and Drug Administration for induction after renal transplantation. Muromonab-CD3 (Orthoklone OKT3) blocks T-cell activation by binding to the CD3 epsilon component.23 Antithymocyte globulin consists of polyclonal antithymocyte antibodies that deplete T cells as well as some B cells, dendritic cells, and natural killer cells.24 The most common neurologic side effects of these biological agents are aseptic meningitis, encephalopathy, headaches, and seizures.22 SEIZURES AFTER ORGAN TRANSPLANTATION
Seizures can be divided into generalized and focal seizures (with and without alterations in awareness). In organ transplant patients with no prior history of seizures,
Table 1 Neurologic complications associated with immunosuppressive medications Medication
Neurologic Complications
Monoclonal antibodies
Aseptic meningitis, encephalopathy, headache, seizures
Steroids
Delirium, insomnia, depression, difficulty concentrating, tremor, myopathy
MMF
Headache, psychiatric
Calcineurin inhibitors Tacrolimus Cyclosporine
PRES, encephalopathy, seizures, akinetic mutism, peripheral neurotoxicity
Noncalcineurin inhibitors Sirolimus Everolimus
Tremor, confusion, paresthesia, hypoesthesia, headache
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2% to 24% of these recipients will have a seizure after transplantation.2 Most seizures after transplantation are due to drug toxicity and present clinically as generalized seizures.25 Generalized seizures can also be due to metabolic derangements, most notably hyponatremia, hypomagnesemia, hypoglycemia, and hyperammonemia. Focal seizures are often due to focal structural abnormalities such as intracranial hemorrhage, abscess (Aspergillus and Nocardia), meningitis (Listeria and Cryptococcus), encephalitis, malignancy such as posttransplantation lymphoproliferative disorder (PTLD), and PRES. Cerebrospinal fluid (CSF) analysis should be conducted if there are signs of infection associated with seizures. If no provoking factors can be identified and corrected, then seizures should be treated to established algorithms. First-line treatment is a benzodiazepine (most often intravenous lorazepam with maximum dose of 0.1 mg/kg). Brain imaging (MRI being preferable) and EEG monitoring should also be done to evaluate for structural causes and to monitor for nonconvulsive seizures/nonconvulsive status epilepticus in the poorly responsive or encephalopathic patient. If seizures are recurrent, an intracranial structural abnormality is identified, or if the EEG demonstrates potentially epileptogenic abnormalities, then an antiepileptic drug (AED) should be started. AED therapy should be tailored to the patient’s organ function associated with that particular medication’s metabolism. Phenytoin, valproic acid, phenobarbital, and carbamazepine are AED medications that undergo hepatic metabolism and affect the metabolism of other medications. Given the adverse effects of these older AEDs, levetiracetam has become the drug of choice for posttransplant seizures.26 Tremors and myoclonus can be mistaken for seizures and are often due to metabolic derangements and medication side effects, such as propofol.27 ENCEPHALOPATHY
Encephalopathy can present with symptoms of altered mental status, such as confusion, changes in alertness and awareness, delirium, headache, changes in vision, hallucinations, tremor, chorea, or seizures. Encephalopathy usually occurs within the first 30 days after transplantation and can be attributed to medication toxicity (especially calcineurin inhibitors), metabolic derangements (hypoglycemia, hyponatremia or hypernatremia, hyperammonemia, hypercalcemia, or hypermagnesemia), infections of the CNS or systemic infections, PRES, and stroke.2 Among the metabolic derangements, hyperammonemia is frequently associated with hepatic transplantation1 and very rarely associated with lung transplantation.28–32 Hyperammonemia can cause encephalopathy because of various mechanisms such as cerebral edema from the accumulation of glutamine from glutamate in astrocytes,33 changes to the blood-brain barrier,34 and alteration of neuronal excitability because of interactions of ammonium ion with potassium and NMDA channels,35,36 which could also lead to seizures. In the lung transplant population, hyperammonemia often leads to coma, seizures, and death with a mortality of 67% to 75%.30,37 The threshold for obtaining an EEG in encephalopathic patients after organ transplantation should be very low in order to evaluate for possible nonconvulsive seizures or nonconvulsive status epilepticus.38 Treatment of hyperammonemia involves varying combinations of protein restriction, bowel decontamination, amino acids, dialysis, and nitrogen scavengers. Pharmaceutical treatment of hyperammonemia include lactulose, rifaximin, metronidazole, levocarnitine, argninine, sodium phenylacetate, sodium benzoate, and zinc, which is a cofactor for various enzymes in the urea cycle (Table 2).30,36,37,39–41 In addition, if ureaplasma infection is suspected as an inciting factor for hyperammonemia, fluoroquinolones and macrolides are recommended.29
Complications of Solid Organ Transplantation
Table 2 Treatment modalities for hyperammonemia Nondrug therapy
Protein restriction Dialysis, CVVH or IHD
Bowel decontamination
Lactulose Rifaximin Metronidazole
Amino acids
Levocarnitine Arginine
Nitrogen scavengers
Sodium phenylacetate Sodium benzoate
Enzyme cofactor
Zinc
Ureaplasma treatment
Fluoroquinolones Macrolides
Abbreviations: CVVH, continuous veno-venous hemofiltration; IHD, hemodialysis.
CEREBROVASCULAR EVENTS
Cerebrovascular events occur most commonly in the heart and kidney transplant population because of concomitant risk factors of hypertension, diabetes, and hyperlipidemia.42 In addition, age, previous stroke, arrhythmias, corticosteroid use, and hypercoagulable states increase the risk of stroke after heart or renal transplant.42 The incidence of stroke after heart transplant is 2% to 10%, 5% to 10% after kidney transplant, 2% to 3% after lung transplant, and 0% to 3% after liver transplant.9 Twenty percent of cerebrovascular events in heart transplant recipients occur in the first 2 weeks after transplant, and 60% of the events are ischemic strokes, 28% are transient ischemic attacks, and 12% are intracerebral hemorrhages (ICHs).43 Perioperative stroke after heart transplant is associated with a higher 1-year mortality compared with postoperative delirium, encephalopathy, peripheral neuropathy and myopathy, and seizures.44 In addition, ICH can also occur after solid organ transplantation, mainly liver and kidney transplant, with an incidence of 1% to 7% and 0.5% to 2%, respectively.9 Polycystic kidney disease in renal transplant patients has been associated with a 10-fold higher risk of ICH because of the presence of berry aneurysms in the anterior circulation.45,46 Other risk factors include poorly controlled hypertension, diabetes, and left ventricular hypertrophy.46,47 Mortality associated with ICH in renal transplant can be as high as 48%.47 With regards to liver transplant, in one review of 22 autopsies, 23.6% were noted to have ICH, and these were likely related to severe coagulopathy associated with severe hepatic failure and/or infectious causes, such as aspergillus and bacterial endocarditis.48 Overall, cerebrovascular events after transplant can lead to significant morbidity and mortality. CENTRAL NERVOUS SYSTEM INFECTIONS
CNS infections are frequent and can increase mortality significantly after solid organ transplant with 44% to 77% of CNS infections leading to death.8 In addition, CNS fungal infections have a mortality greater than 90%.49 However, because of improvements in immunosuppressive therapy and routine surveillance, the prevalence of these infections has dropped to 1% to 2% from 7%.44,50 Unfortunately, because of an impaired inflammatory response because of immunosuppression, the clinical manifestations of CNS infections can be blunted, and patients may only present with fever
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and headache.49 Therefore, it is important to be mindful of CNS infections in the setting of fever, headache, and altered mental status even in the absence of other manifestations. CNS infections can be stratified by time course after transplantation and then further into bacterial, fungal, viral, and protozoal (Tables 3 and 4). In the first month after transplant, CNS infections are rare; however, when they do occur, they are usually related to donor-transmitted infections, nosocomial pathogens, or infections already present before transplantation.8,51 The second to sixth month posttransplant period is when patients are at the greatest risk for infection, predominately viral and opportunistic pathogens.52 Varicella zoster (VZV), Epstein-Barr (EBV), and cytomegalovirus (CMV) are the main viral pathogens, whereas herpes simplex virus 1 and 2 (HSV) and human herpes virus 6 (HHV-6) are rarely encountered.8,51,52 Opportunistic infections can be caused by nocardia, aspergillus, toxoplasma, listeria, and Cryptococcus, and out of these, aspergillus, listeria, and Cryptococcus account for 80% of CNS infections seen in this population.8 After 6 months, infections are stratified into 1 of 3 categories: reactivation of previous infections, opportunistic infections secondary to chronic high immunosuppression, and community-acquired infections, also seen in nonimmunocompromised patients.8,51,52 Bacterial Infections
Opportunistic bacterial CNS infections are rare and mainly due to nocardia, listeria, and mycobacterium. Systemic nocardia affects 0.7% to 6% of solid organ transplant recipients; CNS is the most frequent secondary site of infection and is involved in onethird of patients with systemic nocardiosis.9,51 The primary entry point for nocardia is pulmonary, and 18% to 40% spread hematogeneously.53 Historically, heart transplant recipients had the highest risk of nocardiosis, which decreased with the use of trimethoprim-sulfamethoxaxole.53 Listeria can be caused by unpasteurized dairy, leading to meningitis and rhomboencephalitis with an associated mortality of 50%, especially if diagnosis is delayed.9,51 Mycobacterium tuberculosis is an extremely rare cause of basilar meningitis and abscess or tuberculoma in the transplant population with an incidence of 0.3% to 1% in liver transplant recipients and 2% to 3% in renal transplant recipients.9,51 Viral Infections
As mentioned above, viral CNS infections are seen in months 1 to 6 after transplant and comprise EBV, CMV, VZV, HSV, HHV-6, and JC virus. Most of these viruses will cause meningitis or encephalitis except EBV, which rarely causes encephalitis
Table 3 Common central nervous system infections by time course posttransplant Time Course
Infections
First 30 d
Pretransplant colonization Nosocomial infections (Methicillin-resistant Staphylococcus aureus, candida, Aspergillus) Donor-derived transmission
30 d to 6 mo
Viral infections (HSV, EBV, CMV) Opportunistic infections (Nocardia, Toxoplasma, Listeria)
>6 mo
Opportunistic infections (Cryptococcus, listeria, Nocardia, Aspergillus) Community-acquired infections Reactivation of previous infections
Complications of Solid Organ Transplantation
Table 4 Common central nervous system infections by pathogen Type
Organism
Clinical Presentation
Treatment
Bacterial
Nocardia
Meningitis, cerebritis, mass lesion Rhomboencephalitis, meningitis Basilar meningitis, tuberculoma
Trimethoprim-sulfamethaxole
Shingles, GuillainBarre syndrome Encephalitis Encephalitis, GuillainBarre syndrome Limbic encephalitis Encephalitis PML
Acyclovir, VZV immunoglobulin
Listeria Mycobacterium Viral
VZV EBV CMV HHV-6 HSV-1/HSV-2 JC virus
Fungal
Aspergillus
Brain abscess, cerebral hemorrhage Cryptococcus Meningitis, mass lesion, increased intracranial pressure Mucormycosis Rhinocerebral infection Candida Meningitis, abscess Coccidiomycosis Basilar meningitis Histoplasma Meningitis
Protozoal Toxoplasmosis
Space-occupying lesion
Ampicillin gentamicin Rifampin 1 isoniazid 1 pyrazinamide 1 ethambutol 1 pyridoxine
Acyclovir, ganciclovir Ganciclovir, foscarnet, CMV immunoglobulin Ganciclovir, foscarnet Acyclovir None Voriconazole or amphotericin 1 flucytosine Amphotericin flucytosine
Amphotericin Amphotericin fluconazole Amphotericin fluconazole Amphotericin itraconazole Pyrimethamine 1 sulfadiazine 1 folinic acid
Data from Conti DJ, Rubin RH. Infection of the central nervous system in organ transplant recipients. Neurol Clin 1988;6(2):241–60; and Pless M, Zivkovic SA. Neurologic complications of transplantation. Neurologist 2002;8(2):107–20.
but is associated with PTLD.49,51 The manifestations of PTLD resemble primary CNS lymphoma, with tumors arising deep in the brain in perivascular spaces and 25% of patients experiencing spread to the leptomeninges.8 In PTLD, the B-cell proliferation contains EBV DNA and expresses EBV gene products, and it is thought to start from an EBV infection or reactivation of a latent infection.8 EBV will infect the B lymphocytes leading to proliferation, which goes unchecked because of abnormal cellular and humoral immune mechanisms.8 In turn, this leads to the formation of a malignant clone, which then proliferates, producing a lymphoma. Treatment involves lowering immunosuppression, antiviral therapy, and chemotherapy and radiation.8 Despite treatment, survival is only 31% in patients who develop PTLD.8 JC virus also does not cause meningitis or encephalitis but instead leads to progressive multifocal leukoencephalopathy (PML), a demyelinating disorder that occurs late in the posttransplant course.53 Clinical signs include personality changes, seizures, headaches, aphasia, gait disturbances, and visual disturbances, with a classic pattern of subcortical white matter lesions with no contrast enhancement or edema.51,53 Unfortunately, PML has a very poor prognosis and typically becomes fatal within 4 to 6 months despite lowering immunosuppression.53,54 No medical therapy has demonstrated clinical benefit in treating PML.55 HHV-6 is increasingly being recognized as a cause for encephalitis in the transplant population and is the most neuroinvasive of the herpesviruses.51,53 Median time of
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onset is about 45 days and manifests as altered mental status, seizures, headaches, and speech disturbance.51,53 Amnesia may also be present because of its predilection for the hippocampus and limbic system.51,53 Ganciclovir and Foscarnet are treatment options, but mortality is still reported to be 58%.53 Fungal Infections
Cryptococcus is the most common cause of CNS meningitis in the posttransplant population, with the highest risk after heart and intestinal transplant leading to mortalities as high as 31% to 66%.51,53 It can lead to elevated intracranial pressure in the absence of a mass lesion or hydrocephalus because of basilar arachnoiditis, blocking the passage of CSF, and patients often need CSF diversion through serial lumbar punctures, external ventricular drains, lumbar drains, and even ventriculoperitoneal shunts in addition to treatment with amphotericin B and flucytosine.51,53 Aspergillus causes abscess formation in the frontoparietal lobe, basal ganglia, cerebellum, and brainstem with radiographic findings of single or multiple nonenhancing, low-density lesions.56 Mortality is high at 65% to 100% despite treatment with voriconazole or amphotericin B.54 It occurs on average 24 days after transplant in all solid organ transplant recipients and, similar to nocardia, is usually spread from the lung.57 Protozoal Infections
Toxoplasmosis has the highest incidence in heart transplant patients because cardiac tissue is a site of latency for the cysts.51,53 Clinical signs include altered mental status, seizures, and focal neurologic findings, and median time to presentation is on average 3 months after transplant.51,53 Typical radiographic findings are multiple, ring-enhancing lesions in the periventricular space. Toxoplasmosis can also involve heart and lungs and is associated with high mortality (65%–92%) if it is disseminated.13 Prevalence has decreased because of the use of trimethoprimsulfamethoxazole for prophylaxis, whereas treatment involves the use of pyrimethamine and sulfadiazine.51,53 CENTRAL PONTINE MYELINOLYSIS
CPM is a serious neurologic complication that characteristically affects liver transplant recipients in the first 1 to 2 weeks after transplant. Incidence is 17% after liver transplant with mortality greater than 50%.58,59 CPM was first described in alcoholic patients after rapid correction of hyponatremia; however, there is no direct link between hyponatremia and the development of CPM in liver transplant patients, and its cause and pathophysiology in these cases remain unknown. Two proposed mechanisms for CPM after liver transplant are a chronic hypoosmolar state leading to oligodendroglial dehydration, resulting in separation of axon from myelin with myelinosis and necrosis, and rapid restoration and maintenance of an intracellular osmolar state provoking high-energy demand with inadequate energy supply and leading to oligodenroglial apoptosis.58 A retrospective study of 1378 liver transplant patients found that severe and very severe hyponatremia, transfusion of greater than 4 platelet units, transfusion of greater than 12 fresh frozen plasma units, hemorrhagic complications, and increasing the sodium more than 12 mmol in the postoperative course were all risk factors for developing CPM.60 In another study of 997 adult liver transplant patients, risk factors for pontine or extrapontine myelinolysis included higher perioperative sodium variation, higher perioperative maximum serum sodium peak, and higher mean perioperative osmolality.61 A retrospective study in China also showed an association between
Complications of Solid Organ Transplantation
CPM and hyponatremia, rapid increase of serum sodium perioperatively, plasma osmolality increase postoperatively, duration of operation, and high cyclosporine levels.62 Other risk factors include electrolyte imbalances, diabetes mellitus, malnutrition, chronic hyponatremia, and cyclosporine use.58,59 Clinical signs and symptoms include progressive confusion and altered mental status, dysarthria, dysphagia, pseudobulbar palsy, ophthalmoplegia, and quadriplegia; tremor, catatonia, ataxia, mutism, and myoclonus can also be seen with extrapontine involvement.63 MRI is the imaging modality of choice and demonstrates T2 hyperintensities in the pons and often in various extrapontine locations. There is no treatment available. COMMON NEUROLOGIC COMPLICATIONS AFTER HEART TRANSPLANTATION
Neurologic complications are the most common adverse events after heart transplantation with rates of occurrence of 50% to 70%, and up to 20% mortality in these patients.44,64,65 Stroke is the most common neurologic complication associated with heart transplant, with a 3% to 10% incidence in these patients.66 Most strokes are due to ischemic infarctions, but hemorrhagic strokes can also occur in 0.6% to 2.5% of heart transplant recipients.67,68 Cardiovascular risk factors for ischemic stroke are found in many heart transplant patients, including hypertension, hyperlipidemia, atrial fibrillation, and diabetes mellitus. Technical and surgical complications of heart transplantation, such as preoperative use of intraaortic balloon pump or left ventricular assist device, prolonged cardiopulmonary bypass, intraoperative hypotension, or perioperative hemodynamic instability, can all contribute to increase the risk of cerebral infarction.69 In a retrospective review of 313 heart transplant patients, perioperative stroke occurred in 5% of patients and was associated with greater than 1-year mortality.64 Hemorrhagic stroke and vasogenic edema, possibly leading to PRES, can be associated with a hyperperfusion state during cardiopulmonary bypass.70 Unilateral vasogenic edema can be seen due to cardiopulmonary cannulation producing a unilateral hyperperfusion syndrome.71 Strict postoperative blood pressure control is essential in these cases, with possible improvement of symptoms over days to weeks. COMMON NEUROLOGIC COMPLICATIONS AFTER LUNG TRANSPLANTATION
Lung transplant patients have the highest mortality of any solid organ transplant recipients with 3-month survival rate of 88%, 5-year survival rate of 53%, and 10-year survival of 30%.72 In a 20-year retrospective review of lung transplants at a single center, 92% of recipients had neurologic complications within 10 years of transplantation.73 Severe encephalopathy was the most common neurologic complication (30% of lung recipients), followed by cerebrovascular events (12.6%). A separate retrospective analysis of 759 lung transplant patients demonstrated early (within 2 weeks of lung transplant) neurologic complications in 9.2% of patients. Forty-one percent of these patients had stroke, followed by encephalopathy (37%) that was attributed to calcineurin inhibitor toxicity in more than half of the cases.74 Severe hyperammonemia was seen in 4 patients (6%) after lung transplant, and despite maximum medical treatment, 3 of the 4 patients died within 30 days from lung transplant. Five-year survival was lower in patients with neurologic complications (51.1%) compared with recipients without neurologic complications (62.1%). It is theorized that lung transplant recipients are susceptible to neurologic complications because of decreased brain “reserve” from chronic hypoxia.75,76 Chronic hypoxia would make these patients more susceptible to hemodynamic instability in the perioperative period, neurotoxicity
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due to calcineurin inhibitors, and proinflammatory molecules that are upregulated in the perioperative period.74 COMMON NEUROLOGIC COMPLICATIONS AFTER LIVER TRANSPLANTATION
The incidence of neurologic complications after liver transplantation varies across studies depending on their definition and the duration of follow-up, ranging from 4 to 75.2,77–79 Most neurologic complications after liver transplant are categorized as encephalopathy and occur most often within 30 days of transplantation. In a retrospective study of 791 liver transplant patients, neurologic complications occurred in 8.2% over a 10-year observation period with nearly half (46.2%) of these neurologic complications occurring within 30 days of transplant.80 The most common neurologic complication over those 10 years of follow-up was cerebrovascular, including ischemic infarction (63%) and ICH (37%). Of the ischemic events, some were noted to span more than one vascular territory, suggesting a venous infarction, which was diagnosed in 5 of 17 ischemic stroke patients. During the initial 30 days after transplantation, metabolic encephalopathy was the most common neurologic complication; causes included calcineurin inhibitors, hyponatremia, and CPM. Seizures are also common after liver transplantation, with an incidence of 16% to 45%,79,81 and therefore, EEG is essential to evaluate for nonconvulsive seizures/nonconvulsive status epilepticus in liver transplant patients with encephalopathy. A prospective study of 136 liver transplant patients at a single institution demonstrated that 32.8% of patients developed neurologic complications and that 27.6% of these patients were diagnosed with metabolic encephalopathy. Independent predictors of metabolic encephalopathy were acute or chronic liver failure, primary sclerosing cholangitis, and number of subsequent surgeries.82 In a prospective study of 84 patients, encephalopathy before liver transplantation was shown to be an independent risk factor for developing a neurologic complication after transplantation.83 Infections of the CNS after liver transplantation have an incidence of approximately 5% and are commonly due to Listeria monocytogenes, Aspergillus fumigates, Cryptococcus neoformans, HSV, and CMV.53 Furthermore, with prolonged immunosuppression, PML caused by the JC virus should be on the differential diagnosis of the liver transplant patient with rapid progressive neurologic decline. There have been 8 case reports of PML in liver transplant patients, with the reason for liver transplant due to hepatitis C virus–related liver cirrhosis.84 COMMON NEUROLOGIC COMPLICATIONS AFTER RENAL TRANSPLANT
Kidneys are the most commonly transplanted solid organ and also have the highest rate of neurologic complications, with reported rates of 10% to 21%.54 The most common neurologic complications after renal transplant are cerebrovascular events, with a prevalence of 8%.54 As mentioned above, this is due to advanced atherosclerosis from preexisting conditions, such as diabetes and hypertension, that often lead to end-stage renal disease (ESRD). Hyperlipidemia is also a risk factor for cerebrovascular events and is commonly found in ESRD. Mechanisms for hyperlipidemia include depressed activity of lipoprotein lipase in uremia combined with the high proportion of lipids in the diet to compensate for protein restriction.42 Renal transplant recipients are also thought to be hypercoagulable because of decreased fibrinolytic activity and overcorrection of platelet aggregation and thrombin generation associated with uremia, which occurs in the first 3 weeks after transplantation.42 Systemic lupus erythematosus and vasculopathies, such as polyarteritis nodosa, Fabry disease, and granulomatosis and polyarteritis, can also lead to cerebrovascular events in this
Complications of Solid Organ Transplantation
population.42 Cerebral hemorrhage is also seen in renal transplant patients because of risk factors of hypertension and polycystic kidney disease. Other common neurologic complications include infections, femoral neuropathy, and immunosuppressive drug toxicities. Infectious complications comprise the infections listed above.85 Femoral neuropathy affects 2% of renal transplant recipients because of compression of the femoral nerve during surgery.85 Tacrolimus and steroids are the most commonly used immunosuppressant drugs in renal transplantation.54 Thus, it is important to keep in mind the various neurotoxicities associated with these medications (see Table 1). COMMON NEUROLOGIC COMPLICATIONS AFTER PANCREAS TRANSPLANT
Pancreas transplantations are performed primarily for the patient with diabetes mellitus and are often done in conjunction with renal transplantation. Another indication for pancreatic transplantation is cystic fibrosis, in which a combined pancreas-lung transplant is done. In a small case series done at the University of Pittsburgh in 1988, 33% of the patients who underwent pancreatic transplantation developed global cerebral ischemia, followed by 13% who developed seizures.86 Other complications documented were cerebral infarction, spinal cord infarction, metabolic encephalopathy, and aseptic meningitis related to immunosuppression, herpes zoster, and compressive neuropathy.86 Most cerebrovascular and ischemic events are due to underlying severe diabetes mellitus with end-organ involvement and advanced atherosclerosis. Another major complication is tacrolimus neurotoxicity, which affects as many as 21% of pancreatic transplantation patients.87 Conversely, pancreatic transplant can actually improve peripheral and autonomic diabetic neuropathy particularly when done in conjunction with renal transplantation.87 SUMMARY
Neurologic complications cause significant morbidity and mortality in solid organ transplant patients. These complications include encephalopathy, seizures, drug toxicities, infections, and cerebrovascular events. Many of the infectious complications have devastating effects, and thus, any patient with fever or altered mental status or headache after transplant should undergo a thorough evaluation, including brain imaging and CSF analysis. REFERENCES
1. Shah M. Inpatient neurologic consultation in solid organ transplant patients. Semin Neurol 2015;35(6):699–707. 2. Senzolo M, Ferronato C, Burra P. Neurologic complications after solid organ transplantation. Transpl Int 2009;22(3):269–78. 3. Dhar R, Human T. Central nervous system complications after transplantation. Neurol Clin 2011;29(4):943–72. 4. Vacca A, Felli MP, Farina AR, et al. Glucocorticoid receptor-mediated suppression of the interleukin 2 gene expression through impairment of the cooperativity between nuclear factor of activated T cells and AP-1 enhancer elements. J Exp Med 1992;175(3):637–46. 5. Hartono C, Muthukumar T, Suthanthiran M. Immunosuppressive drug therapy. Cold Spring Harb Perspect Med 2013;3(9):a015487. 6. Baumgartel K, Mansuy IM. Neural functions of calcineurin in synaptic plasticity and memory. Learn Mem 2012;19(9):375–84.
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7. Asai A, Qiu J, Narita Y, et al. High level calcineurin activity predisposes neuronal cells to apoptosis. J Biol Chem 1999;274(48):34450–8. 8. Patchell RA. Neurological complications of organ transplantation. Ann Neurol 1994;36(5):688–703. 9. Pustavoitau A, Bhardwaj A, Stevens R. Neurological complications of transplantation. J Intensive Care Med 2011;26(4):209–22. 10. Fugate JE, Rabinstein AA. Posterior reversible encephalopathy syndrome: clinical and radiological manifestations, pathophysiology, and outstanding questions. Lancet Neurol 2015;14(9):914–25. 11. Bartynski WS, Boardman JF. Distinct imaging patterns and lesion distribution in posterior reversible encephalopathy syndrome. AJNR Am J Neuroradiol 2007; 28(7):1320–7. 12. Burnett MM, Hess CP, Roberts JP, et al. Presentation of reversible posterior leukoencephalopathy syndrome in patients on calcineurin inhibitors. Clin Neurol Neurosurg 2010;112(10):886–91. 13. Cauduro RL, Costa C, Lhulier F, et al. Endothelin-1 plasma levels and hypertension in cyclosporine-treated renal transplant patients. Clin Transplant 2005;19(4): 470–4. 14. Osorio JM, Bravo J, Perez A, et al. Magnesemia in renal transplant recipients: relation with immunosuppression and posttransplant diabetes. Transplant Proc 2010;42(8):2910–3. 15. Bronster DJ, Emre S, Boccagni P, et al. Central nervous system complications in liver transplant recipients–incidence, timing, and long-term follow-up. Clin Transplant 2000;14(1):1–7. 16. Sierra-Hidalgo F, Martinez-Salio A, Moreno-Garcia S, et al. Akinetic mutism induced by tacrolimus. Clin Neuropharmacol 2009;32(5):293–4. 17. Garrido SM, Chauncey TR. Neuroleptic malignant syndrome following autologous peripheral blood stem cell transplantation. Bone Marrow Transplant 1998;21(4): 427–8. 18. Wijdicks EF, Wiesner RH, Krom RA. Neurotoxicity in liver transplant recipients with cyclosporine immunosuppression. Neurology 1995;45(11):1962–4. 19. Labate A, Morelli M, Palamara G, et al. Tacrolimus-induced polyneuropathy after heart transplantation. Clin Neuropharmacol 2010;33(3):161–2. 20. Wilson JR, Conwit RA, Eidelman BH, et al. Sensorimotor neuropathy resembling CIDP in patients receiving FK506. Muscle Nerve 1994;17(5):528–32. 21. Rompianesi G, Montalti R, Cautero N, et al. Neurological complications after liver transplantation as a consequence of immunosuppression: univariate and multivariate analysis of risk factors. Transpl Int 2015;28(7):864–9. 22. Anghel D, Tanasescu R, Campeanu A, et al. Neurotoxicity of immunosuppressive therapies in organ transplantation. Maedica (Buchar) 2013;8(2):170–5. 23. Taylor AL, Watson CJ, Bradley JA. Immunosuppressive agents in solid organ transplantation: mechanisms of action and therapeutic efficacy. Crit Rev Oncol Hematol 2005;56(1):23–46. 24. Mueller T. Mechanisms of action of thymoglobulin. Transplantation 2007;84: S5–10. 25. Wijdicks EF, Plevak DJ, Wiesner RH, et al. Causes and outcome of seizures in liver transplant recipients. Neurology 1996;47(6):1523–5. 26. Shepard PW, St Louis EK. Seizure treatment in transplant patients. Curr Treat Options Neurol 2012;14(4):332–47. 27. Walder B, Tramer MR, Seeck M. Seizure-like phenomena and propofol: a systematic review. Neurology 2002;58(9):1327–32.
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28. Anwar S, Gupta D, Ashraf MA, et al. Symptomatic hyperammonemia after lung transplantation: lessons learnt. Hemodial Int 2014;18(1):185–91. 29. Bharat A, Cunningham SA, Scott Budinger GR, et al. Disseminated ureaplasma infection as a cause of fatal hyperammonemia in humans. Sci Transl Med 2015;7(284):284re3. 30. Chen C, Bain KB, Iuppa JA, et al. Hyperammonemia syndrome after lung transplantation: a single center experience. Transplantation 2016;100(3):678–84. 31. Hocker S, Rabinstein AA, Wijdicks EF. Pearls & oy-sters: status epilepticus from hyperammonemia after lung transplant. Neurology 2011;77(10):e54–6. 32. Lichtenstein GR, Kaiser LR, Tuchman M, et al. Fatal hyperammonemia following orthotopic lung transplantation. Gastroenterology 1997;112(1):236–40. 33. Gropman AL, Summar M, Leonard JV. Neurological implications of urea cycle disorders. J Inherit Metab Dis 2007;30(6):865–79. 34. Walker V. Ammonia toxicity and its prevention in inherited defects of the urea cycle. Diabetes Obes Metab 2009;11(9):823–35. 35. Braissant O, McLin VA, Cudalbu C. Ammonia toxicity to the brain. J Inherit Metab Dis 2013;36(4):595–612. 36. Tapper EB, Jiang ZG, Patwardhan VR. Refining the ammonia hypothesis: a physiology-driven approach to the treatment of hepatic encephalopathy. Mayo Clin Proc 2015;90(5):646–58. 37. Lichtenstein GR, Yang YX, Nunes FA, et al. Fatal hyperammonemia after orthotopic lung transplantation. Ann Intern Med 2000;132(4):283–7. 38. Hocker SE. Status epilepticus. Continuum (Minneap Minn) 2015;21(5 Neurocritical Care):1362–83. 39. Teperman LW. Impact of pretransplant hepatic encephalopathy on liver posttransplantation outcomes. Int J Hepatol 2013;2013:952828. 40. Berry GT, Bridges ND, Nathanson KL, et al. Successful use of alternate waste nitrogen agents and hemodialysis in a patient with hyperammonemic coma after heart-lung transplantation. Arch Neurol 1999;56(4):481–4. 41. Rueda JF, Caldwell C, Brennan DC. Successful treatment of hyperammonemia after lung transplantation. Ann Intern Med 1998;128(11):956–7. 42. Bruno A, Adams HP Jr. Neurologic problems in renal transplant recipients. Neurol Clin 1988;6(2):305–25. 43. Alejaldre A, Delgado-Mederos R, Santos MA, et al. Cerebrovascular complications after heart transplantation. Curr Cardiol Rev 2010;6(3):214–7. 44. Heroux A, Pamboukian SV. Neurologic aspects of heart transplantation. Handb Clin Neurol 2014;121:1229–36. 45. Zivkovic SA, Abdel-Hamid H. Neurologic manifestations of transplant complications. Neurol Clin 2010;28(1):235–51. 46. Wijdicks EF, Torres VE, Schievink WI, et al. Cerebral hemorrhage in recipients of renal transplantation. Mayo Clin Proc 1999;74(11):1111–2. 47. Mour G, Wu C. Neurologic complications after kidney transplantation. Semin Nephrol 2015;35(4):323–34. 48. Bronster DJ, Emre S, Mor E, et al. Neurologic complications of orthotopic liver transplantation. Mt Sinai J Med 1994;61(1):63–9. 49. Conti DJ, Rubin RH. Infection of the central nervous system in organ transplant recipients. Neurol Clin 1988;6(2):241–60. 50. Zivkovic SA. Neurologic aspects of multiple organ transplantation. Handb Clin Neurol 2014;121:1305–17. 51. Avila JD, Zivkovic S. The neurology of solid organ transplantation. Curr Neurol Neurosci Rep 2015;15(7):38.
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52. Pless M, Zivkovic SA. Neurologic complications of transplantation. Neurologist 2002;8(2):107–20. 53. Singh N, Husain S. Infections of the central nervous system in transplant recipients. Transpl Infect Dis 2000;2(3):101–11. 54. Potluri K, Holt D, Hou S. Neurologic complications in renal transplantation. Handb Clin Neurol 2014;121:1245–55. 55. Tan CS, Koralnik IJ. Progressive multifocal leukoencephalopathy and other disorders caused by JC virus: clinical features and pathogenesis. Lancet Neurol 2010; 9(4):425–37. 56. Baddley JW, Salzman D, Pappas PG. Fungal brain abscess in transplant recipients: epidemiologic, microbiologic, and clinical features. Clin Transplant 2002; 16(6):419–24. 57. Hotson JR, Pedley TA. The neurological complications of cardiac transplantation. Brain 1976;99(4):673–94. 58. Fukazawa K, Nishida S, Aguina L, et al. Central pontine myelinolysis (CPM) associated with tacrolimus (FK506) after liver transplantation. Ann Transplant 2011; 16(3):139–42. 59. Fryer JP, Fortier MV, Metrakos P, et al. Central pontine myelinolysis and cyclosporine neurotoxicity following liver transplantation. Transplantation 1996;61(4): 658–61. 60. Morard I, Gasche Y, Kneteman M, et al. Identifying risk factors for central pontine and extrapontine myelinolysis after liver transplantation: a case-control study. Neurocrit Care 2014;20(2):287–95. 61. Crivellin C, Cagnin A, Manara R, et al. Risk factors for central pontine and extrapontine myelinolysis after liver transplantation: a single-center study. Transplantation 2015;99(6):1257–64. 62. Yu J, Zheng SS, Liang TB, et al. Possible causes of central pontine myelinolysis after liver transplantation. World J Gastroenterol 2004;10(17):2540–3. 63. Cascales Campos P, Ramirez P, Gonzalez R, et al. Central pontine and extrapontine myelinolysis: a rare and fatal complication after liver transplantation. Transplant Proc 2011;43(6):2237–8. 64. van de Beek D, Kremers W, Daly RC, et al. Effect of neurologic complications on outcome after heart transplant. Arch Neurol 2008;65(2):226–31. 65. Perez-Miralles F, Sanchez-Manso JC, Almenar-Bonet L, et al. Incidence of and risk factors for neurologic complications after heart transplantation. Transplant Proc 2005;37(9):4067–70. 66. Zierer A, Melby SJ, Voeller RK, et al. Significance of neurologic complications in the modern era of cardiac transplantation. Ann Thorac Surg 2007;83(5):1684–90. 67. Cemilla´n CA, Alonso-Pulpon L, Burgos-Lazaro R, et al. Neurological complications in a series of 205 orthotopic heart transplant patients. Rev Neurol 2004; 38(10):906–12 [in Spanish]. 68. Guillon B, Wiertlewski S, Trochu JN, et al. Late cerebrovascular complications of cardiac transplantation. Rev Neurol (Paris) 2000;156(3):264–9 [in French]. 69. Acampa M, Lazzerini PE, Guideri F, et al. Ischemic stroke after heart transplantation. J Stroke 2016;18(2):157–68. 70. Belvis R, Marti-Fabregas J, Cocho D, et al. Cerebrovascular disease as a complication of cardiac transplantation. Cerebrovasc Dis 2005;19(4):267–71. 71. Wijdicks EF, Campeau N, Sundt T. Reversible unilateral brain edema presenting with major neurologic deficit after valve repair. Ann Thorac Surg 2008;86(2): 634–7.
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72. Christie JD, Edwards LB, Kucheryavaya AY, et al. The registry of the International Society for Heart and Lung Transplantation: twenty-eighth adult lung and heartlung transplant report–2011. J Heart Lung Transplant 2011;30(10):1104–22. 73. Mateen FJ, Dierkhising RA, Rabinstein AA, et al. Neurological complications following adult lung transplantation. Am J Transplant 2010;10(4):908–14. 74. Shigemura N, Sclabassi RJ, Bhama JK, et al. Early major neurologic complications after lung transplantation: incidence, risk factors, and outcome. Transplantation 2013;95(6):866–71. 75. Liao D, Higgins M, Bryan NR, et al. Lower pulmonary function and cerebral subclinical abnormalities detected by MRI: the atherosclerosis risk in communities study. Chest 1999;116(1):150–6. 76. Pierson DJ. Pathophysiology and clinical effects of chronic hypoxia. Respir Care 2000;45(1):39–51 [discussion: 51–3]. 77. Ghaus N, Bohlega S, Rezeig M. Neurological complications in liver transplantation. J Neurol 2001;248(12):1042–8. 78. Lewis MB, Howdle PD. Neurologic complications of liver transplantation in adults. Neurology 2003;61(9):1174–8. 79. Saner FH, Sotiropoulos GC, Gu Y, et al. Severe neurological events following liver transplantation. Arch Med Res 2007;38(1):75–9. 80. Kim JM, Jung KH, Lee ST, et al. Central nervous system complications after liver transplantation. J Clin Neurosci 2015;22(8):1355–9. 81. Derle E, Kibaroglu S, Ocal R, et al. Seizure as a neurologic complication after liver transplant. Exp Clin Transplant 2015;13(Suppl 1):323–6. 82. Bernhardt M, Pflugrad H, Goldbecker A, et al. Central nervous system complications after liver transplantation: common but mostly transient phenomena. Liver Transpl 2015;21(2):224–32. 83. Pujol A, Graus F, Rimola A, et al. Predictive factors of in-hospital CNS complications following liver transplantation. Neurology 1994;44(7):1226–30. 84. Verhelst X, Vanhooren G, Vanopdenbosch L, et al. Progressive multifocal leukoencephalopathy in liver transplant recipients: a case report and review of the literature. Transpl Int 2011;24(4):e30–4. 85. Ponticelli C, Campise MR. Neurological complications in kidney transplant recipients. J Nephrol 2005;18(5):521–8. 86. Kiok MC. Neurologic complications of pancreas transplants. Neurol Clin 1988; 6(2):367–76. 87. Jacewicz M, Marino CR. Neurologic complications of pancreas and small bowel transplantation. Handb Clin Neurol 2014;121:1277–93.
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