Neurologic Complications of Organ Transplantation

Eelco F. M. Wijdicks

INTRODUCTION

Organ transplantation has been associated with a distinct spectrum of neurologic complications. Complications can emerge during pretransplant preparation (e.g., hematopoietic stem cell transplantation and chemotherapy), perioperative support (e.g., cardiac transplantation with cardiopulmonary bypass), and postoperative management (e.g., newly introduced immunosuppression). Some neurologic complications, particularly peripheral nerve injury, are related to the surgical procedure and are less specific.

When large series are reported, neurologic complications from organ transplantation occur in approximately 5% to 10% of patients. Of course, the prevalence depends on the motivation of transplant teams to consult a neurologist and thus is a reflection of how relevant a neurologic complication is when seen in the whole of the clinical picture. Prospective incidence studies may not capture all the postoperative neurologic events if they are not carefully examined by neurologists. Moreover, over the years, there has been a continuous decline in neurologic complications in some types of organ transplantation (e.g., renal, liver).

Neurologic complications are major when they involve recurrent seizures, postoperative failure to awaken, immunosuppression neurotoxicity, or acute disabling neuromuscular disease. Familiarity with the administration and dosing of the main intravenous immunosuppressive drugs has reduced the risk of major neurotoxicity, and extreme cases with coma and seizures and neuroimaging showing diffuse white matter edema are now rarely seen.

This chapter does not attempt to fully discuss all neurologic complications described over the years but will concentrate on the most common considerations (Table 125.1).

TABLE 125.1 Neurologic Syndromes in Transplant Recipients and Causes

Failure to awaken or acute coma	Hypoxic-ischemic brain injury, brain edema, oversedation, acute graft failure, calcineurin neurotoxicity, intracranial hemorrhage, fulminant CNS infection
Seizures	Calcineurin neurotoxicity, intracranial hemorrhage, new mass (abscess, tumor), posterior reversible encephalopathy syndrome
Aphasia, dysarthria	Calcineurin neurotoxicity, ischemic stroke
Hemiparesis	Brachial plexopathy, ischemic or hemorrhagic stroke, brain tumor, brain abscess
Tremors	Calcineurin neurotoxicity
Myoclonus, asterixis	Acute liver, renal, or pulmonary disease; drug toxicity
CNS, central nervous system.

GENERAL CONSIDERATIONS

Generally speaking, and not surprisingly, a patient with more elaborate surgery has a higher risk of an early neurologic complication. For instance, liver transplantation carries a much higher risk of early neurologic complications than renal transplantation. Once the patient goes successfully through the first critical weeks, a later phase includes a proclivity for central nervous system (CNS) infections, and much later—although it may be only a few months—serious malignancies may appear. Dramatic is the appearance of posttransplant lymphoproliferative disease (PTLD) and likely explained from introducing genetic material of an Epstein-Barr virus (EBV)-seropositive donor into an EBV-seronegative recipient. It may involve the CNS.

The threshold for cerebral fluid examination should be low even if meningitis is not suspected. Because an infectious mass lesion may be present, a computed tomography (CT) scan may need to be performed to exclude such a lesion. An acutely febrile patient with an abnormal level of consciousness should prompt an aggressive search for a CNS infection. Immunosuppressed transplant recipients have a proclivity for infections with Listeria monocytogenes, Nocardia, or Aspergillus. Infections with Cryptococcus neoformans or Toxoplasma gondii are rarely seen within 6 months after transplantation. All of these infections present often with meningeal enhancement on a CT or magnetic resonance imaging scan, solitary or multiple abscesses, or ring lesions. None of them are specific and can only be documented by biopsy.

Neurologic complications may result in an increased risk of early demise. Most instructively—when reviewed in more detail—the majority of patients with a lung transplantation were found to have a neurologic manifestation or complication with a third seriously affecting quality of life or resulting in a fatal outcome. That leaves the question of whether neurologic complications are sufficiently recognized.

There are several other considerations. First, neurologic complications may be specific to the type of transplantation. Neurologic complications associated with bone marrow transplantation are quite different than those from organ transplants such as a kidney or liver. Second, seizures are often drug related and less commonly due to a permanent structural lesion. It is a difficult task to implicate certain drugs, but several drugs lower the seizure threshold (i.e., calcineurin inhibitors and antibiotics such as imipenem). Third, any structural lesion in the brain, whether it has the appearance of a cerebritis or ring enhancing, is most often due to an infectious cause and requires immediate treatment. Fourth, major sodium abnormalities and osmotic shifts can be seen after liver transplantation causing osmotic demyelination.

ENCEPHALOPATHY AND DELIRIUM

In actuality, there are particular syndromes that most often present to the neurologist. The most commonly encountered reason
for a consultation has to do with assessment of an “altered state of consciousness.” The appearance of a new encephalopathy may be due to rejection causing dysfunction of the graft or may have other causes.

Acute confusional state remains difficult to define in transplant recipients and can be considered if it lasts more than 2 to 3 consecutive days. Postoperative hyperactive delirium associated with hallucinations is common post transplantation, and some circumstances should be recognized. If patients are seen in the immediate postoperative period, both hyperactive and hypoactive delirium after liver transplantation occurs in about a third of the patients. This is more often in patients who had a pretransplant encephalopathy and is more often seen in alcoholic liver disease.

In evaluating patients with impaired consciousness, some guidance can be provided. All potential sedative drugs should be carefully scrutinized, and the time remaining to clearance should be calculated. Physicians should consider administration of flumazenil or naloxone to eliminate the remaining effects. Neurotoxicity of immunosuppressive drugs is frequently implicated, and it continues to be a concern to be dealt with. None of these drugs do cause other structural disease other than a leukoencephalopathy, which cannot be clinically or radiographically distinguished from posterior reversible encephalopathy syndrome (PRES) (see also Chapter 43).

DRUG TOXICITY

There are many drugs and medications that need to be considered in acute confusion. This includes the use of calcineurin inhibitors, opioid antagonists, β-adrenergic blockers, and high-dose corticosteroids. All of these drugs can be implicated. Other commonly used drugs, such as midazolam and propofol, may impact level of consciousness, particularly because they have different pharmacokinetics in transplant patients. Midazolam, for example, although relatively short acting in comparison with other sedative agents, has a prolonged activity if the liver graft is not functioning fully. It is also highly protein bound, and preexisting low protein levels may increase its sedative effects. Clearance of propofol is dependent on hepatic blood flow and cardiac output; and if both are disturbed, awakening from propofol may be markedly delayed, and the patient may not characteristically awaken as usually anticipated 10 to 15 minutes after discontinuation of infusion. Opioids may continue to linger after cardiac transplantation; typically, very large doses are used during the procedure.

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