Neurologic Complications of Transplantation and Immunosuppressive Agents

Encephalopathy

Altered mental status is one of the most common reasons for neurologic consultation in the post-transplantation period. The degree of encephalopathy can range from mild confusion to coma. A wide array of etiologies may be responsible including infection, metabolic disturbances, seizures, cerebrovascular disorders, and medication toxicity (discussed separately below). Postoperative hepatic or renal dysfunction may contribute to prolonged metabolism of sedative-hypnotic agents. Electrolyte abnormalities should be recognized as a potential etiology; in the case of hyponatremia, clinicians should be careful to ensure slow correction (<8 mmol/L in 24-hour period) in order to avoid osmotic demyelination syndromes.

Due to their prolonged illness course, decreased oral nutrition, and occasional caloric supplementation with total parenteral nutrition, transplant recipients are susceptible to the development of Wernicke’s encephalopathy from thiamine deficiency. In addition to encephalopathy, patients may also exhibit other features of the classic triad including eye movement abnormalities and ataxia. Magnetic resonance imaging (MRI) may demonstrate symmetric increased T2 signal intensity as well as contrast enhancement or restricted diffusion in the mammillary bodies, dorsomedial thalami, or periaqueductal area ( Fig. 44-1 ), but cerebrospinal fluid (CSF) analysis is normal and EEG often demonstrates nonspecific diffuse slowing. Prompt supplementation with intravenous thiamine is imperative to reduce neurologic morbidity and prevent progression to Korsakoff syndrome.

Post-transplantation encephalopathy may also be caused by posterior reversible encephalopathy syndrome (PRES). While the syndrome preferentially affects the posterior cerebral regions ( Fig. 44-2 ), variations do occur, most frequently involving the frontotemporal lobes and rarely the basal ganglia, brainstem, or thalami. Patients often present with headache, encephalopathy ranging from mild inattention to akinetic mutism or coma, seizures, or various visual syndromes. Transplant recipients are particularly vulnerable to developing PRES as they experience significant fluctuations in blood pressure, renal failure, and sepsis, all known risk factors for the development of the disorder. Medications that commonly trigger PRES include the calcineurin inhibitors tacrolimus and cyclosporine, but the condition has also been described with other immunomodulatory therapies used in this population. The patient’s blood pressure need not be very high for occurrence of this syndrome, which appears to be related to the rate of change of blood pressure from baseline combined with a loss of cerebral autoregulation and endothelial dysfunction. Lowering of the blood pressure by any means will usually result in resolution of both the clinical syndrome and imaging abnormalities, although in some cases permanent neurologic sequelae can occur.

Seizures

Seizures are particularly common in the post-transplantation period. The most common causes of seizures are immunosuppressive agents (especially cyclosporine, tacrolimus, and OKT3), metabolic derangements, and hypoxic-ischemic injury. Infection, stroke, and tumor are less frequent causes of seizures in this population. Often, the seizure disorder is transient and requires no treatment other than reduction in the dose of offending medications, correction of metabolic derangements, or treatment of underlying infection. Long-term therapy with antiepileptic drugs is undesirable in transplant recipients as interactions can occur with their immunosuppressive regimen; inducers of the hepatic cytochrome oxygenase P-450 system (e.g., carbamazepine, phenytoin) result in a decrease in the levels of many calcineurin inhibitors, necessitating dose adjustments. As such, if antiseizure medication is required, selection of a nonenzyme-inducing agent such as levetiracetam, lacosamide, or valproic acid is often preferable, although in liver transplantation, valproic acid should be avoided given potential hepatotoxicity.

Cerebrovascular Complications

Patients undergoing both hematopoietic cell and solid organ transplantation (SOT) are at risk of cerebrovascular events especially during the surgical and postoperative periods. Cerebral ischemia occurs as a result of arrhythmias, hypercoagulable states, underlying atherosclerosis, cardiac emboli, or prolonged hypoxic injury. Both ischemic and hemorrhagic stroke may occur in the setting of PRES and thus perioperative blood pressure management in this population is critical. Transplanted organ-specific cerebrovascular complications will be highlighted below.

Infections

Patients receiving long-term immunosuppression are at an increased risk of developing infections. Neurologic infections are particularly clinically relevant as they have the potential to cause significant morbidity and mortality in an immunocompromised host. Nearly every conceivable type of infection—bacterial, viral, fungal, and parasitic—has been reported to infect transplant recipients, but about 75 percent of cases are due to Listeria monocytogenes , Cryptococcus neoformans , or Aspergillus fumigatus .

One important risk factor for infection is the immunosuppression necessary to prevent rejection of the allograft. The single most important risk factor for developing post-transplantation central nervous system (CNS) infection is the magnitude and length of immunosuppression. In addition, after transplantation, patients often have indwelling catheters, endotracheal tubes, and other portals of entry for infection. Patients’ underlying diseases and their complications also contribute to the net state of immunosuppression. Certain infections themselves, especially viruses, also cause suppression of the immune system, in turn leading to increased susceptibility to additional infections.

CNS infections in immunocompromised hosts may be difficult to recognize. The usual signs of infection, such as fever and meningismus, may be subtle or absent, as they depend on a vigorous immune response. As a result, clinicians should have a high index of suspicion for infectious causes of neurologic symptoms in transplant recipients. Evidence of infection outside the nervous system may provide clues to a possible etiology. For example, skin lesions may be found to harbor Cryptococcus and co-existent lung infection suggests Aspergillus , Nocardia , or Cryptococcus .

Specific infectious pathogens complicating the post-transplantation period depend on a number of factors including the time from receipt of the graft, the specific immunosuppressive regimen, exposure and travel history, and the type of transplantation itself. Common culprit infectious organisms particular to each type of transplanted graft are discussed below. Table 44-1 lists important pathogens affecting the nervous system in recipients of both hematopoietic cell and SOT.

Viral

Several different viral infections may occur in recipients of transplants. In cases of cytomegalovirus (CMV) and Epstein–Barr virus (EBV), these infections themselves may predispose patients to infections with additional opportunistic organisms including Listeria , Aspergillus , and Nocardia . CMV results in a spectrum of neurologic complications including retinitis, ventriculoencephalitis, and polyradiculitis with a predilection for the caudal spine. Diagnosis is made with CSF PCR and treatment typically includes a combination of ganciclovir and foscarnet. Infection with EBV may similarly result in an encephalitic or myeltic picture, but also predisposes this patient population to post-transplant lymphoproliferative disorder (PTLD). Treatment of EBV involves ganciclovir for infectious presentations and immunosuppression with B-cell depleting therapies for EBV-associated lymphoproliferative disorders.

Varicella-zoster virus can involve both the central and peripheral nervous systems. Due to widespread use of antiviral prophylaxis in the pretransplantation period, complications related to reactivation of varicella-zoster virus now emerge later than in the past. The most common complication is cutaneous zoster, but transverse myelitis, vasculitis, and polyneuritis also occur. Often when a dermatomal rash is absent, the etiology of the neurologic syndrome is uncertain and confirmation of VZV is necessary using CSF VZV IgM and IgG along with PCR testing. Treatment with IV acyclovir is recommended in this immunocompromised population.

Progressive multifocal leukoencephalopathy (PML), a severe demyelinating disorder of the CNS resulting from reactivation of polyomavirus JC virus (JCV), may develop in recipients of both hematopoietic cell and SOT. Patients present with subacute neurologic deficits that reflect the area of white matter injury, typically sparing the optic nerves and spinal cord. MRI demonstrates multifocal, often asymmetric, white matter lesions involving the subcortical U fibers but without mass effect or evidence of enhancement ( Fig. 44-3 ). Diagnosis is confirmed by positive JCV in the CSF but, given its poor sensitivity, brain biopsy is sometimes necessary and remains the gold standard. Unfortunately, there is no proven effective treatment for PML, though reducing immunosuppression is recommended and emerging therapies including checkpoint inhibitors are being explored. A reduction in immunosuppression may occasionally lead to the development of immune reconstitution inflammatory syndrome (IRIS) with clinical worsening of PML as well as new enhancement on MRI, often necessitating steroids.

Immune Reconstitution Inflammatory Syndrome

Although well-recognized in HIV patients receiving highly active antiretroviral therapy, IRIS may also occur in recipients of hematopoietic cell and SOTs in the context of immunosuppression withdrawal. The condition features an intense inflammatory response that occurs as immune function is restored in the presence of an underlying opportunistic infection (typically Cryptococcus , tuberculosis, or PML). When transplanted patients develop symptoms of CNS infection, immunosuppressive medications are often decreased to allow for a more robust immune response, leading to an increased risk of IRIS. Clinical presentation typically consists of paradoxical worsening of symptoms of a known infection or unmasking of a previously unrecognized infection in this clinical setting. As symptoms may mimic those of the original infection, the diagnosis of CNS IRIS is often difficult to make, especially since treatment failure, antimicrobial resistance, and additional neurologic infections are other important diagnostic considerations. Management of IRIS involves prompt treatment of underlying infection and consideration of adjunctive corticosteroids to reduce the severe inflammatory response, although no related randomized controlled studies exist.

Lymphoproliferative Disorders

The chronic use of immunosuppressive agents to prevent allograft rejection increases the long-term risk of malignancy. Lymphoproliferative syndromes may occur in recipients of both hematopoietic cell and SOTs, often in the first year. The term PTLD is used to describe a wide spectrum of disorders characterized by abnormal proliferation of B cells (less commonly T cells) ranging from “benign” diffuse polyclonal lymphoid hyperplasia to malignant monoclonal lymphoma. CNS involvement occurs in up to 15 percent with PTLD and is the most common type of malignancy involving the brain in transplant recipients. B-cell malignancies in transplanted patients are strongly associated with EBV infection unlike primary CNS lymphoma in immunocompetent patients. These B-cell lymphomas arise in deep areas of the brain with a propensity for the perivascular spaces. CNS lymphoma is distinguished radiographically from PML on brain MRI by its significant mass effect, restricted diffusion secondary to hypercellularity, and enhancement. Therapy for PTLD consists primarily of reduction of immunosuppression and a combination of conventional cytotoxic chemotherapy, radiotherapy, and often B-cell depleting agents. Unfortunately, the mortality rate remains high with CNS involvement leading to a poorer prognosis.