Keywords
transplantation, immunosuppression, cyclosporine, tacrolimus, corticosteroids, meningitis, abscess, encephalitis, stroke, embolus, encephalopathy, neuropathy, seizure, infection
Over the past 60 years, organ transplantation has become the treatment of choice for many otherwise fatal diseases. Advances in tissue matching, improvements in surgical technique, and the development of new immunosuppressive agents have increased both the number and type of transplantations performed. Kidney, bone marrow, heart, lung, liver, and pancreas transplants are now used regularly in the treatment of end-stage disease.
Three types of transplants exist: syngeneic (identical twins), allogeneic (different genetic origins), and autologous (patient’s own tissue). Of these, allogeneic transplants are the most common, although autologous transplants of bone marrow have become common in conjunction with chemotherapy. When a new organ is implanted in the same anatomic site as the old one (e.g., liver transplantation), the transplant is said to be orthotopic. When the organ is transplanted into a site that was not the original location of the organ being replaced, the transplant is termed heterotopic.
Advances in immunology and transplant technique have allowed longer survival for transplant recipients, but long survival has resulted in the emergence of an increased number of neurologic complications. Depending on the type of organ transplanted, 30 to 60 percent of transplant recipients will develop neurologic problems that can be divided into two major categories: (1) those common to all allogeneic transplants, which are due primarily to the effects of long-term immunosuppression, and (2) those specific to particular transplant types, due either to the underlying disease that led to the need for a transplant or to some phenomenon particular to the transplantation technique.
Neurologic Complications Common to All Transplantation Types
Long-Term Effects of Immunosuppressants
Syngeneic and autologous transplants do not require immunosuppression; however, most transplants are allogeneic, and most transplant recipients therefore require some degree of chronic, lifelong immunosuppressive therapy in order to prevent rejection of the transplanted organ. Both immunosuppressive agents themselves and the resulting immunosuppression may affect the nervous system either directly or indirectly. The major neurologic complications of immunosuppression include direct neurotoxic side effects of immunosuppressive drugs, infections, and the development of new malignancies.
Direct Neurologic Side Effects
Calcineurin Inhibitors
Cyclosporine and tacrolimus (FK-506) are the most commonly used immunosuppressive drugs in organ transplantation. These agents bind to calcineurin and selectively inhibit both helper and cytotoxic T cells by blocking antigen-induced T-cell activation ; these drugs also inhibit lymphokine production and release. Renal and hepatic toxicity along with hypertension are the most serious systemic complications of these drugs, although neurologic complications occur in 15 to 40 percent of patients.
Calcineurin inhibitors (CNIs) are used for both chronic maintenance immunosuppression and for the treatment of acute organ rejection. Cyclosporine and tacrolimus produce almost identical side effects, although some evidence indicates that neurologic side effects are slightly more common with tacrolimus.
Although higher blood levels of CNIs are generally associated with side effects, there is no simple correlation between serum levels and the development of any specific neurologic complication. Other factors in combination with CNIs increase the risk of developing neurologic problems including cranial radiation, hypocholesterolemia, hypomagnesemia, β-lactam antibiotic therapy, high-dose corticosteroids, hypertension, and uremia.
Tremor is the most common neurologic complication of CNIs and is present in up to 40 percent of patients. The tremor is usually mild and develops within days of initiation of the medication. It is typically caused by sympathetic activation, but patients with CNI-induced encephalopathy or leukoencephalopathy may also experience tremor, and tremor may be a part of a syndrome of generalized cerebellar dysfunction. Approximately one-third of patients who receive parenteral tacrolimus develop headache; oral administration is only rarely associated with headaches.
Most of the serious neurologic toxicity of CNIs is due to their tendency to produce hypertension. The hypertension that nearly always complicates CNI use is due in part to renal toxicity and, to a larger extent, to stimulation of the sympathetic nervous system. The encephalopathy of CNI toxicity is better correlated with the rate of change in blood pressure from the patient’s baseline level than with serum drug levels. CNI neurotoxicity may be thought of as a forme fruste of hypertensive encephalopathy and is characterized by tremor, abnormalities in mental state ranging from mild inattention to akinetic mutism and coma, seizures, and various visual syndromes characteristic of dysautoregulation in the posterior circulation. Magnetic resonance imaging shows increased signal on T2-weighted images in the occipital white matter, although the anterior circulation territory and gray matter may be involved. Flow studies such as single-photon emission computed tomography demonstrate increased flow with extravasation of water. These clinical and white matter findings are identical to those found in patients with hypertensive encephalopathy and are termed the posterior reversible encephalopathy syndrome (PRES). 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 combined with a loss of cerebral autoregulation. Lowering of the blood pressure by any means, including but not limited to lowering the blood level of the drug, will usually result in resolution of the clinical syndrome and the imaging abnormalities.
CNIs are epileptogenic and cause seizures in 2 to 6 percent of recipients. The seizures may be focal or generalized and are usually (but not invariably) associated with high serum levels. Hypertension, hypomagnesemia, hypocholesterolemia, aluminum overload, and the concomitant administration of high-dose corticosteroids have been identified as aggravating or precipitating factors.
Neuralgia and neuropathy are less common complications of CNIs. Sensory disturbances consisting of paresthesias, dysesthesias, and hyperesthesias of the distal extremities (especially hands) are more common than weakness. Nerve conduction and electromyographic abnormalities are rarely present, although evidence of combined demyelination and axonal damage has been reported.
The treatment for all the direct neurotoxic side effects of CNIs is either to decrease the dose or to eliminate the drug entirely, if possible. Nearly all of the direct side effects are usually reversible after drug discontinuation.
mTOR Inhibitors
Sirolimus and everolimus drugs are immunosuppressive drugs that act by inhibiting the mammalian target of rapamycin (mTOR) and ultimately blockading T-cell activation. These agents have similar side effects and cause increases in serum cholesterol and triglycerides. Myelosuppression is also common as are dermatologic problems. These agents have relatively few neurologic side effects but a PRES-like syndrome which resolves on discontinuation of the drug has been reported rarely.
Corticosteroids
Corticosteroids were the first immunosuppressive agents used in transplantation and continue to be used for long-term immunosuppression and for the treatment of acute rejection. Corticosteroids affect both cellular and humoral immunity and expose patients to a greater risk of opportunistic infection than do the newer immunosuppressive agents that are relatively T-cell specific. The most common neurologic side effects of corticosteroids are myopathy, steroid psychosis, and problems resulting from corticosteroid withdrawal. The systemic side effects of corticosteroids are not reviewed here.
The exact frequency of corticosteroid myopathy is unknown, but many patients on moderate-dose corticosteroids develop some signs of myopathy 2 to 3 weeks after the start of therapy. The syndrome is characterized by proximal muscle weakness that is most severe in the hip girdle. Treatment is to discontinue the corticosteroids (if possible) or to change to a nonfluorinated corticosteroid (e.g., hydrocortisone) and decrease the dose. The myopathy usually resolves completely in 2 to 8 months after corticosteroid therapy is stopped.
Psychiatric complications occur frequently in patients taking corticosteroids. The phrase steroid psychosis refers to several psychiatric syndromes that are associated with corticosteroids. Many patients develop mild psychiatric symptoms including anxiety, insomnia, irritability, difficulties with concentration and memory, and mood changes. More severe acute psychiatric syndromes occur in about 3 percent of patients including affective disorders, schizophrenia-like syndromes, or delirium. The treatment of steroid psychosis involves stopping the drug (when possible) or changing over to dexamethasone (the corticosteroid least likely to cause steroid psychosis) and reducing the dose. In addition, affective syndromes may respond to lithium, and schizophrenia-like syndromes are treatable with major tranquilizers.
Withdrawal from corticosteroids also may cause neurologic complications, including myalgias and arthralgias (“steroid pseudorheumatism”), and a syndrome consisting of headache, lethargy, and nausea, with or without a low-grade fever.
Spinal cord or cauda equina compression from epidural lipomatosis caused by corticosteroids has been reported in transplant recipients. This rare complication usually does not occur in patients taking less than the equivalent of 30 mg/day of prednisone. Clinical manifestations can include back pain, myelopathy, and radiculopathy. The usual treatment is surgical decompression, although simply discontinuing corticosteroid therapy occasionally has improved symptoms.
OKT3 Monoclonal Antibody and other Monoclonal Antibodies
OKT3 (Muromonab-CD3) is a monoclonal antibody directed against CD3 + lymphocytes. Its major neurologic side effect is aseptic meningitis, which occurs in about 5 percent of patients during the first 3 days of exposure. Cerebrospinal fluid analysis shows a lymphocytic pleocytosis with normal glucose and normal or slightly elevated protein concentration. The syndrome is self-limited and benign. Lumbar puncture and culture of the cerebrospinal fluid should be performed to exclude bacterial or fungal meningitis. The meningeal inflammation is probably part of a cytokine release syndrome or an allergic process similar to that which occurs with nonsteroidal anti-inflammatory drugs or intravenous immunoglobulin.
A more severe syndrome with variable degrees of mental status derangement, including seizures, may occur even more rarely. It is associated with neuroimaging evidence of cerebral edema, but it is also self-limited and benign, even if the OKT3 is continued. OKT3 use also predisposes patients to develop lymphoproliferative processes (including lymphoma), a side effect that appears to be dose related.
Antithymocyte and Antilymphoblast Globulins
Antithymocyte globulin (ATG) and antilymphoblast globulin (ALG) are antisera directed against thymocytes or lymphocytes. Rarely, patients develop an aseptic meningitis similar to that seen with OKT3, which is also self-limited and benign.
Azathioprine
Azathioprine is an antimetabolite that suppresses both cell-mediated and humoral immunity. Although used less frequently now that more specific immunosuppressants are available, the drug is still occasionally used for long-term immunosuppression. There are no direct neurotoxic side effects, although the nervous system may be affected secondary to infection or liver failure.
Neurologic Infections
Patients who receive long-term immunosuppression are at increased risk of developing infections. Neurologic infections occur in 5 to 15 percent of all transplant recipients, but are important clinically since about half of the central nervous system (CNS) infections that occur in immunocompromised patients result in death. Nearly every conceivable organism has been reported to infect transplant recipients, but about 75 percent of the cases are due to Listeria monocytogenes , Cryptococcus neoformans , or Aspergillus fumigatus.
Transplant recipients are at increased risk of infection for several reasons, the most important of which is the immunosuppression necessary to prevent rejection of the allograft. However, factors other than exogenous immunosuppressive agents also contribute to the risk of infection. After transplantation, patients often have indwelling catheters, endotracheal tubes, and other portals of entry for infection. The patients’ underlying diseases and their complications (especially hyperglycemia and uremia) also contribute to the net state of immunosuppression. In addition, certain infections (especially viruses) themselves also cause suppression of the immune system leading to increased susceptibility to other infections. The single most important risk factor for developing post-transplantation CNS infection is the magnitude and length of immunosuppression.
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 these signs depend on a vigorous immune response to the infection. Because the usual signs of CNS infection may be absent and because nearly any organism—bacteria, fungus, parasite, or virus—may be responsible, the clinician should have a high index of suspicion for infectious causes of neurologic deterioration in any transplant recipient.
An infection outside the nervous system should alert the clinician to a possible neurologic infection. Skin lesions may be found to harbor Cryptococcus , and lung infection suggests Aspergillus , Nocardia , or Cryptococcus.
Acute meningitis is often due to L. monocytogenes , whereas chronic meningitis, often with cranial nerve palsies, suggests tuberculosis or fungal organisms. A progressive syndrome with hemiparesis, visual symptoms, ataxia, dysarthria, and dementia should raise suspicion of progressive multifocal leukoencephalopathy caused by the JC polyomavirus (see Chapter 43 ). A localized mass lesion (e.g., a brain abscess) is often due to multiple organisms including anaerobes, but the predominant organism in the immunocompromised patient is usually Aspergillus , Nocardia , or Toxoplasma.
Another clue to the causative organism is the time period following transplantation. In the early period (up to 1 month after transplantation), CNS infections are rare; when infections are present, they usually were acquired before the transplantation or from the donor organ itself, or relate to surgical complications of the transplant including the presence of indwelling catheters. These infections are usually due to common pathogens that are found in the general (nonimmunosuppressed) population. If opportunistic infections occur during the first month after transplantation, there is usually some environmental problem (e.g., Aspergillus in the air supply).
In the intermediate period (between 1 and 6 months after transplantation), the net state of immunosuppression is usually at its peak due to prolonged immunosuppressive therapy and the immunomodulatory effect of common viral infections. During this period, the risk of CNS infection is greatest. Two types of infections predominate—viruses and opportunistic organisms. Viral infections (especially cytomegalovirus and Epstein–Barr virus) predispose patients to develop infections with opportunistic organisms, including Listeria , Aspergillus , and Nocardia.
Most late infections (more than 6 months after transplantation) fall into three categories: the lingering effects of an infection acquired earlier, opportunistic infections related to long-term immunosuppression, or the return to a pattern of infection similar to that seen in nonimmunosuppressed individuals. Most lingering infections are caused by viruses and include progressive chorioretinitis from cytomegalovirus as well as Epstein–Barr virus–related B-cell lymphoproliferative disease such as CNS lymphoma.
Opportunistic infections that develop more than 6 months after transplantation tend to occur in patients with chronic allograft rejection who have been maintained on higher than usual doses of long-term immunosuppressive agents (e.g., corticosteroids) and have received additional antirejection therapy (usually with OKT3, antithymocyte globulin, or antilymphoblast globulin). These patients are at the greatest risk of developing opportunistic CNS infections. Cryptococcus , Listeria , and Nocardia species are the most common organisms responsible. Most instances of cryptococcal meningitis that occur in transplant recipients are found in these patients.
Not all patients who survive for longer than 6 months after transplantation are at a substantially increased risk of developing opportunistic infections. Patients who are maintained on minimal long-term immunosuppression and whose post-transplantation courses have been free of chronic viral infections or the need for excessive antirejection therapy have only a slightly increased risk of infection. In these patients, the organisms causing CNS infections are usually the same as those present in the nonimmunosuppressed population.
Lymphoproliferative Disorders
Lymphoproliferative syndromes can occur after prolonged immunosuppression. Early reports identified an increase in non-Hodgkin lymphoma (including CNS lymphoma) in transplant recipients, but many of these apparently malignant lymphomas lacked the histologic and genotypic characteristics of true lymphomas. The term post-transplantation lymphoproliferative disorder is now used to describe a wide spectrum of abnormal proliferations of B lymphocytes ranging from “benign” diffuse polyclonal lymphoid hyperplasia to malignant monoclonal lymphoma. CNS involvement occurs in 15 to 25 percent of patients with post-transplantation lymphoproliferative disorder, and the CNS is the only site of detectable disease in about 85 percent of cases that involve the CNS.
Post-transplantation lymphoproliferative syndromes are strongly associated with Epstein–Barr virus infection (unlike primary CNS lymphoma in immunocompetent patients). These B-cell lymphomas arise deep in the brain with a propensity for the perivascular spaces. CNS lymphoma is distinguished from progressive multifocal leukoencephalopathy by mass effect and enhancement on magnetic resonance imaging (MRI).
Therapy for CNS post-transplantation lymphoproliferative disorder consists of reduction of immunosuppression, antiviral therapy, conventional cytotoxic chemotherapy, radiotherapy, and experimental therapies including anti–B-cell antibodies and interferon-α. The overall survival rate of patients with the disorder is only about 30 percent. Outcome data in large series are not available, but it is clear that CNS involvement makes the prognosis extremely poor.
Seizures
Seizures are a common neurologic complication after organ transplantation, occurring in 6 to 36 percent of patients. The most common causes of seizures are immunosuppressive drugs (especially cyclosporine, tacrolimus, and OKT3), metabolic derangements, and hypoxic-ischemic injury (usually producing seizures in the first weeks after heart, lung, or liver transplantation). Infection, stroke, and tumor are less frequent causes of seizures in these patients. Often, the seizure disorder is transient and requires no treatment other than reduction in the dose of responsible medications, correction of metabolic problems, or treatment of underlying infection.
Long-term treatment with antiepileptic drugs is undesirable in transplant recipients because many of the older anticonvulsants (e.g., phenytoin, phenobarbital, and carbamazepine) interfere with the metabolism of commonly used immunosuppressive agents due to induction of the hepatic cytochrome oxygenase P450 system. Anticonvulsants may lead to a decrease in CNI levels, and the dose of immunosuppresants may need to be adjusted.
Patients who have had only a single seizure should not be started on long-term anticonvulsants. For short-term acute management of status epilepticus, the benzodiazepines are the least likely to interfere with the metabolism of immunosuppressive drugs and can be given either orally or intravenously.
In patients who require long-term treatment with anticonvulsants, the choice should involve agents that have oral and intravenous formulations and do not induce hepatic enzymes, such as valproic acid and levetiracetam. Valproic acid should be avoided in patients with liver transplants, however, because of potential hepatotoxicity.
Neurologic Complications Associated with Specific Transplantation Types
Renal Transplantation
Since the first successful human renal transplantation in 1954, the procedure has developed into the best therapy for most patients with end-stage renal disease. The kidney is the most frequently transplanted solid organ, and there is now a virtually 100 percent 1-year survival rate, with an approximately 90 percent graft survival rate. The 5-year survival rate for nondiabetic renal transplant recipients exceeds 90 percent. Approximately 30 percent of renal transplant recipients develop neurologic complications ( Table 45-1 ).
| Complication | Percentage Affected |
|---|---|
| Cerebrovascular events | 10 |
| CNS infections | 9 |
| Metabolic encephalopathy | 10 |
| Seizures | 6 |
| Peripheral nerve lesions | 5 |
| CNS post-transplantation lymphoproliferative disease | 0.3 |
Renal transplantation is most often performed in patients with glomerulonephritis (membranous or membranoproliferative), diabetes mellitus, or hypertensive renal disease. Other common underlying disorders include polycystic kidney disease, systemic lupus erythematosus, amyloidosis, analgesic nephropathy, and obstructive nephropathy. The toxic effects of pretransplantation uremia may cause subclinical neurologic impairment and leave the nervous system vulnerable to subsequent injury following transplantation. Many underlying diseases, especially diabetes and hypertension, are associated with accelerated atherosclerosis and therefore predispose patients to develop cerebrovascular complications before and after transplantation.
Most of the neurologic complications of renal transplantation are due to the underlying disease for which the transplantation was performed. Polycystic kidney disease may be associated with cerebral berry aneurysms, hypertension with ischemic and hemorrhagic stroke, and systemic lupus erythematosus with mental state changes. Rapid correction of hyponatremia may lead to central pontine myelinolysis, a syndrome that can range in severity from mild quadriparesis to deep coma or even death (see Chapter 17 ).
The renal transplantation procedure itself is relatively benign. Neurologic complications, other than those caused by anesthesia or intraoperative hypotension, consist mainly of peripheral nerve injuries. The most common peripheral nerve injuries involve the femoral and lateral femoral cutaneous nerves due to compressive injury caused by self-retaining retractors. In a few patients, the caudal spinal cord is supplied by branches of the internal iliac arteries rather than by intercostal arteries; in these patients, when the iliac artery is used to supply blood to the allograft, spinal cord ischemia may result.
Many renal transplant recipients have some degree of vascular compromise either as a result of their underlying disease (e.g., hypertension, diabetes) or because of emboli associated with underlying atherosclerosis or heart disease. The most common post-transplantation neurologic complications in this patient population are therefore cerebrovascular, occurring in approximately 9 percent of all renal transplant recipients.
Acute rejection of the renal allograft can produce an encephalopathic syndrome presenting as a nonfocal encephalopathy with headache, altered mental state, and seizures. Systemic manifestations may include fever, weight gain, renal failure, and swelling and tenderness of the graft. This syndrome has been described only in renal transplantations, and the mechanism is unclear; soluble neuroactive immune factors (e.g., cytokines) released during the rejection process may play a role. A similar syndrome occurs as a side effect of OKT3.
Bone Marrow Transplantation
Bone marrow transplantation became a viable treatment option in the late 1960s, and with improvements in tissue matching, immunosuppression, and supportive care, the technique has developed into an important treatment for aplastic anemia, certain inborn errors of metabolism, and a variety of hematologic, lymphoreticular, and solid malignancies. Today, bone marrow transplantation is the second most common type of organ transplantation. Most of the associated neurologic complications occur in allogeneic transplants, which usually require long-term immunosuppression. These neurologic complications occur in 60 to 70 percent of allogeneic bone marrow recipients and are the cause of death in 5 to 10 percent ( Table 45-2 ).
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