Investigations

The classification of clinical syndromes occurring after transplantation requires neuroradiological, laboratory, microbiological, and electrophysiological investigation. Computed tomography or magnetic resonance imaging (MRI) can identify ischemic infarction, intracerebral bleeding, brain abscess, granuloma, white matter abnormalities, or brain edema.² Laboratory parameters should include electrolytes, glucose, ammonia, renal function, coagulation status, and concentration of immunosuppressants (cyclosporine or tacrolimus). The examination of the cerebrospinal fluid (CSF) should include testing for routine parameters, and microbiological or serological testing for bacteria and fungi, including specific antigen testing as well as cytological examination and culture. In cases of a suspected viral etiology, PCR and serological CSF/serum antibody index have to be determined. Systemic infections, mainly pulmonary infection with Aspergillus, Nocardia, and cryptococci, are potential sources of secondary CNS infections and must be diagnosed, or ruled out if suspected. Electroencephalography is necessary for patients with epileptic seizures or suspected nonconvulsive status epilepticus.

Nonspecific Neurological Complications Following Organ Transplantation

Posttransplantation patients require lifelong immunosuppression to prevent organ rejection, except in cases of organ transplantation between identical twins, and in some patients following bone marrow transplantation (who may develop immunological tolerance 1 to 2 years following the transplantation). Thus, regardless of the transplanted organ, several neurological complications may arise from immunosuppressive treatment due to its direct neurotoxicity or because of increased occurrence of CNS infections and epileptic seizures, or, in rare cases, induction of CNS malignancies.

Cyclosporine

Cyclosporin A has been used for many years for chronic immunosuppression following transplantation and also for the treatment of acute organ rejection. Cyclosporine suppresses T-helper cells and cytotoxic T cells by reducing their release of interleukin-2 and other cytokines. It is associated with systemic side effects, such as nephrotoxicity, hepatotoxicity, and arterial hypertension.

Neurological complications following cyclosporin A occur in 15% to 30% of patients.³ The most common complications are isolated tremor (40%), headache (10% to 20%), and distal sensory deficits (electrophysiological examination shows a combined demyelinating and axonal neuropathy only in severe cases). About 5% of patients develop severe neurological side effects, with predominantly two distinct clinical syndromes: (1) Acute neurotoxicity may occur within the first weeks after transplantation as an encephalopathy combined with headache, dysarthria, depressive or manic symptoms, visual hallucinations, cortical blindness, seizures, or impaired consciousness, and (2) weeks to months after transplantation, cyclosporine neurotoxicity can manifest as a subacute motor syndrome with hemiparesis, paraparesis, or tetraparesis, possibly accompanied by cerebellar tremor, ataxia, and cognitive impairment. Cyclosporine is epileptogenic, and 2% to 6% of patients develop focal or generalized seizures. Status epilepticus may occur in patients with high cyclosporine serum levels.

It has been suggested that activation of the sympathetic system causes cyclosporine-induced tremor. Headache may result from the release of nitric oxide. In cases with severe neurotoxicity syndromes, there may be impairment of the blood-brain barrier. Cyclosporine serum concentrations in patients with neurotoxicity are generally in the upper range of therapeutic levels. Higher cyclosporine concentrations always cause neurological side effects.

The neurotoxicity of cyclosporine is exacerbated by low cholesterol or magnesium levels, concomitant ß-lactam-antibiotic treatment, high-dose steroid medication, hypertension, and uremia, previous irradiation, or microangiopathy, which might occur after bone marrow transplantation.

Magnetic resonance imaging using FLAIR sequences typically shows confluent parieto-occipital white matter lesions without contrast enhancement.⁴ CSF analysis shows elevated CSF albumin concentrations in almost all patients with cyclosporine neurotoxicity because of impaired blood-brain barrier function.

The treatment of cyclosporine-induced neurological side effects consists of dose reduction for patients with mild symptoms. Patients with severe neurotoxicity have to be switched to tacrolimus or to mycophenolate mofetil (see below).

Concomitantly, elevated blood pressure and metabolic disturbances (e.g., impaired creatinine clearance, magnesium or cholesterol levels) must be normalized. Epileptic seizures should be treated with valproic acid or gabapentin because they do not induce hepatic enzymes. Patients with isolated headache should be treated with propanolol. Most of the cyclosporine-induced neurological side effects are reversible if the drug is discontinued in time.

Tacrolimus

Tacrolimus is increasingly being used instead of cyclosporine because of its more pronounced immunosuppressive effects in renal, liver, or heart transplantation. Although the pharmacological mechanism of tacrolimus is similar to that of cyclosporine, less frequent rejection episodes have occurred, and arterial hypertension is rare. However, systemic side effects such as nephrotoxicity or hepatotoxicity and also neurologic complications are slightly more frequent than with cyclosporine.

Neurotoxicity is observed in 30% to 50% of patients following organ transplantation. Symptoms include headache, sensory deficits, tremor, anxiety, nightmares, and sleep disorders. Severe neurologic complications include disorientation, dysarthria, epileptic seizures, encephalopathy, apraxia, akinetic mutism, and impaired consciousness and occur in about 5% of patients, mainly during the initial treatment.⁵ Tacrolimus has been reported to cause a severe demyelinating polyneuropathy, which responds to treatment with corticosteroids or immunoglobulins, as well as a changeover to cyclosporine.⁶ In such cases, however, polyradiculitis due to cytomegalovirus infection (CMV) has to be ruled out.

Patients with tacrolimus neurotoxicity may have multifocal white matter lesions on magnetic resonance imaging, but radiographic abnormalities generally develop with some latency after clinical symptoms. In contrast to cyclosporine neurotoxicity, the lesions may show contrast enhancement, and are not typically distributed like a posterior leukoencephalopathy. Tacrolimus neurotoxicity may result in both subcortical and cortical lesions. In these patients, however, neurovascular diseases of other etiology, CNS infections, or an extrapontine myelinolysis (e.g., following liver transplantation) have to be ruled out. The majority of tacrolimus-associated neurological symptoms are reversible if the dosage is reduced or if the immunosuppressive drug is changed. White matter lesions, however, may persist even after clinical symptoms have resolved.

Mycophenolate mofetil

Mycophenolate mofetil is generally used after organ transplantation in addition to other immunosuppressive drugs to reduce the rejection rate. It acts as an antimetabolite and suppresses T cells, the proliferation of B cells, and the antibody production of plasma cells. Systemic side effects consist of reduced leukocyte counts, gastrointestinal disorders, and possibly an increased rate of viral infections (especially CMV). Neurotoxic side effects have been reported for single patients, but in general there is a possible association only with headache, tremor, vertigo, sleep disorders, depression, and sensory deficits.

Steroids

Corticosteroids are used after transplantation as treatment for chronic immunosuppression and for acute organ rejection. Because of their nonselective effect on cellular and humoral immunity, steroids increase the risk of opportunistic infections. Other systemic steroid side effects (e.g., osteoporosis, diabetes mellitus) are well known and therefore not reported on in detail.

Common neurological side effects of steroids include myopathies and psychiatric symptoms.⁷ It is probable that 50% of patients treated with medium to high doses of steroids for more than 3 weeks will develop a proximal myopathy (manifesting initially in the hip muscles). Because it is seldom possible to reduce the dosage in symptomatic patients, a nonfluorized steroid should be tried instead. Steroid myopathy usually resolves only after 2 to 8 months following discontinuation.^8,9