Has tacrolimus (FK-506) been reported to cause fatal encephalopathy?/nA 52-year-old female patient

Fråga: Has tacrolimus (FK-506) been reported to cause fatal encephalopathy?

A 52-year-old female patient who had been on total parenteral nutrition (TPN) for 9 years because of intestinal pseudoobstruction underwent a successful small bowel transplantation March 1997. Two months after the operation she started to deteriorate showing signs of infection, acidosis, renal and hepatic malfunction. Finally, she developed seizures, went into coma and died. Extensive cerebral lesions were observed at autopsy. These were mostly typical of hepatic encephalopathy or some other severe metabolic perturbation. However, since the patient had high levels of tacrolimus in the blood since the operation, the possibility of a drug-specific neurotoxicity is also raised.

Sammanfattning: Tacrolimus is known to cause neurological adverse effects. However, these usually resolve upon dose reduction or drug withdrawal. Fatal neurological complications in transplantation patients are probably multifactorial and have not hitherto been unequivocally linked to tacrolimus treatment alone.

Svar: A number of neurological disturbances have been reported in patients treated with tacrolimus after transplantation. These encompass minor symptoms such as headache and tremor as well as major complications including encephalopathy (1). However, since patients who develop a major neurological abnormality after transplantation are usually seriously ill and suffer a number of other complications, the role of a drug-specific toxicity ascribed to tacrolimus has been difficult to determine. The occurrence of severe neurological complications was recorded and assessed in 100 liver transplantation patients under tacrolimus therapy (2). 34 per cent of these developed such a complication. Delirium was observed in 16, coma in 9, seizures in 4 and 5 developed focal motor deficits associated with a brain abscess, transient ischemic attack or central pontine myelinolysis. No direct relationship between tacrolimus blood levels and the presence or absence of major neurological complications could be demonstrated. The authors concluded that the pathogenesis of major neurological complications after liver transplantation is multifactorial and cannot be solely ascribed to tacrolimus toxicity (2). Jain and colleagues examined survival and adverse events in 1000 liver transplant recipients treated with tacrolimus (3). Seven percent of these patients developed major neurological complications including seizures. These complications, possibly related to the posterior leukoencephalopathy syndrome (see below) were almost always dose related and reversible with reductions in immunosuppression (3).

It should be pointed out that although neuropathological findings such as infarction, necrosis, hemorrhage and inflammatory lesions are frequently found in transplantation patients with lethal outcome (4), concomitant sepsis and MOFS (multiple organ failure syndrome) are the usual causes of death and probably account for the neurological complications (4).

Recently, Hinchey and co-workers described a reversible syndrome of headache, altered mental functioning, seizures and visual loss in patients with renal insufficiency or hypertension or who are treated with immunosuppressive agents (cyclosporine,4 cases, and tacrolimus, 3 cases)(5). The syndrome, referred to as the posterior leukoencephalopathy syndrome, is characterized by white-matter edema seen on neuroimaging, in particular in the parieto-occipital region (5). Small et al reported 3 cases of this syndrome in patients treated with tacrolimus (6). Although the syndrome was not associated with a particular serum level of tacrolimus, it resolved spontaneously upon decreasing the dose (6). In another study, multifocal white matter lesions could be demonstrated by neuroimaging (CT and MR) in five of six patients who showed severe neurological side effects of tacrolimus therapy (7). For each patient neurologic symptoms appeared when the tacrolimus levels in the blood were at a peak, exceeding the therapeutic limits in all but one case. In five patients, neurologic symptoms eventually resolved after the tacrolimus dose was reduced or after the drug was withdrawn (7). Although the course of this syndrome seems to be benign and reversible (5,6,7), a case of fatal posterior encephalopathy was reported in a 27-year-old man after sequential treatment with cyclosporin and tacrolimus (8). Death was caused by hyperacute cerebellar swelling leading to brainstem compression.

In the present case, the patient had received high doses of tacrolimus and high blood levels were observed on several occasions. However, during the terminal phase of her illness, the patient also showed signs of infection (CRP 126 mg per liter), renal insufficiency (creatinine 184 umol per liter), lactic acidosis (P-lactate 13.3 mmol per liter, reference interval 0.5-2.3) and possibly disseminated intravascular coagulopathy (DIC). She also had abnormal liver function tests with moderate increases of transaminases, ALP and bilirubin. At autopsy, no signs of white matter involvement were observed. Rather, changes were compatible with a general metabolic disturbance. Taken together, the findings suggest that the lethal course of the illness resulted from a number of deleterious factors and cannot solely be attributed to a tacrolimus-specific neurotoxicity.

We recommend this case be reported to SADRAC (The Swedish Adverse Drug Reactions Advisory Committee).