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The principal side effects of the new immunosuppressive drug FK506 have been low-grade nephrotoxicity, a mild diabetogenic effect, and annoying but relatively minor manifestations of neurotoxicity (1). The neurotoxic symptoms have included tremors, paresthesias, insomnia, headaches, increased visual sensitivity to light, nightmares, a sense of racing, and mood changes. Such complaints, which are similar to those caused by cyclosporine, have provided a much-needed means of dose adjustment (1). However, we report here 2 examples of reversible expressive dysphasia that may have been caused by FK506 since it was reversed by dose reduction.
Both patients were treated from the time of liver transplantation with FK506, starting with an initial intravenous dose of 0.15 mg/kg FK506 intraoperatively. Subsequent intravenous doses of 0.075 mg/kg were given every 12 hr, until the patients were able to take oral medications. At this time, 0.15 mg/kg FK506 was given orally every 12 hours. Methylprednisolone was started at 200 mg on day 1 and reduced by 40 mg steps/day to 20 mg on day 6.
A 43-year-old man with end-stage postnecrotic cirrhosis (liver weight 1400 g) secondary to hepatitis B did not have disabling encephalopathy preoperatively. He had an uncomplicated orthotopic liver transplantation, with a 3000 ml blood loss. He was discharged from the ICU after 3 days. On day 12, he was noted to have slurring of speech. He complained of numbness and tingling in his feet and also that his head was “racing.” There was no arterial hypertension, nor any elevation of BUN or creatinine. Serum electrolytes were never abnormal, intraoperatively or later. The neurologic examination revealed an expressive dysphasia with slight tremors of the extremities. Fundoscopic findings, magnetic resonance imaging of the brain, and the spinal fluid were normal. A cerebral CT scan showed mild cortical atrophy, a finding that had been noted in the preoperative CT scan. An EEG showed generalized slowing. The neurologic symptoms gradually resolved after an FK506 dose reduction. Despite a minor rejection episode, he improved steadily, and by the time of discharge, 25 days postoperatively, the speech defect was barely perceptible. He is neurologically normal 4 months postoperatively on FK506 doses of 0.09 mg/kg/day (less than one-third of early postoperative oral dose) and 10 mg/day prednisone.
A 38-year-old woman with chronic HBV hepatitis and grade III encephalopathy had an uncomplicated urgent liver transplantation. Preoperatively, she was agitated and disoriented. Later, she became drowsy, disoriented, and bradykinetic. Immunosuppression was as in case 1. Postoperatively, she required prolonged ventilatory support and developed nonoliguric renal insufficiency—the serum creatinine rising from normal preoperatively to a peak of 5.3 mg/dl. The intravenous dose of FK506 was decreased to .035 mg/kg/b.i.d. When the endotracheal tube was removed on day 6, she was noted to have an expressive speech deficit. Talking required a severe effort and there were occasional paraphasias. Her comprehension appeared to be normal, and repetitive speech was easier than spontaneous expression. A small subcortical left hemispheric stroke was suspected. However, a CT brain scan on days 6 and 12, carotid doppler examination, and echocardiogram (to rule out valve vegetations as an embolic source) were normal. The cerebrospinal fluid was normal. Her subsequent course was stormy and included Pseudomonas pneumonia, abdominal reoperation to remove a subhepatic hematoma, acute renal failure requiring 7 hemodialyses, tracheostomy, and CMV gastritis. The FK506 doses were intermittently stopped during this time and eventually resumed with oral doses of .07 mg/kg/day (about a quarter of the usual dose).
When her tracheostomy was capped on day 41, she was noted still to have slurring of speech. Magnetic resonance imaging on the 41st postoperative day showed areas of demyelinization in the pons (Fig. 1). The oral dose of .07 mg/kg FK506 per day was maintained. The expressive dysphasia slowly improved and she was discharged on the 56th postoperative day. Her speech abnormalities completely resolved by postoperative day 90. She has never had a rejection. Maintenance immunosuppression 5 months postoperatively is with 0.06 mg/kg/day FK506 without steroids, which were stopped on the 16th postoperative day.
Pathologic changes can frequently be found in the central nervous system of patients who die of chronic liver disease (2). The same abnormalities have been seen at autopsy after unsuccessful transplantation under azathioprine and cyclosporine regimens (3,4). In order of frequency, these include Alzheimer type II changes in the glial tissue, depletion of the myelin in the pons (central pontine myelinolysis) or elsewhere in the brain stem or higher brain (extrapontine myelinolysis), and cortical atrophy.
The neurologic syndromes have included prolonged obtundation or disorientation, flaccid quadriplegia, pseudobulbar palsy, expressive dysphasia, akinetic mutism, neuroopthomologic abnormalities, convulsions, and coma (3, 4). Similar Alzheimer and myelinolytic changes can be produced reliably in rats by surgical portacaval anastomosis, even though the animals may appear well clinically (5). Thus, vulnerability from underlying neuropathologic abnormalities of the central nervous system during the stressful period of liver transplantation is the background against which the role of any single factor, including drugs, must be evaluated in the event of a neurologic complication. The possible aggravating role of overly aggressive electrolyte correction has been emphasized by many workers, as summarized by Wszolek et al. (6).
Nevertheless, the possible neurologic complications of FK506—including the reversible pontine demyelinization seen in case 2 by NMR–resemble some of those ascribed to cyclosporine (7). In the cyclosporine reports, the neurotoxicity was associated casually with low cholesterol (8), hypomagnesemia (7), and aluminum overload (9). These latter findings are probably epiphenomena even if they are contributory to the pathogenesis.
A more fundamental explanation may be advanced for the neurotoxicity of these drugs.3 Although they are distinct, the binding sites of both cyclosporine and FK506 contain cis-trans peptidyl prolyl isomerase (10, 11). Inhibition of this enzyme could explain many metabolic effects of both drugs, including cholesterol regulation3 and reduction of magnesium (12). It is also doubtful that hypocholesterolemia has a direct casual role in the neurotoxicity (13). Although hypocholesterolemia is uniformly produced by FK506, the 2 examples of major neurologic complications herein reported were the only ones with a probable FK506 etiology seen in recipients of 180 livers, 55 kidneys, and 18 hearts, lungs, and heart-lungs treated primarily with this drug in the last 13 months. Seizures have occurred in our liver transplant recipients with a lower frequency than in the past. Although we are making a systematic search to establish a specific etiology in each case, this has been difficult because of the multifactorial nature of this complication in liver recipients. Seizures have not been seen in the recipients of extrahepatic organs.
An important possibility is that there is a direct inhibitory effect of drugs like cyclosporine and FK506 on cis-trans peptidyl prolyl isomerase receptors in the central nervous system as has been suggested elsewhere.3 Focal CNS targets made more susceptible by previous liver disease or any of the contributory factors mentioned earlier could be selectively affected by Over-dosage. The first intravenous dose of 0.15 mg/kg FK506 used in our early experience has been reduced since to 0.075 mg/kg in order to reduce this possibility.
1This work was supported by Research Grants from the Veterans Administration and Project Grant DK 29961 from the National Institutes of Health, Bethesda, MD.
3Starzl TE, Porter KA, Mazzaferro V, Todo S, Fung J, Francavilla A. Hepatotrophic effects of FK 506 in dogs. (Submitted for publication.)