FK506-induced leukoencephalopathy in children with organ transplants

FK506-induced leukoencephalopathy is a well-known entity in adult organ transplant patients. The neurotoxicity of FK506 immunosuppression is frequently reversible, with either reduction or cessation of the drug. This neurologic syndrome is not well documented in children. We report the clinical and radiologic features in four pediatric cases of FK506 leukoencephalopathy. In two of the four patients this syndrome was reversible.     

Immunosuppression-induced leukoencephalopathy from tacrolimus (FK506)

Tacrolimus (FK506) has recently been approved for immunosuppressionin organ transplantation, although its use is accompanied by a wide spectrum ofneurotoxic side effects. We describe the clinical, radiological, and pathological features of 3 cases of tacrolimus-related leukoencephalopathy. The syndrome of immunosuppression-related leukoencephalopathy is proposed as an uncommon neurological syndrome occurring in patintw with organ transplants involving demyelination, in particular in the parieto-occipital region and centrum semiovale. Although the syndrome is not associated with a particular (absolute) serum level of tacrolimus, it resolves spontaneously upon decreasing the dose. The tacrolimus-related syndrome has a similar radiographic and pathologic appearance as the analogous syndrome that occurs in patients taking cyclosporine.     

FK506-induced neurotoxicity in liver transplantation

We report FK506-induced neurotoxicity in 14 of 44 consecutive patients following orthoptic liver transplantation. In 10 of these 14 patients, postural hand tremors were found in the first weeks following surgery, transient apraxia of speech in 3, and generalized tonic-clonic seizures were noted in 2 patients. Other manifestations included nightmares, agitation, and acute delirium. Reduction of the FK506 dose resulted in resolution of symptoms, but in 1 patient mild speech difficulties and in 3 patients a fine tremor remained. Blood and plasma levels of FK506 were similar in patients with and without neurotoxicity. FK506 neurotoxicity in patients with liver transplantation commonly results in transient neurological manifestations. The incidence of neurotoxicity in FK506 is dramatically reduced in maintenance doses of 0.075 mg/kg twice a day.     

Tacrolimus (FK506)-induced mutism after liver transplant

Tacrolimus (FK506), an immunosuppressant, has been associated with mutism in adults after liver transplant. Speech arrest, agitation, tremor, ataxia, and downward gaze deviation in a 5-year-old female 13 days after orthotopic liver transplant are reported. FK506, which began to be administered 12 days earlier, rose to a level of 44 ng/mL (normal range, 10-20 ng/mL) 1 day before neurologic abnormalities began. FK506 dose level was maintained and then reduced. Three days later the patient could say a few single words and extra-ocular movement returned to normal. Four months later, she continued to exhibit decreased fluency and dysarthria with ataxia. One year later, decreased fluency and mild ataxia persists. Rapid identification of speech loss linked to FK506 may be important because reduction or cessation of the drug may be associated with reverse of speech loss.     

Effects of novel immunosuppressant FK 506 in acute experimental allergic encephalomyelitis]

Experimental allergic encephalomyelitis (EAE) is a T cell-mediated autoimmune disease. It is widely used as an animal model of multiple sclerosis (MS). We studied the prophylactic effects of FK 506 electrophysiologically and immunohistochemically in acute EAE. Female Lewis rats were sensitized with guinea pig spinal cord in complete Freund's adjuvant. FK 506 suspended in distilled water was orally administered at 1.0, 3.2, 5.0 or 10.0 mg/kg per day for 12 successive days starting from the day of sensitization. A placebo was used as the control. Administration of FK 506 at doses of 3.2 mg/kg per day and over significantly delayed the onset of clinical signs. However, the FK 506 group showed a relapse or a chronic state following the onset of EAE. We made a time course recording of cortical somatosensory evoked potential (cortical SEP: P 15). P 15 latency in the placebo group was significantly delayed in accordance with the clinical signs and showed immediate improvement upon recovery. Prolongation of P 15 latency in the FK 506 group also occurred concomitantly with the clinical signs, but the delay continued after the loss of symptoms as well. After the onset of EAE, the infiltrating lymphocyte subset was examined by the avidin-biotin peroxidase complex (ABC) method in the lumbar spinal cord. In the placebo group, the number of OX3+ (Ia) cells and the W 3 25+: OX8+ (helper/inducer T: suppressor/cytotoxic T) ratio clearly reflected the development and remission of EAE. In the FK 506 group, however, increases in OX8+ lymphocytes were observed irrespective of clinical sign fluctuation, and there were corresponding decreases in the W 3/25+: OX8+ ratio.(ABSTRACT TRUNCATED AT 250 WORDS)     

A case of neuroleptic malignant syndrome associated with reversible leukoencephalopathy]

We report a case of neuroleptic malignant syndrome associated with reversible leukoencephalopathy. The patient was a 60-year-old woman. Soon after ingesting an antipsychotic drug, the patient developed neuroleptic symptoms. After hydration and dantrolene sodium were administered, muscular rigidity gradually improved and serum levels of CK became normal. On the 7th hospital day, however, she fell into coma and showed tetraplegia. Although brain CT was normal on admission, diffuse low density areas were observed on the parieto-occipital cerebral white matter. The same lesions were observed on T2-weighted MRI. On the 20th hospital day, after giving her glycerol and adrenocorticosteroid, not only abnormal neurological findings but also abnormal CT and MRI findings disappeared. There were only two case reports of leukoencephalopathy with malignant syndrome in the literature. This is a rare case of reversible leukoencephalopathy with neuroleptic malignant syndrome due to the antipsychotic drug.     

Familial subcortical dementia with arteriopathic leukoencephalopathy. A clinico-pathological case]

A 54-year-old man died after a subcortical dementia that had developed over 7 years with focal neurological signs and a stepwise course. Clinical and radiological features were similar to those of Binswanger's disease but there was no vascular risk factor, especially no hypertension. Three similar cases had occurred in the family affecting the patient's mother, her brother and sister, suggesting an autosomal dominant hereditary disease. Postmortem examination disclosed an arteriopathic leukoencephalopathy. The white matter was mainly affected in the periventricular areas of the frontal and parietal lobes with myelin loss and pallor, sparing the U fibers. The vascular changes involved the small vessels and were not arteriosclerotic. There was severe thickening of the internal lamina and degradation products of the elastic fibers. There was no amyloid. This vascular leukoencephalopathy was different from Binswanger's disease and amyloid angiopathy. We think that the vascular lesions could correspond to a genetically transmitted specific degenerative pathology of the small arteries of the brain.     

Reversible bilateral internuclear ophthalmoplegia associated with FK506

A 50 year old man developed tonic-clonic seizures while receiving cyclosporin A after orthotopic cardiac transplant. The seizures resolved after cessation of cyclosporin A. Thirteen months later, he developed diplopia from bilateral internuclear ophthalmoplegia while receiving intravenous FK506. A temporal association was found between his symptoms and the serum FK506 concentrations. Withdrawal of the intravenous FK506 led to prompt resolution of the bilateral internuclear ophthalmoplegia.     

Acceleration of peripheral nerve regeneration following FK506 administration

Purpose: The severe functional and sensory deficits seen following injury to peripheral nerves makes facilitation of nerve regeneration a primary goal of the reconstructive surgeon. This study examines whether daily administration of FK506 or Cyclosporin A expedites peripheral nerve regeneration following neurotmetic injury in a rat model Methods: Inbred Buffalo rats were randomized to three experimental groups. Group I rats served as untreated controls. Rats in groups II and III received daily subcutaneous CsA (5 mg/kg), and FK506 (1 mg/kg), respectively. Each animal underwent unilateral posterior tibial nerve transection with immediate epineurial reapproximation. Functional recovery of the injured limb was assessed by serial walking track analysis. Nerve regeneration was assessed histomorphometrically via light microscopy. Results: Return of hindlimb function in control animals occurred at 32 days post injury. CsA and FK506-treated transection animals recovered at 26 and 18 days post injury, respectively. Statistically significant greater fiber density and percent neural tissue were seen in FK506- treated animals compared to control animals four weeks post transection. Conclusions: This data suggest that the daily systemic administration of both CsA and FK506 accelerate the rate of functional regeneration, following neurotmetic injuries in tbc rat model. FK506's effect on nerve growth is significantly greater than that of CsA.     

The effects of FK506 on refractory inflammatory myopathies

We performed an observational clinical study, the effects of tacrolimus (FK506) on the thymic output in patients with refractory inflammatory myopathies. Sixteen patients with polymyositis (PM) and 15 with dermatomyositis (DM) were treated orally with tacrolimus. Serum CK levels significantly decreased 2 to 4 months after tacrolimus therapy (p < 0.01), and MRC (Medical Research Council) scores were significantly improved 2 months after tacrolimus therapy (p < 0.01). T-cell receptor excision circle (TREC) content, a proxy for thymic export was not significantly different from that in age-matched controls, except for an increase in the TREC content within CD8+ single positive cells in patients with DM. TREC contents within double-positive cells and CD4+ single-positive cells were significantly decreased 4 M after tacrolimus therapy (p < 0.05) in PM/DM patients. Tacrolimus treatment significantly attenuated TREC content within cultured CD4+CD8- cells from PM/DMpatients (p < 0.05), but total cell counts were not significantly changed. These results indicate that tacrolimus therapy suppresses not only activated T-lymphocytes, but also some na?ve T-cell subsets in both PM and DM.     

Juvenile arteriosclerotic leukoencephalopathy: anatomoclinical study of a case]

A 34-year old right-handed man was suffering from recurrent cerebro-vascular insults. CT-scans revealed several subcortical lacunar infarcts, and leukoara?osis. Arteriography of the left and the right carotid arteries was performed respectively on the 4th and the 9th year of the disease, and did not elicit significant extracranial and intracranial vascular lesions. There were no arguments in favor of infectious, inflammatory, or auto-immune vascular diseases. The patient had tardive hypertension and dementia, and died at the age of 44. Pathological findings, limited to the brain and cervical spinal cord, revealed numerous ischemic lacunar infarcts. Histological lesions were consistent with the diagnosis of arteriosclerotic leukoencephalopathy. There were oedema, palor, and loss of myelin in the white matter, and nonspecific diffuse arteriosclerotic lesions that were particularly pronounced in the intimal part of the arterial wall. No inflammatory process nor amyloid deposits were found. Despite the onset of the disease in a young adult and the late occurrence of hypertension, our case report shares most of the pathological features of the Binswanger's type of arteriosclerotic encephalopathy.     

Anti-ryanodine receptor antibodies and FK506 in myasthenia gravis

Anti-ryanodine receptor (RyR) antibodies were measured in sera from 33 myasthenia gravis (MG) patients using three peptides from the human RyR1 sequence, two C-terminal peptides included in the functional calcium release channel, and an N-terminal peptide implicated in ion-conduction. Antibodies were more frequently positive against the two C-terminal peptides, particularly in thymoma-associated MG. In a preliminary open trial with FK506, immunosuppressant and enhancer of RyR-related sarcoplasmic calcium release, the authors observed the sustained benefits in anti-RyR-positive MG patients.     

Sensorimotor neuropathy resembling CIDP in patients receiving FK506

FK506 is an important immunosuppressant that has shown great promise in the treatment of autoimmune diseases. Approximately 5% of patients receiving FK506 develop major central nervous system toxicity, but the peripheral nerves are usually spared During 1990–1991, some 1000 patients received liver transplants under FK506 immunosuppression. Of these, 3 patients developed severe multifocal demyelinating sensorimotor polyneuropathy 2–10 weeks after initiation of FK506 therapy. Improvement followed plasmapheresis or intravenous immunoglobulin (IVIG), suggesting an immune-mediated cases. Although autoimmune neuropathy has been previously reported in immunedeficient states such as Hodgkin's disease and AIDS, it is not an expected complication of immunosuppresissive therapy. However, other have shown that this phenomeno can be produced in rats with cyclosporine A (CsA), whose effects on T-cell subsets are similar to those seen with FK506. These T-cell subset changes may have precipitated this dysimmune neuropathy in our patients. © 1994 John & Sons, Inc.     

Neuroprotective effect of immunosuppressant FK506 in transient focal ischemia in rats: Therapeutic time window for FK506 in transient focal ischemia

Abstract

Tacrolimus (FK506), an immunosuppressant currently used in clinic, is known to have neuroprotective properties. However, effects in focal ischemia are shown only in a endothelin induced middle cerebral artery (MCA) occlusion model or with filament technique at a relatively high dose. We have previously shown that FK506 had significant protective effects at a low dose of 0.3mg kg^-1 when administered immediately after ischemia. In this study, we explored the therapeutic time window of FK506 at this low dose, in a transient focal ischemia model using filament technique. Male Sprague-Dawley rats were subjected to 2 h MCA occlusion and subsequent reperfusion. They received FK506 or vehicle (0.3 mg kg^-1) i.v. at 30, 60 or 120 min after induction of ischemia, and were decapitated 24 h after ischemia. FK506 injected at 30 and 60 min significantly reduced cortical infarction volume (FK506 vs. vehicle; 30 min: 95 ± 33 mm³ vs. 170 ± 62 mm³, p < 0.05; 60 min: 93 ± 45 mm³, vs. 168 ± 35 mm³, p < 0.05, respectively). FK506 was ineffective when given at 120 min after ischemia. FK506 had no effect on edema formation, nor on the infarct volume in striatum. The therapeutic time window for this low dose of FK506 given i.v. is between 60 and 120 min in this model. [Neurol Res 2001; 23: 755-760]     

Age-related changes of sodium-dependentd-[3H]aspartate and [3H]FK506 binding in rat brain

Summary We investigated age-related changes in excitatory amino acid transport sites and FK506 binding protein (FKBP) in 3-week-, and 6-, 12-, 18- and 24-month-old Fischer 344 rat brains using receptor autoradiography. Sodium-dependentd-[³H]aspartate and [³H]FK506 were used to label excitatory amino acid transport sites and immunophilin (FKBP), respectively. In immature rats (3-week-old), sodium-dependentd-[³H]aspartate binding was lower in the frontal cortex, parietal cortex, striatum, nucleus accumbens, whole hippocampus, thalamus and cerebellum as compared to adult animals (6-month-old), whereas [³H]FK506 binding was significantly lower only in the hippocampus, thalamus and cerebellum. [³H]FK506 binding exhibited no significant change in the brain regions examined during aging. However, sodium-dependentd-[³H]aspartate binding showed a conspicuous reduction in the substantia nigra in 18-month-old rats. Thereafter, a significant reduction in sodium-dependentd-[³H]aspartate binding was found in the thalamus, substantia nigra and cerebellum in 24-month-old rats. Other regions also showed about 10–25% reduction in sodium-dependentd-[³H]aspartate binding. The results indicate that excitatory amino acid transport sites are more susceptible to aging process than immunophilin. Further, our findings demonstrate the conspicuous differences in the developmental pattern between excitatory amino acid transport sites and immunophilin in immature rat brain.     

FK506 prevents stroke-induced generation of ceramide and apoptosis signaling

Ceramide is a key mediator of apoptosis during the cellular stress response which is also involved in stroke-induced death. Transient occlusion of the middle cerebral artery (MCA) in rats led to a strong generation of ceramide as measured in thalamus and entorhinal cortex of the ischemic brain tissue. Enhanced levels of ceramide may be involved in apoptosis signaling following stroke since exogenously added synthetic C2-ceramide increased expression of c-jun and the death-inducing ligands (DILs) CD95-L, TRAIL and TNF-alpha in neuroblastoma cells. DILs in turn mediated death via binding to their respective receptors as concluded from diminished apoptosis upon blocking of the common pathway by dominant negative FADD. C2-ceramide induced both necrosis and apoptosis in a concentration-dependent manner corresponding to the situation present in the ischemic brain. The immunosuppressant FK506 inhibited the release of ceramide, expression of CD95-L and apoptosis in an in vitro and in vivo model for ischemia/reperfusion. These data suggest that ceramide is a crucial initiator of death, e.g., by induction of DILs following stroke.     

Neuroprotective effect of immunosuppressant FK506 in transient focal ischemia in rat: therapeutic time window for FK506 in transient focal ischemia.

Tacrolimus (FK506), an immunosuppressant currently used in clinic, is known to have neuroprotective properties. However, effects in focal ischemia are shown only in a endothelin induced middle cerebral artery (MCA) occlusion model or with filament technique at a relatively high dose. We have previously shown that FK506 had significant protective effects at a low dose of 0.3 mg kg(-1) when administered immediately after ischemia. In this study, we explored the therapeutic time window of FK506 at this low dose, in a transient focal ischemia model using filament technique. Male Sprague-Dawley rats were subjected to 2 h MCA occlusion and subsequent reperfusion. They received FK506 or vehicle (0.3 mg kg(-1)) i.v. at 30, 60 or 120 min after induction of ischemia, and were decapitated 24 h after ischemia. FK506 injected at 30 and 60 min significantly reduced cortical infarction volume (FK506 vs. vehicle; 30 min: 95 +/- 33 mm3 vs. 170 +/- 62 mm3, p < 0.05; 60 min: 93 +/- 45 mm3, vs. 168 +/- 35 mm3, p < 0.05, respectively). FK506 was ineffective when given at 120 min after ischemia. FK506 had no effect on edema formation, nor on the infarct volume in striatum. The therapeutic time window for this low dose of FK506 given i.v. is between 60 and 120 min in this model.