tacrolimus and Brain-Edema

A 58-year-old woman developed rapidly progressive neurological symptoms and finally loss of vigilance 5 weeks following primarily successful lung transplantation. A posterior reversible encephalopathy syndrome (PRES) under treatment with tacrolimus as well as hyperammonemia due to sepsis with Ureaplasma urealyticum could be identified as the causes. Infections with Ureaplasma, bacteria which produce ammonia as a product of metabolism, are increasingly being identified in immunocompromised people by specific PCR (polymerase chain reaction) procedures and should routinely be taken into consideration as the cause of unspecific neurological symptoms.

Topics: Brain Edema; Female; Humans; Hyperammonemia; Immunocompromised Host; Lung Transplantation; Middle Aged; Posterior Leukoencephalopathy Syndrome; Postoperative Complications; Status Epilepticus; Tacrolimus; Ureaplasma Infections; Ureaplasma urealyticum

Reversible cerebral vasoconstriction syndrome (RCVS) is a cerebrovascular syndrome characterized by multi-segmental constrictions of the cerebral arteries that resolves spontaneously within 3 months. Although RCVS is considered to be due to transient dysregulation of vascular tone, the exact pathomechanism remains unclear. We describe the case of a 15-year-old girl with RCVS induced by tacrolimus, who developed generalized seizure during the postoperative course of orthotropic heart transplantation. Magnetic resonance imaging at symptom onset showed a few vasoconstrictions accompanying brain edema and convexity subarachnoid hemorrhage. Although her neurological conditions rapidly improved after discontinuing tacrolimus, a repeat magnetic resonance angiogram demonstrated delayed progression of the multi-segmental vasoconstrictions followed by subsequent resolution. Our case demonstrates that cautious observation of the cerebral arteries using magnetic resonance angiography and careful management of vasoconstrictions with vasodilators are necessary for delayed vasoconstrictions even when the clinical symptoms improve.

Topics: Adolescent; Brain Edema; Cerebral Angiography; Cerebral Arteries; Disease Progression; Electroencephalography; Female; Heart Transplantation; Humans; Immunosuppressive Agents; Magnetic Resonance Angiography; Multimodal Imaging; Seizures; Subarachnoid Hemorrhage; Syndrome; Tacrolimus; Time Factors; Tomography, X-Ray Computed; Vasoconstriction; Vasodilator Agents; Vasospasm, Intracranial

We report on tacrolimus-associated posterior reversible encephalopathy syndrome with the previously unreported finding of leptomeningeal enhancement occurring separate from the site of parenchymal magnetic resonance signal abnormality. Recognition of this atypical finding as a noninfectious cause of leptomeningeal enhancement may assist those caring for patients affected by posterior reversible encephalopathy syndrome.

Topics: Brain Edema; Female; Humans; Immunosuppressive Agents; Infant; Magnetic Resonance Imaging; Meninges; Mesencephalon; Posterior Leukoencephalopathy Syndrome; Seizures; Tacrolimus

We examined the protective effects of the immunosuppressants cyclosporin A (CsA) and FK506 on abnormal cytosolic Ca²⁺ ([Ca²⁺]c) and mitochondrial Ca²⁺ concentration ([Ca²⁺]m) dynamics induced by ischemia or high L-glutamate concentration in mouse brain slice preparations. We used fura-4F and rhod-2 as indicators for [Ca²⁺]c and [Ca²⁺]m, respectively, in their acetoxymethylester form. Slice preparations loaded with either of these two indicators were exposed to ischemic artificial cerebrospinal fluid (oxygen- and glucose-deprived medium) for 12 min or to aerobic medium with high L-glutamate concentration (isotonic 20 mM L-glutamate) for 5 min. CsA (1 - 10 μM) showed significant protective effects on the maximum increase in ischemia-induced [Ca²⁺]c and [Ca²⁺]m. FK506 (10 μM) showed significant protective effects on the [Ca²⁺]m increase, but not on the ischemia-induced [Ca²⁺]c increase. Both immunosuppressants showed almost equal protective effects on the [Ca²⁺]c and [Ca²⁺]m increases induced by high L-glutamate concentration. These results suggest that the protective effects of CsA and FK506 on Ca²⁺ overloading may be dependent upon the common pharmacological sites of actions relating to their effects as immunosuppressants. The small, but significant depressant effects of these drugs could give us important clues for rescuing critical brain damage induced by Ca²⁺ overloading.

Topics: Animals; Brain; Brain Edema; Brain Ischemia; Brain Mapping; CA1 Region, Hippocampal; Calcium Signaling; Cerebral Cortex; Cyclosporine; Cytosol; Glutamic Acid; Immunosuppressive Agents; In Vitro Techniques; Male; Mice; Mice, Inbred C57BL; Mitochondria; Neurons; Neuroprotective Agents; Osmolar Concentration; Tacrolimus

Tropisetron is widely used to counteract chemotherapy-induced emesis. Evidence obtained from human and animal studies shows that tropisetron possesses anti-inflammatory properties. In this study, we assessed the effect of tropisetron on brain damage in a rat thromboembolic model of stroke. Stroke was rendered in rats by introduction of an autologous clot into the middle cerebral artery (MCA). Tropisetron (1 or 3mg/kg); m-chlorophenylbiguanide (mCPBG), a selective 5-HT(3) receptor agonist (15 mg/kg); tropisetron (3mg/kg) plus mCPBG (15 mg/kg); granisetron (3mg/kg); tacrolimus (1mg/kg); or tacrolimus (1mg/kg) plus tropisetron (3mg/kg) were administered intraperitoneally 1h prior to embolization. Behavioral scores and infarct volume as well as myeloperoxidase (MPO) activity and tumor necrosis factor-alpha (TNF-α) level were determined in the ipsilateral cortex 4h and 48 h following stroke induction. Forty-eight hours after embolization, tropisetron (1 or 3mg/kg), tropisetron (3mg/kg) plus mCPBG (15 mg/kg), tacrolimus (1mg/kg), or tacrolimus (1mg/kg) plus tropisetron (3mg/kg) significantly curtailed brain infarction, improved behavioral scores, diminished elevated tissue MPO activity, and reduced TNF-α levels compared to control group (n=6; P<0.05). mCPBG or granisetron had no effect on the mentioned parameters. Tropisetron attenuates brain damage after a thromboembolic event. Beneficial effects of tropisetron in this setting are receptor independent.

Topics: Analysis of Variance; Animals; Biguanides; Blood Gas Analysis; Brain Edema; Brain Infarction; Brain Injuries; Cerebral Cortex; Disease Models, Animal; Dose-Response Relationship, Drug; Immunosuppressive Agents; Indoles; Ischemia; Male; Nervous System Diseases; Peroxidase; Rats; Rats, Wistar; Seizures; Serotonin Antagonists; Stroke; Tacrolimus; Tropisetron; Tumor Necrosis Factor-alpha

Posterior reversible encephalopathy syndrome, a serious neurotoxicity, may develop rarely in patients receiving tacrolimus. Because the underlying etiology of posterior reversible encephalopathy syndrome is vasogenic edema, it is generally accepted to be a reversible neurologic condition. Cranial magnetic resonance imaging techniques enable detection of the type of edema, and they are widely used in the differential diagnosis and prognostic prediction of posterior reversible encephalopathy syndrome. Presented here is a case of posterior reversible encephalopathy syndrome in which the patient recovered completely, despite radiologic findings indicating the coexistence of vasogenic and cytotoxic edema secondary to tacrolimus therapy after liver transplantation.

Topics: Brain Edema; Child; Diffusion Magnetic Resonance Imaging; Hepatitis B, Chronic; Humans; Immunosuppressive Agents; Leukoencephalopathies; Liver Failure, Acute; Liver Transplantation; Male; Tacrolimus

Topics: Adult; Brain Edema; Emergencies; Female; Follow-Up Studies; Humans; Hypertensive Encephalopathy; Immunosuppressive Agents; Liver Transplantation; Magnetic Resonance Imaging; Tacrolimus; Time Factors

FK506 (tacrolimus), an immunosuppressant, reportedly reduces ischemic brain injury following transient middle cerebral artery occlusion (MCAO) in rats. The authors previously reported that the therapeutic window of FK506 in this model is more than 1 h, but less than 2 h. The aim of the present study is to determine whether mild hypothermia (35 degrees C) enhances the neuroprotective effects of FK506 and expands its therapeutic window. Sprague-Dawley rats were subjected to 2 h MCAO followed by 24 h reperfusion. Animals were randomly divided into four groups: (I) vehicle-treated normothermic group; (II) FK506-treated normothermic group; (III) vehicle-treated hypothermic group; (IV) FK506-treated hypothermic group. Animals received a single injection of FK506 (0.3 mg/kg) or vehicle intravenously at 2 h after ischemic induction. During ischemia, temporal muscle and rectal temperatures were maintained at 37 degrees C in the normothermic animals and at 35 degrees C in the hypothermic animals. Infarct volumes and neurological performance were evaluated at 24 h after reperfusion. The combination of FK506 and mild hypothermia significantly reduced infarct volume (cortex, -61%; striatum, -31%) and edema volume (cortex, -57%; striatum, -41%), while mild hypothermia or FK506 alone failed to improve ischemic brain damage. Furthermore, this combination also provided for the best functional outcome. These results demonstrate that the combination of FK506 and mild hypothermia significantly reduces ischemic brain damage following transient MCAO in rats, and expands the therapeutic window for FK506. This therapy may be a new approach for treatment of acute stroke.

Topics: Animals; Body Temperature; Brain Edema; Cerebral Infarction; Cerebrovascular Circulation; Hypothermia, Induced; Immunosuppressive Agents; Ischemic Attack, Transient; Laser-Doppler Flowmetry; Male; Neuroprotective Agents; Rats; Rats, Sprague-Dawley; Reperfusion Injury; Tacrolimus

Topics: Adult; Brain Edema; Cerebral Hemorrhage; Fatal Outcome; Female; Graft Rejection; Humans; Hypercholesterolemia; Hypertension; Liver Cirrhosis, Alcoholic; Liver Transplantation; Magnetic Resonance Imaging; Myelin Sheath; Postoperative Complications; Seizures; Tacrolimus

A 66-year-old man developed a focal status epilepticus and left hemiparesis 4 days after an orthotopic liver transplantation and administration of FK 506. The magnetic resonance image revealed areas of increased signal on diffusion-weighted imaging (DWI) equally distributed to all vascular territories, most of which resolved completely within 2 weeks after discontinuation of FK 506. We conclude that DWI cannot reliably distinguish between reversible and irreversible lesions and that the presence of hyperintense lesions on DWI is not a definitive predictor of poor prognosis in reversible leukoencephalopathy patients.

Topics: Aged; Brain Edema; Diffusion Magnetic Resonance Imaging; Humans; Immunosuppressive Agents; Liver Transplantation; Male; Paresis; Status Epilepticus; Syndrome; Tacrolimus

FK506 is a newly developed potent immunosuppressant for preventing rejection after organ transplantation. However, FK506 can induce central nervous system toxicity. Until now the pathogenic mechanism of FK506 neurotoxicity was unclear. We report the findings of diffusion-weighted MRI and apparent diffusion coefficient (ADC) mapping of a FK506 neurotoxicity patient who showed increased signal intensities in both parieto-occipital lobes on T(2) weighted images, diffusion-weighted images and ADC maps. These findings suggest that a vasogenic oedema rather than a cytotoxic oedema may play a pivotal role in FK506 neurotoxicity pathogenesis.

Topics: Adult; Anemia, Aplastic; Bone Marrow Transplantation; Brain Edema; Brain Mapping; Humans; Immunosuppressive Agents; Magnetic Resonance Imaging; Male; Tacrolimus

Topics: Brain; Brain Edema; Coma; Consciousness Disorders; Cranial Nerve Diseases; Drug Administration Schedule; Evoked Potentials, Somatosensory; Female; Humans; Immunosuppression Therapy; Immunosuppressive Agents; Kidney Transplantation; Magnetic Resonance Imaging; Middle Aged; Neurotoxicity Syndromes; Neurotoxins; Quadriplegia; Recovery of Function; Recurrence; Seizures; Tacrolimus; Tomography, X-Ray Computed

Topics: Adolescent; Brain; Brain Edema; Cerebral Infarction; Dementia, Vascular; Humans; Immunosuppressive Agents; Kidney Failure, Chronic; Kidney Transplantation; Magnetic Resonance Imaging; Male; Postoperative Complications; Tacrolimus

Disturbance of calcium homeostasis contributes to evolving tissue damage and energetic impairment following traumatic brain injury (TBI). Calcium-mediated activation of calcineurin results in production of tissue-damaging nitric oxide and free oxygen radicals. Inhibition of calcineurin induced by the immunosuppressant tacrolimus (FK506) has been shown to reduce structural and functional damage after ischemia. The aims of the present study were to investigate time- and dose-dependent short-term antiedematous effects of tacrolimus following TBI.. A left temporoparietal contusion (controlled cortical impact injury [CCII]) was induced in 51 male Sprague-Dawley rats. Tacrolimus (1 or 3 mg/kg body weight) was administered by a single intraperitoneal injection at 5 minutes, 30 minutes, or 4 hours after CCII occurred. Control rats received physiological saline. Water contents of traumatized and nontraumatized hemispheres, as well as cerebrospinal fluid (CSF) levels of mediators reflecting tissue damage (the proinflammatory cytokines interleukin [IL]-6 and tumor necrosis factor [TNF]-alpha, the excitotoxin glutamate, and the adenosine triphosphate-degradation product hypoxanthine), were determined 24 hours after trauma. Although CSF levels of IL-6 and TNFalpha were completely suppressed by tacrolimus at all time points and at both concentrations, CSF levels of glutamate and hypoxanthine, as well as edema formation, were only marginally influenced. Significant reduction of cerebral water content was confined to nontraumatized hemispheres. In addition, the higher dose of tacrolimus failed to exert significant antiedematous effects on traumatized hemispheres.. Under the present study design, the potency of tacrolimus in reducing edema formation following CCII seems limited. However, its immunosuppressive effects could be of value in influencing the posttraumatic inflammatory response known to aggravate tissue damage.

Topics: Animals; Brain Edema; Brain Injuries; Calcineurin; Cerebral Cortex; Energy Metabolism; Glutamic Acid; Hypoxanthine; Immunosuppressive Agents; Interleukin-6; Male; Rats; Rats, Sprague-Dawley; Tacrolimus; Tumor Necrosis Factor-alpha; Water

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.

Topics: Animals; Blood Glucose; Brain; Brain Edema; Brain Ischemia; Cardiovascular Physiological Phenomena; Cerebral Infarction; Drug Administration Schedule; Immunosuppressive Agents; Infarction, Middle Cerebral Artery; Male; Neurons; Neuroprotective Agents; Rats; Rats, Sprague-Dawley; Reperfusion Injury; Tacrolimus; Treatment Outcome

A 21-year-old woman with severe aplastic anemia received an allogeneic bone marrow transplant (allo-BMT) from an HLA-matched and ABO-matched sibling donor after conditioning with cyclophosphamide, rabbit ATG (Lymphoglobuline; Aventis-Pharma), and total lymphoid irradiation. She had a long history of cyclosporin A (CsA) therapy before conditioning. She complained of severe headache and convulsions on day 0, and findings on magnetic resonance images suggested CsA-induced encephalopathy. CsA was immediately stopped, and tacrolimus for prevention of graft-versus-host disease (GVHD) was started on day 2. Hematological engraftment was observed on day 14 without serious GVHD. Prompt diagnosis, replacement of immunosuppressive agents, and careful monitoring of serum drug concentrations are thought to have contributed to the patient's good clinical course, since CsA-induced encephalopathy tends to be recurrent but to improve completely without any sequelae.

Topics: Adult; Anemia, Aplastic; Anticonvulsants; Blood-Brain Barrier; Bone Marrow Transplantation; Brain Diseases; Brain Edema; Ceftazidime; Cerebral Hemorrhage; Cyclosporine; Diagnosis, Differential; Diuretics; Endothelium, Vascular; Epilepsy, Generalized; Female; Fluconazole; Graft vs Host Disease; Headache; Humans; Immunosuppressive Agents; Intracranial Hypertension; Magnetic Resonance Imaging; Tacrolimus; Transplantation Conditioning; Transplantation, Homologous

The purpose of the present study was to compare the characteristics of the photochemical-induced thrombotic occlusion model and the thermocoagulated occlusion model of the middle cerebral artery in rats. We evaluated the neuroprotective effects of a NMDA receptor antagonist, (+)-MK-801 (dizocilpine, (+)-5-methyl-10,11-dihydro-5H-dibenzo[a,d]cycloheptan-5,10-imine), an alpha-amino-3-hydroxy-5-methylisoxazole-4-propionic acid receptor antagonist, YM90K (6-(1H-imidazol-1-yl)-7-nitro-2,3(1H,4H)-quinoxalinedione monohydrochloride), a Ca2+ channel antagonist, S-312-d (S-(+)-methyl-4,7-dihydro-3-isobutyl-6-methyl-4-(3-nitrophenyl)-thieno[2 ,3-b]pyridine-5-carboxylate), the radical scavengers, MCI-186 (3-methyl-1-phenyl-2-pyrazolin-5-one) and EPC-K1 (L-ascorbic acid 2-[3,4-dihydro-2,5,7,8-tetramethyl-2-(4,8,12-trimethyl-tridecyl)-2H-1-be nzopyran-6yl-hydrogen phosphate] potassium salt), and a calcineurin inhibitor, FK506 (tacrolimus, Prograf). Although all tested agents in the present study attenuated the brain damage in the photochemical-induced thrombotic occlusion model, the radical scavengers did not attenuate the brain damage in the thermocoagulated occlusion model. The time course of brain damage and brain edema formation in the two models was examined. The time course of brain damage was not different in the two models, but the time course of brain edema was quite different. Brain edema formation in the photochemical-induced thrombotic occlusion model was significantly greater (P < 0.01) than that in the thermocoagulated occlusion model at all time point studied until 24 h after occlusion of the middle cerebral artery. The present study suggests that the photochemical-induced thrombotic occlusion model has characteristics of both permanent ischemia and ischemia-reperfusion.

Topics: Animals; Brain Edema; Brain Ischemia; Disease Models, Animal; Dizocilpine Maleate; Electrocoagulation; Immunosuppressive Agents; Injections, Intraperitoneal; Injections, Intravenous; Intracranial Embolism and Thrombosis; Male; Neuroprotective Agents; Quinoxalines; Rats; Rats, Sprague-Dawley; Tacrolimus

Topics: Adult; Bone Transplantation; Brain; Brain Edema; Cyclosporine; Hodgkin Disease; Humans; Immunosuppressive Agents; Magnetic Resonance Imaging; Male; Syndrome; Tacrolimus