tacrolimus and Subarachnoid-Hemorrhage

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

Posterior reversible encephalopathy syndrome (PRES) is a disorder characterized by gray and white matter abnormalities in the temporal, parietal, and occipital lobes of the brain. Its etiology has been attributed to renal failure, immunosuppressive drugs such as cyclosporine and tacrolimus, and other potential entities leading to acute hypertension. Clinical findings include headaches, altered mental status, seizures, visual changes, and focal neurologic deficits. We report the case of a child who developed PRES with intracerebral and subarachnoid hemorrhages associated with tacrolimus exposure 10 days after heart transplantation for restrictive cardiomyopathy. The patient initially presented with complex partial seizures, headache, agitation, and hypertension. Head MRI was suggestive of PRES along with intracerebral and subarachnoid hemorrhages. Tacrolimus was discontinued and blood pressure was controlled. The patient's encephalopathy resolved, but he has had ongoing neurologic symptoms secondary to hemorrhage. Generally, PRES is less common in children than in the adult population and is a rare complication of calcineurin inhibitors (CNI). Presentation with secondary hemorrhage also can occur. In children receiving CNIs presenting with new neurologic symptoms, PRES should be considered as prompt discontinuation of the offending agent can induce resolution of symptoms. Children can develop hemorrhage in the context of PRES, leading to increased morbidity.

Topics: Cerebral Hemorrhage; Child; Heart Transplantation; Humans; Immunosuppressive Agents; Male; Posterior Leukoencephalopathy Syndrome; Postoperative Complications; Subarachnoid Hemorrhage; Tacrolimus

We hypothesized that the immunological reaction against extravasated blood might play a role in the development of vasospasm after subarachnoid hemorrhage. Under the hypothesis, we had reported significant therapeutic efficacy of cyclosporin A on vasospasm in canine models. We here investigated the efficacy of a new, potent immunosuppressant, FK-506, on vasospasm in animal models. Dogs were randomly classified into sham operated, subarachnoid hemorrhage treated-1 group, (FK-506, 0.3 mg/kg-d, intramuscular injection), and treated-2 group (FK-506, 0.15 mg/kg-d, intramuscular injection). Levels of the third factor of complement (C3) and the activity of serum complement inducing 50% hemolysis of sheep erythrocytes (CH50) in serum were also determined. In the treated groups, the levels of FK-506 in serum were monitored. As for C3 and CH50, there were no statistically significant differences among the groups and there were no changes between Day 1 and Day 7 in any group. Angiographical diameters of a basilar artery on Days 1 and 7 were measured with a computed image analyzer, and the extent of vasospasm was compared among the groups. Statistically significant differences between the sham-operated group and the other three groups were noted. However, under sufficient levels of FK-506 in serum, the extent of vasospasm in either treated group was the same as that in the subarachnoid hemorrhage group. These results indicate a significant discrepancy in the therapeutic mechanism for vasospasm between cyclosporin A and FK-506. They have common aspects in the immunosuppressive mechanism. However, in T-cell suppression, the different mechanism in situ between the two drugs is also postulated.(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: Animals; Cerebral Angiography; Complement C3; Dogs; Female; Ischemic Attack, Transient; Male; Muscle, Smooth, Vascular; Subarachnoid Hemorrhage; Tacrolimus

To define the relationship between the immunologic reaction and the pathogenesis of cerebral vasospasm (VS) following experimental subarachnoid hemorrhage (SAH), we examined the effect of a cell mediated immunosuppressive agent, FK-506, isolated from Streptomyces tsukubaensis, by using the canine SAH model. There was a significant vasoconstriction in the basilar artery in the control group after SAH. This constriction, however was not successfully prevented by FK-506 or combination of FK-506 and steroid, since there was no significant difference in the vessel caliber size among these groups. The pathologic approach, accompanied by immunohistochemistry, could not discriminate the differences in the nature of the lesion between the untreated group and FK-506 treated groups, except for slight lymphocytic infiltrations present around the basilar artery of untreated group. Histopathologically, inflammatory reactions consisting of neutrophils, that were not suppressed by FK-506 treatment, were clearly seen around the spastic vessels in the subarachnoid space. Furthermore, several constrictive changes or degenerative alterations were also observed in the spastic vascular wall. Immunohistochemically, the deposition of IgG, IgM and C3 was present in the intima and the luminal side of the smooth muscle layer, and capillary vessels of the brain stem. It is considered that this deposition was caused by increased vascular permeability in VS. On the basis of the above findings that the cell mediated immunosuppressive agent, FK-506 failed to prevent vasoconstriction or pathologic lesions but lymphocytic infiltrations, it is considered that the cell mediated immunopathogenesis may play little role in producing VS following SAH.

Topics: Animals; Basilar Artery; Brain Stem; Dogs; Female; Ischemic Attack, Transient; Male; Muscle, Smooth, Vascular; Subarachnoid Hemorrhage; Tacrolimus

In order to clarify the possible role of immunological reaction in the pathogenesis of cerebral vasospasm, the authors examined the prophylactic effect of the immunosuppressant agents FK-506 and cyclosporin A on chronic vasospasm in a canine two-hemorrhage model. While a mean constriction of the basilar artery to 81.0% +/- 4.0% (+/- standard error of the mean) occurred on Day 2 and to 63.8% +/- 3.5% on Day 7 in the untreated group, constriction to 77.9% +/- 3.4% on Day 2 and 62.8% +/- 3.0% on Day 7 was demonstrated in the FK-506-treated group (difference not significant). This tendency was also noted in the cyclosporin A-treated group, with basilar artery constriction to 81.8% +/- 3.7% and 56.3% +/- 2.7%, respectively (difference not significant). The histological changes of the basilar artery, including corrugation of the elastic lamina, detachment of endothelial cells, and vacuolar formation in the smooth-muscle layer were not different in the two treated groups and the one control group. Since these immunosuppressant agents are known to inhibit the release of interleukin-2 (IL-2), the level of IL-2 was examined in the cerebrospinal fluid of patients with cerebral vasospasm. While interleukin-1 gradually increased in level as time passed, the level of IL-2 was consistently low during the course of the study, indicating less participation of IL-2 in the pathogenesis of cerebral vasospasm. This clinical observation matched the experimental results. The authors conclude that cell-mediated immunoreaction, initiated mainly by IL-2, plays little role in the pathogenesis of cerebral vasospasm.

Topics: Animals; Cyclosporine; Dogs; Immunosuppressive Agents; Interleukin-2; Ischemic Attack, Transient; Subarachnoid Hemorrhage; T-Lymphocytes, Cytotoxic; T-Lymphocytes, Helper-Inducer; Tacrolimus