tacrolimus and Encephalitis

Rasmussen encephalitis (RE) leads to progressive tissue and function loss of one brain hemisphere and often intractable epilepsy. This is the first randomized prospective treatment trial in RE.. Germany-wide, patients with suspected recent-onset RE were recruited and if eligible randomized to tacrolimus or intravenous immunoglobulins (IVIGs). A loss of motor function or hemispheric volume by ≥ 15% (in patients >12 years at disease onset: ≥ 8%) led to study exit. Untreated patients served as a historical control group.. Over 6.3 years, 21 patients with recent-onset RE were identified. Sixteen were randomized to tacrolimus (n = 9) or IVIG (n = 7). Immunotreated patients had a longer "survival" than the historical controls. Neither treatment was more efficacious than the other. Two tacrolimus patients experienced serious adverse events. No immunotreated but several untreated patients developed intractable epilepsy. No patient with refractory epilepsy became treatment-responsive under immunotherapy.. The countrywide incidence rate of diagnosed RE is estimated as 2.4 cases/10⁷ people ≤ age 18/year. Treatment with tacrolimus or IVIG may slow down tissue and function loss and prevent development of intractable epilepsy. However, immunotherapy may "arrest" patients in a dilemma state of pharmacoresistant epilepsy but too good function to be offered functional hemispherectomy. These compounds may therefore contribute to the therapeutic armamentarium for RE patients without difficult-to-treat epilepsies.

Topics: Adolescent; Adult; Child; Child, Preschool; Encephalitis; Female; Follow-Up Studies; Humans; Immunoglobulins, Intravenous; Immunosuppressive Agents; Incidence; Longitudinal Studies; Male; Prospective Studies; Retrospective Studies; Tacrolimus; Young Adult

Seven patients with Rasmussen encephalitis (RE) were treated with the immunosuppressant tacrolimus and followed for a median of 22.4 months. They were compared with 12 historical untreated RE patients (median follow-up 13.9 months). The tacrolimus-treated patients had a superior outcome regarding neurologic function and progression rate of cerebral hemiatrophy but no better seizure outcome. No treated patient, but 7 of 12 control patients, became eligible for hemispherectomy. Tacrolimus did not have any major side effects.

Topics: Adolescent; Adult; Anticonvulsants; Atrophy; Brain; Cerebral Cortex; Child; Child, Preschool; Drug Therapy, Combination; Encephalitis; Female; Follow-Up Studies; Humans; Immunosuppressive Agents; Male; Neuropsychological Tests; Paresis; Tacrolimus; Treatment Outcome

Autoimmune encephalitis is a rare spectrum of disease that can be a complication of chronic immunosuppression. Diagnosis often requires the presence of antineuronal antibodies, but many causative antibodies have not yet been identified. Antibody-negative autoimmune encephalitis (AbNAE) is especially difficult to diagnose and must rely largely on exclusion of other causes. In chronically immune-suppressed transplant recipients, the differential is broad, likely resulting in underdiagnosis and worse outcomes. Here, we present a 58-year-old liver transplant recipient taking tacrolimus for prevention of chronic rejection who presented with 5 days of confusion, lethargy and lightheadedness. He was diagnosed with AbNAE after an extensive workup and recovered fully after high-dose corticosteroids. Our case highlights the importance of recognising the association between chronic immunosuppression and autoimmune encephalitis. Autoimmune encephalitis, even in the absence of characterised antibodies, should be considered when transplant recipients present with central neurologic symptoms.

Topics: Antibodies; Encephalitis; Hashimoto Disease; Humans; Immunosuppression Therapy; Immunosuppressive Agents; Liver Transplantation; Male; Middle Aged; Postoperative Complications; Tacrolimus; Time Factors

Prion infections of the central nervous system (CNS) are characterized by initial reactive gliosis followed by overt neuronal death. Gliosis is likely to be caused initially by the deposition of misfolded, proteinase K-resistant, isoforms (termed PrP

Topics: Animals; bcl-Associated Death Protein; Behavior, Animal; Brain; Calcineurin; Cricetinae; Cyclic AMP Response Element-Binding Protein; Encephalitis; Gliosis; MAP Kinase Signaling System; Mesocricetus; Minocycline; Motor Activity; Nesting Behavior; Neurons; Prion Diseases; Survival Analysis; Synapses; Tacrolimus; Transcription Factor RelA

Acute encephalitis with refractory, repetitive partial seizures (AERRPS) is characterized by prolonged severe seizures and a high-grade fever. We experienced a boy with severe AERRPS with frequent partial seizures that exhibited right-side predominance. The patient required the continuous intravenous administration of many antiepileptic drugs and respirator management for several months. Methylprednisolone pulse therapy and intravenous immunoglobulin administration were only temporarily effective. The MRI and EEG showed the abnormality in the left occipital lobe. Although occipital lobectomy was performed, his seizures continued. His cerebrospinal fluid exhibited elevated protein and proinflammatory cytokine levels, and was positive for anti-glutamate receptor ε2 antibodies. Pathological examination showed infiltration of many neutrophilic leukocytes, T cells, and microglia in the area exhibiting severe spongiosis. We thought that the exaggerated microglia and T-cell responses were related to the pathogenesis of the patient's seizures, and we therefore initiated treatment with tacrolimus. As a result, many of the daily seizure clusters were ameliorated, and the patient was discharged. We attempted to discontinue the tacrolimus twice, but the patient's seizure clusters recurred each time. This is the first case report of the pathological findings of AERRPS and showing an effective therapeutic approach using tacrolimus. Tacrolimus may be an effective immunosuppressant, especially for patients with severe AERRPS.

Topics: Acute Disease; Anticonvulsants; Brain; Child; Drug Resistant Epilepsy; Electroencephalography; Encephalitis; Epilepsies, Partial; Humans; Immunohistochemistry; Magnetic Resonance Imaging; Male; Seizures, Febrile; Tacrolimus

HIV-associated neurocognitive disorders (HAND) continue to be a common morbidity associated with chronic HIV infection. It has been shown that HIV proteins (e.g., gp120) released from infected microglial/macrophage cells can cause neuronal damage by triggering inflammation and oxidative stress, activating aberrant kinase pathways, and by disrupting mitochondrial function and biogenesis. Previous studies have shown that FK506, an immunophilin ligand that modulates inflammation and mitochondrial function and inhibits calcineurin, is capable of rescuing the neurodegenerative pathology in models of Parkinson's disease, Alzheimer's disease, and Huntington's disease. In this context, the main objective of this study was to evaluate if FK506 could rescue the neuronal degeneration and mitochondrial alterations in a transgenic (tg) animal model of HIV1-gp120 neurotoxicity.. GFAP-gp120 tg mice were treated with FK506 and analyzed for neuropathology, behavior, mitochondrial markers, and calcium flux by two-photon microscopy.. We found that FK506 reduced the neuronal cell loss and neuro-inflammation in the gp120 tg mice. Moreover, while vehicle-treated gp120 tg mice displayed damaged mitochondria and increased neuro-inflammatory markers, FK506 rescued the morphological mitochondrial alterations and neuro-inflammation while increasing levels of optic atrophy 1 and mitofusin 1. By two-photon microscopy, calcium levels were not affected in the gp120 tg mice and no effects of FK506 were detected. However, at a functional level, FK506 ameliorated the gp120 tg mice hyperactivity in the open field.. Together, these results suggest that FK506 might be potentially neuroprotective in patients with HAND by mitigating inflammation and mitochondrial alterations.

Topics: Analysis of Variance; Animals; Calcium; Calcium-Binding Proteins; Disease Models, Animal; Encephalitis; HIV Envelope Protein gp120; Immunosuppressive Agents; Interleukin-6; Mice; Microfilament Proteins; Mitochondria; Nerve Degeneration; Nerve Tissue Proteins; Neurotoxicity Syndromes; Tacrolimus; Tacrolimus Binding Proteins; Treatment Outcome

We examined seizure, cognitive, and motor outcomes in patients with Rasmussen syndrome or Rasmussen encephalitis (RS), after recent initiation of immunomodulatory therapies. Among 53 patients with a diagnosis of RS referred from all over Japan, 49 patients (male 22, female 27) with symptoms and findings characteristic of RS were evaluated. Regular intravenous immunoglobulin (IVIg) therapy was administered at a dose of 100mg/kg/day, etc. Regular steroid pulse therapy was conducted with methylprednisolone at a dose of 30mg/kg/day (children) or 1000mg/day (adults) for 3days. Tacrolimus was given at an initial dose of 0.1mg/kg/day (children). Mean onset age was 8.7±10.5years. Seizure-free rate was 71% after treatment by functional hemispherectomy (FH), and response rate for seizures was 81% by regular steroid pulse therapy, 42% by tacrolimus therapy, and 23% by regular IVIg therapy. Rate of patients with IQ higher than 80 (R80) was 50% by regular steroid pulse therapy, 43% by regular IVIg therapy, 29% by tacrolimus therapy, and 0% by FH. R80 after regular steroid pulse therapy was 100% in patients without MRI lesions, and 37% in those with advanced MRI lesions. Improvement of motor function (paresis) was observed only by immunomodulatory therapy. Motor function was aggravated in 100% of patients treated by FH, 62% by regular IVIg, and 10% by regular steroid pulse therapy. We suggest a new treatment strategy for RS using early immunomodulatory therapy: initiation of regular steroid pulse therapy after early diagnosis indicated by biomarkers, then switching to tacrolimus therapy after several months.

Topics: Child; Child, Preschool; Cognition; Encephalitis; Female; Hemispherectomy; Humans; Immunoglobulins, Intravenous; Immunomodulation; Male; Tacrolimus; Treatment Outcome

Early diagnosis and treatment of acute cellular rejection (ACR) after intestinal transplantation (ITx) is challenging. We report the outcome of three patients: two presented mild ACR improved with steroids. One presented steroid-resistant severe rejection, improved after rabbit anti-thymocyte globulin (r-ATG), but unfortunately died for encephalitis caused by opportunistic infections.

Topics: Adolescent; Anastomosis, Surgical; Antibodies, Monoclonal; Antibodies, Monoclonal, Humanized; Antilymphocyte Serum; Basiliximab; Child; Daclizumab; Encephalitis; Fatal Outcome; Female; Graft Rejection; Humans; Immunoglobulin G; Immunosuppressive Agents; Intestinal Diseases; Intestinal Volvulus; Intestines; Male; Nervous System Diseases; Recombinant Fusion Proteins; Short Bowel Syndrome; Tacrolimus

Topics: Adult; Anti-Inflammatory Agents; Atrophy; Brain; Chronic Disease; Cyclophosphamide; Encephalitis; Epilepsy; Facial Hemiatrophy; Female; Humans; Immunosuppressive Agents; Male; Tacrolimus; Young Adult

Posterior reversible encephalopathy syndrome (PRES) is one of the serious adverse side effects of calcineurin inhibitors, which are used for the prophylaxis of graft-versus-host disease (GVHD) after allogeneic stem cell transplantation (allo-SCT). We retrospectively analyzed 12 patients who developed PRES after allo-SCT aiming to clarify the clinical features, risk factors, and prognosis of PRES. Median onset of PRES is 17 days after allo-SCT. The most frequent primary symptom was high blood pressure, followed by headache and visual disturbance. Nine of our patients subsequently developed systemic seizure. Sites of PRES by MRI were detected in the frontal, temporal, and parietal lobes, basal ganglia, and brain stem in addition to occipital lobe. Serum creatinine that had increased two-fold from the baseline value was identified as the only risk factor for developing PRES after allo-SCT. The incidence of acute GVHD (grade II-IV) in patients with PRES and those without were 88.9% and 48.7%; respectively (P<0.001), and most of these patients died of GVHD or GVHD-related causes. The 2-year overall survival of patients with PRES and those without were 16.7% and 72.4%, respectively (P<0.001). These data suggested the importance of early intervention for PRES and exploitation of optimal GVHD prophylaxis after developing PRES.

Topics: Acute Disease; Adolescent; Adult; Calcineurin Inhibitors; Creatinine; Cyclosporine; Encephalitis; Female; Graft vs Host Disease; Humans; Immunosuppressive Agents; Male; Middle Aged; Prognosis; Retrospective Studies; Risk Factors; Stem Cell Transplantation; Syndrome; Tacrolimus; Transplantation, Homologous; Young Adult

The immunosuppressant FK506 (1 mg/kg, i.p.) reduces the infarct size following 90 min occlusion of the middle cerebral artery (MCAo) in adult rat brain. Here we have investigated the effect of FK506 on cerebral immune cells that are considered to contribute to neurodegeneration. FK506 substantially attenuated the response of resident and peripheral immune cells following transient ischemia. Between 24 hr and 5 days after MCAo, FK506 reduced the T-cell infiltration in the infarct area as well as the presence of activated and/or phagocytic OX-18, OX-42, GSA-IB4, Iba1, and ED1 positive microglia/macrophages. FK506 also lowered the protein levels of TNFalpha and IL-2 in ischemic brain areas. Repetitive application of FK506 over 20 days attenuated the activation of microglia in the substantia nigra (SN), an area of secondary degeneration. Importantly, FK506 conferred also lasting protection of the neurons of SN; these neurons degenerate by withdrawal of neurotrophic factors from the striatum that undergoes necrotic death as part of the ischemic core. To understand the molecular basis of FK506 effects in cerebral immune cells, we determined in primary postnatal day 0/1 (P0/P1) microglia (i) the expression of the FK506 binding proteins FKBP12, FKBP52, and FKPB65 and (ii) that FK506 (1-100 ng/mL) lowered the number of resting or lipopolysaccharide stimulated microglia as well as we induced the lipopolysaccharide release of TNFalpha in a dose-dependent manner. In summary, FK506 confers rescue of brain tissue following cerebral ischemia not only by neuronal protection, but also by suppression of microglial activation and peripheral immune responses.

Topics: Animals; Biomarkers; Brain Ischemia; Cells, Cultured; Cerebral Infarction; Chemotaxis, Leukocyte; Coculture Techniques; Corpus Striatum; Cytokines; Disease Models, Animal; Encephalitis; Gliosis; Immunosuppressive Agents; Macrophages; Male; Microglia; Nerve Degeneration; Nerve Tissue Proteins; Neuroprotective Agents; Protein Binding; Rats; Rats, Sprague-Dawley; Substantia Nigra; T-Lymphocytes; Tacrolimus

We report a 17-year-old boy who was diagnosed as autoimmune encephalitis with various neurological complications such as hemiplegia, aphasia and seizures. An autoimmune process was considered to be responsible for the repeated episodes of encephalitis because the symptoms were highly responsive to steroids and anti-glutamate receptor antibodies were detected in the CSF. After administration of the immunosuppressant tacrolimus, we could taper the steroid dosage. He has had no relapse for three years to date. We demonstrated the possibility of steroid-sparing treatment with tacrolimus for a patient with steroid-responsive encephalitis. There were few reports describing tacrolimus therapy for encephalitis. Tacrolimus may be effective for selected patients with recurrent encephalitis in which an autoimmune mechanism is considered as the pathogenesis.

Topics: Adolescent; Autoimmune Diseases; Encephalitis; Humans; Immunosuppressive Agents; Male; Tacrolimus

The case of inflammatory vasculopathy and encephalopathy caused by treatment with tacrolimus is reported. This 49-year-old woman developed progressive gait ataxia and right-sided hemiparesis after 7 years of tacrolimus therapy for focal sclerosing glomerulonephritis. MRI presented multifocal cerebral lesions with contrast enhancement. Oligoclonal banding was positive. When the treatment with tacrolimus was stopped, the clinical symptoms resolved completely and the MRI findings improved with corticoid monotherapy.

Topics: Encephalitis; Female; Humans; Immunosuppressive Agents; Middle Aged; Tacrolimus; Vasculitis, Central Nervous System