tacrolimus and Demyelinating-Diseases

Tumefactive demyelinating lesions (TDLs) are rare and specific types of inflammatory demyelinating lesions. Its clinical manifestations are nonspecific, and the imaging findings are similar to those of other intracranial space-occupying lesions, which are usually misdiagnosed as tumors or abscesses and require a pathologic examination to confirm the diagnosis. Tumefactive demyelinating lesions after kidney transplantation are even rarer. This article reports a case of TDLs after kidney transplantation. A 60-year-old female patient underwent kidney transplantation 15 years ago and took anti-rejection drugs such as tacrolimus, tacrolimus, and corticosteroids after surgery. The patient was admitted with headache and left limb weakness, and magnetic resonance imaging of the head showed multiple space-occupying lesions with surrounding edema. The patient underwent a stereotactic biopsy of the encephalopathy lesion, and postoperative pathology confirmed TDLs. She was treated with corticosteroids and discharged after the improvement of her symptoms. Here, to our knowledge, we report the first case of TDLs after kidney transplantation. We report this case to provide clinicians with useful information on intracranial demyelinating disease after kidney transplantation.

Topics: Adrenal Cortex Hormones; Demyelinating Diseases; Female; Humans; Kidney Transplantation; Magnetic Resonance Imaging; Middle Aged; Tacrolimus

Peripheral neuropathy after bone marrow transplantation can produce motor disability with significant morbidity and mortality, particularly when the neuropathy occurs within the first few months of the transplant. Most of these severe neuropathies have demyelinating features on electrophysiologic tests and histopathology, characteristic of immunologically-mediated neuropathies. The specific immune mechanism is uncertain. It is possible that cyclosporin, FK-506, and interferon-alpha may all trigger immunologically mediated neuropathies in rare patients. Transplants in patients with pre-existing demyelinating neuropathy may result in abrupt exacerbation of the neuropathy. Other causes of severe neuropathies include high-dose cytosine arabinoside and critical illness polyneuropathy. Less severe neuropathies with primarily sensory deficits may result from etoposide conditioning, thalidomide treatment for graft-versus-host disease, and the chemotherapeutic agents cisplatin and paclitaxel when used at high-dose with peripheral stem cell support. When encountering patients with disabling motor neuropathies, transplant physicians must identify (with the aid of nerve conduction tests) those neuropathies that are likely to be immunologically mediated and then empirically add or alter immunosuppressant therapies. Unfortunately, experience has been too limited to suggest specific regimens or the optimal sequence of immunosuppressant therapies.

Topics: Bone Marrow Transplantation; Cyclosporine; Cytarabine; Demyelinating Diseases; Humans; Immunosuppressive Agents; Interferon-alpha; Peripheral Nervous System Diseases; Tacrolimus; Time Factors

Remyelination occurs in multiple sclerosis (MS) lesions but is generally considered to be insufficient. One of the major challenges in MS research is to understand the causes of remyelination failure and to identify therapeutic targets that promote remyelination. Activation of pancreatic endoplasmic reticulum kinase (PERK) signaling in response to endoplasmic reticulum stress modulates cell viability and function under stressful conditions. There is evidence that PERK is activated in remyelinating oligodendrocytes in demyelinated lesions in both MS and its animal model, experimental autoimmune encephalomyelitis (EAE). In this study, we sought to determine the role of PERK signaling in remyelinating oligodendrocytes in MS and EAE using transgenic mice that allow temporally controlled activation of PERK signaling specifically in oligodendrocytes. We demonstrated that persistent PERK activation was not deleterious to myelinating oligodendrocytes in young, developing mice or to remyelinating oligodendrocytes in cuprizone-induced demyelinated lesions. We found that enhancing PERK activation, specifically in (re)myelinating oligodendrocytes, protected the cells and myelin against the detrimental effects of interferon-γ, a key proinflammatory cytokine in MS and EAE. More important, we showed that enhancing PERK activation in remyelinating oligodendrocytes at the recovery stage of EAE promoted cell survival and remyelination in EAE demyelinated lesions. Thus, our data provide direct evidence that PERK activation cell-autonomously enhances the survival and preserves function of remyelinating oligodendrocytes in immune-mediated demyelinating diseases.

Topics: Animals; Axons; Cell Death; Cell Survival; Cuprizone; Cytoprotection; Demyelinating Diseases; eIF-2 Kinase; Encephalomyelitis, Autoimmune, Experimental; Enzyme Activation; Inflammation; Interferon-gamma; Mice; Mice, Inbred C57BL; Myelin Sheath; Oligodendroglia; Signal Transduction; Tacrolimus; Tremor

Multiple sclerosis (MS) is a demyelinating disease of the central nervous system that presents with variable pathologies that may reflect different disease-causing mechanisms. Existing animal models of MS induce pathology using either local injection of gliotoxins or stimulation of the immune system with myelin-related peptides. In none of these models is the primary cellular target well characterized, and although demyelination is a hallmark pathological feature in MS, it is unclear to what extent this reflects local oligodendrocyte loss. To unambiguously identify the effects of oligodendrocyte death in the absence of inflammatory stimulation, we developed a method for experimentally inducing programmed cell death selectively in mature oligodendrocytes and assessed the effects on demyelination, immunological stimulation, and gliosis. The resulting pathology is discussed relative to observed MS pathologies.. Oligodendrocyte apoptosis was induced in the adult rat brain using a lentivirus to express experimentally inducible caspase 9 (iCP9) cDNA under transcriptional control of the promoter for myelin basic protein, which is oligodendrocyte-specific. Activation of iCP9 was achieved by distal injection of a small molecule dimerizer into the lateral ventricle resulting in localized, acute oligodendrocyte apoptosis.. Induced oligodendrocyte apoptosis resulted in rapid demyelination and robust, localized microglial activation in the absence of peripheral immune cell infiltration. Lesion borders showed layers of preserved and degraded myelin, whereas lesion cores were demyelinated but only partially cleared of myelin debris. This resulted in local proliferation and mobilization of the oligodendrocyte progenitor pool.. This approach provides a novel model to understand the pathological changes that follow from localized apoptosis of myelinating oligodendrocytes. It provides the first direct proof that initiation of apoptosis in oligodendrocytes is sufficient to cause rapid demyelination, gliosis, and a microglial response that result in lesions sharing some pathological characteristics with a subset of MS lesions.

Topics: Animals; Apoptosis; Apoptotic Protease-Activating Factor 1; Basic Helix-Loop-Helix Transcription Factors; Brain; Caspase 9; Cell Count; Cells, Cultured; Demyelinating Diseases; Disease Models, Animal; Enzyme Activation; Gangliosides; Glial Fibrillary Acidic Protein; Gliotoxin; Green Fluorescent Proteins; Immunosuppressive Agents; Myelin Basic Protein; Nerve Tissue Proteins; O Antigens; Oligodendrocyte Transcription Factor 2; Oligodendroglia; Protein Multimerization; Rats; Tacrolimus; Transduction, Genetic; Transfection

To report the first histopathologic description of optic nerve demyelination from tacrolimus (FK 506) toxicity in the absence of toxic levels of tacrolimus in a patient presenting with asymmetric bilateral visual loss after 5 years of tacrolimus therapy.. We report a patient status post cardiac and renal transplantation who developed severe, progressive and asynchronous bilateral visual loss after prolonged treatment with tacrolimus. Orbital MRI showed an enlarged left optic nerve that enhanced with gadolinium.. After extensive negative work up, biopsy of one optic nerve was performed. Microscopic analysis showed extensive demyelination in the absence of vasculitis, neoplastic or infectious etiologies. Our patient illustrates that demyelination of the optic nerve causing asynchronous vision loss can be associated with tacrolimus toxicity in the absence of toxic drug levels.

Topics: Biopsy; Demyelinating Diseases; Diabetes Complications; Disease Progression; Heart Transplantation; Humans; Immunosuppressive Agents; Kidney Transplantation; Magnetic Resonance Imaging; Male; Middle Aged; Optic Nerve; Optic Nerve Diseases; Postoperative Complications; Risk Factors; Tacrolimus; Visual Acuity

Topics: Carcinoma; Demyelinating Diseases; Female; Humans; Immunosuppressive Agents; Liver Neoplasms; Magnetic Resonance Imaging; Middle Aged; Neurotoxicity Syndromes; Tacrolimus

Tacrolimus has been often described to induce neuropathy in liver-, pancreas-, and renal-transplanted patients. Here, we report the first case of a 56-year-old woman who developed a progressive symmetric demyelinating sensorimotor polyneuropathy in the distal muscles of the lower limbs after therapy with tacrolimus because of heart transplantation. This condition suddenly reverted after the tacrolimus was stopped.

Topics: Demyelinating Diseases; Diagnosis, Differential; Disease Progression; Drug Monitoring; Female; Heart Transplantation; Humans; Immunosuppressive Agents; Lower Extremity; Middle Aged; Polyneuropathies; Polyradiculoneuropathy, Chronic Inflammatory Demyelinating; Tacrolimus; Treatment Outcome

Mice hetero- or homozygously deficient for myelin protein zero (P0+/-, P0-/- mice) are models for distinct forms of inherited de- or dysmyelinating neuropathies, respectively. P0+/- mice show a demyelinating neuropathy with a pathogenetic implication of CD8+ T-lymphocytes and macrophages, while P0-/- mice show dysmyelination with axonal loss. It was, therefore, of interest to treat both mutants with FK506 (Tacrolimus), an agent with immunosuppressive and neuroprotective properties. Treatment of P0+/- mice led to an aggravation of demyelination, without affecting nervous CD8+ T-lymphocytes, but reducing splenic CD4+ cells. Treatment of P0-/- mice resulted in a substantial increase of the dysmyelination-related axon loss. Treatment of wildtype mice did not cause pathological changes in peripheral nerves. Our study shows that FK506 may not be suitable for the treatment of the human nerve disorders. Furthermore, when used as an immunosuppressant, the drug may generate detrimental neurological side effects in patients with an additional hereditary neuropathy.

Topics: Animals; Axons; CD4-Positive T-Lymphocytes; CD8-Positive T-Lymphocytes; Charcot-Marie-Tooth Disease; Demyelinating Diseases; Disease Models, Animal; Flow Cytometry; Immunohistochemistry; Immunosuppressive Agents; Macrophages; Mice; Mice, Inbred C57BL; Mice, Transgenic; Microscopy, Electron; Myelin P0 Protein; Myelin Sheath; Neural Conduction; Peripheral Nerves; Spleen; Tacrolimus

Several kinds of injury models, such as crush, transection and graft repair have been well studied in terms of neuroprotective effect of FK506. However, definitive experimental studies are lacking on focal degeneration or ischemia. In the present study, our goal was to investigate the effect of FK506 on functional recovery of the sciatic nerve after focal ischemia, produced by stripping of the epineurial vessels. A total number of 48 Wistar rats were used for this purpose and divided into four groups (control, sham-operated, FK506-treated, and Vehicle-treated). Sciatic nerves were approached by femoral and gluteal muscle splitting. Then, epineurial vessels around the sciatic nerve were stripped in the FK506-treated and Vehicle-treated groups. After operation, 5mg/kg/day FK506 administration was initiated by subcutaneous injection until animal sacrifice. The same volume of saline was administrated to the vehicle-treated group. The functional and sensory recoveries were tested by walking pattern analysis and pinch test in every postoperative week. The animals were sacrificed in the end of the fourth postoperative week and sciatic nerve samples were harvested and processed for electron microscopic evaluation. Our data revealed that FK506 administration showed beneficial effect on subperineurial degeneration/demyelinization from functional, sensorial, and ultrastructural points of view. The sciatic nerve samples in the FK506-treated group had several remyelinated fibers compared to the vehicle-treated group. Our literature searches revealed that FK506 administration has not, to our knowledge, been studied in focal ischemic degeneration produced by stripping of the epineurial vessels.

Topics: Animals; Demyelinating Diseases; Female; Gait Disorders, Neurologic; Immunosuppressive Agents; Microscopy, Electron; Nerve Degeneration; Neurons; Pain Measurement; Rats; Rats, Wistar; Recovery of Function; Sciatic Nerve; Sensation; Tacrolimus; Walking

FK 506 is a potent immunosuppressive agent in clinical use in solid organ transplantation since 1989. Approximately 5% of patients receiving FK 506 develop major central nervous system toxicity but peripheral nervous system involvement is very uncommon, and there are only 4 reported cases of demyelinating polyneuropathy in patients who received a liver transplant. We report a case of demyelinating polyneuropathy associated with the use of FK 506 in a renal transplant recipient.

Topics: Acute Disease; Acute Kidney Injury; Adult; Demyelinating Diseases; Humans; Immunosuppressive Agents; Kidney Transplantation; Male; Neural Conduction; Polyneuropathies; Tacrolimus

Topics: Adult; Azathioprine; Brain Diseases; Cyclosporine; Demyelinating Diseases; Drug Therapy, Combination; Family; Female; Humans; Immunosuppressive Agents; Liver Transplantation; Living Donors; Magnetic Resonance Imaging; Middle Aged; Prednisolone; Syndrome; Tacrolimus; Tomography, X-Ray Computed

Topics: Adult; Chronic Disease; Demyelinating Diseases; Electromyography; Female; Humans; Immunosuppressive Agents; Polyneuropathies; Prednisolone; Psoriasis; Recurrence; Tacrolimus

Topics: Demyelinating Diseases; Humans; Liver Diseases; Liver Transplantation; Male; Middle Aged; Peripheral Nervous System Diseases; Tacrolimus

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 cause. Although autoimmune neuropathy has been previously reported in immune-deficient states such as Hodgkin's disease and AIDS, it is not an expected complication of immunosuppressive therapy. However, others have shown that this phenomenon 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.

Topics: Demyelinating Diseases; Electromyography; Humans; Male; Middle Aged; Neural Conduction; Peripheral Nerves; Polyradiculoneuropathy; Tacrolimus