Cyclosporin A-induced neurotoxicity

Monteiro, L.; Almeida-Pinto, J; Rocha, Noeme Sousa; Lopes, Gilberti Helena Hübscher; Rocha, José Antonio

doi:10.1259/0007-1285-66-783-271

Cited by 21 publications

(13 citation statements)

References 9 publications

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“…The symmetric polyneuropathy experienced by this patient was thought to be caused by axonal degeneration of the peripheral nerves. Another patient with idiopathic uveitis developed acute encephalopathy 2 weeks after beginning a combination regimen of CsA and methylprednisolone [58]. One OLT recipient developed a rapidly progressing irreversible neurotoxic syndrome with brain, kidney, and lung involvement that resembled thrombotic thrombocytopenia purpura (TTP) [6], while another developed late-occurring severe neurotoxicity including leukoencephalopathy [9].…”

Section: Overview Of Csa-associated Neurotoxicitymentioning

confidence: 99%

“…T2-weighted MRI scans of one patient with CsA-associated cortical blindness revealed increased signal intensity in two focal areas (bilateral and Many factors appear to predispose patients treated with either CsA or tacrolimus to develop drug-related neurotoxicial adverse events. Some of these factors are advanced liver failure [20], hypertension [26], hypocholesterolemia [19], elevated CsA-or tacrolimus blood levels [12], hypomagnesemia [86], intravenous administration of drug [19,24,691, and administration of other drugs that inhibit CsA and tacrolimus metabolism (including high-dose methylprednisolone) [49,58].…”

Section: Concomitant Factors In the Development Of Csa-and Tacrolimusmentioning

confidence: 99%

“…Methylprednisolone inhibits metabolism of CsA in the liver [58]. The occurrence of GVHD with concomitant use of highdose corticosteroids is the single predisposing factor in the occurrence of convulsions in BMT recipients [26].…”

Section: Concomitant Factors In the Development Of Csa-and Tacrolimusmentioning

confidence: 99%

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Neurotoxicity of calcineurin inhibitors: impact and clinical management

Bechstein¹

2000

Transplant Int

475

284

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Between 10 %-28 % of patients who receive the immunosuppressant cyclosporine (CsA) experience some form of neurotoxic adverse event. Both sensorial motoric functions may be adversely affected, and thus patients present with a wide range of neurological and psychiatrical disorders. Mild symptoms are common and include tremor, neuralgia, and peripheral neuropathy. Severe symptoms affect up to 5 % of patients and include psychoses, hallucinations, blindness, seizures, cerebellar ataxia, motoric weakness, or leukoencephalopathy.

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Section: Overview Of Csa-associated Neurotoxicitymentioning

confidence: 99%

Section: Concomitant Factors In the Development Of Csa-and Tacrolimusmentioning

confidence: 99%

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Neurotoxicity of calcineurin inhibitors: impact and clinical management

Bechstein¹

2000

Transplant Int

475

284

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“…3,4 Infectious and metabolic causes of progressive encephalopathy were excluded. He probably had symptoms of CsA neurotoxicity with his earliest complaint of 'blurred vision'.…”

Section: Discussionmentioning

confidence: 99%

“…2,3 This distinguishable clinical and radiographic syndrome, however, has not been reported to be directly fatal. [2][3][4] Here, we present a patient with typical CsA CNS neurotoxicty, a fatal outcome, and no other overt cause of death. We also describe the previously unreported …”

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confidence: 99%

Fatal outcome due to cyclosporine neurotoxicity with associated pathological findings

Gopal

Thorning

Back

1999

Bone Marrow Transplant

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Summary:We present a case of death likely to be directly due to cyclosporine (CsA) neurotoxicity. To date, there have been no reports of deaths directly due to CsA neurotoxicity, nor has an associated histological lesion been described independent of confounding processes. A 54-year-old male received an HLA-matched-unrelated BMT for CML. He developed progressive encephalopathy and on day ؉79 had a generalized seizure. All CSF studies were negative for infectious causes. MRI revealed diffuse, symmetrical white matter abnormalities located in the occipital sub-cortex, thalamus, mid brain, pons, and cerebellum which were typical of CsA toxicity. The patient died of central respiratory failure within 72 h of discontinuing CsA. Autopsy revealed diffuse patchy white matter edema and astrocytic injury without evidence of axonopathy, demyelination, microvascular injury, or infectious/inflammatory process. This case demonstrates previously undescribed lethal CsA neurotoxicity and may reveal an associated primary pathological lesion. Keywords: cyclosporine; neurotoxicity; MRI; CML; allogeneic bone marrow transplant Neurological complications cause morbidity and mortality in up to 37% of patients following allogeneic bone marrow transplantation. 1 Case reports and retrospective case series implicate CsA neurotoxicity as a significant contributor to these complications. 1,2 This toxicity can range from the most common finding of tremors to the most severe syndrome of seizures, visual disturbances, and radiographically characteristic white matter abnormalities often involving the occipital lobes. 2,3 This distinguishable clinical and radiographic syndrome, however, has not been reported to be directly fatal. [2][3][4] Here, we present a patient with typical CsA CNS neurotoxicty, a fatal outcome, and no other overt cause of death. We also describe the previously unreported Case reportPhiladelphia chromosome-negative CML was diagnosed in June 1996 in a 54-year-old male with adult onset diabetes. In July 1997, while still in chronic phase, he received an HLA-identical unrelated allogeneic BMT following CY/TBI conditioning. He was treated with routine GVHD prophylaxis consisting of CsA/MTX according to the Seattle regimen. 5 Engraftment (Ͼ500 neutrophils) occurred on day ϩ20, and platelet requirements ceased after day ϩ22. His post-transplant course was notable for the development of acute skin GVHD on day ϩ26 not requiring increased immunosuppression and symptomatic biopsyproven upper gastrointestinal GVHD on day ϩ65 requiring treatment with methylprednisolone (1 mg/kg i.v. twice daily).After complaining of intermittent 'blurred vision' for several days, he was noted by his wife to be confused on day ϩ78. Neurological examination and routine laboratory studies were normal. The following day he was increasingly somnolent. Deep tendon reflexes were symmetrical but plantar reflexes were absent. Otherwise, sensory/motor and cranial nerve examinations were normal. On day ϩ79 he had a single generalized tonic-clonic seizure that was...

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Cyclosporine induces neuronal apoptosis and selective oligodendrocyte death in cortical cultures

McDonald

Goldberg

Gwag

et al. 1996

Annals of Neurology

121

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Cyclosporine is used clinically as an immunosuppressant, but carries a risk of central nervous system toxicity due to undefined mechanisms. We examined the ability of cyclosporine exposure to kill cultured mouse cortical neurons and glia. Mixed neuron/glial cultures exposed to 1 to 20 microM cyclosporine for 24 to 48 hours developed concentration-dependent neuronal death, with most neurons destroyed by 20 microM cyclosporine. This neuronal death was characterized by cell body shrinkage and blebbing, chromatin condensation, and internucleosomal DNA fragmentation, consistent with apoptosis. Neuronal death was reduced by addition of cycloheximide, brain-derived neurotrophic factor, or insulin-like growth factor I but not N-methyl-D-aspartate- or AMPA-type glutamate receptor antagonists. Oligodendrocytes were more sensitive to cyclosporine-induced damage than were neurons, but astrocytes were relatively resistant. Oligodendrocyte death was accompanied by positive TUNEL (terminal deoxynucleotidyl transferase-mediated deoxyuridine triphosphate-biotin nick end-labeling) staining and was attenuated by application of ciliary neurotrophic factor or insulin-like growth factor I but not glutamate receptor antagonists. Present observations raise the possibility that the central nervous system toxicity syndrome associated with cyclosporine may be caused by the drug-induced death of oligodendrocytes and neurons.

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Cyclosporin A-induced neurotoxicity

Cited by 21 publications

References 9 publications

Neurotoxicity of calcineurin inhibitors: impact and clinical management

Neurotoxicity of calcineurin inhibitors: impact and clinical management

Fatal outcome due to cyclosporine neurotoxicity with associated pathological findings

Cyclosporine induces neuronal apoptosis and selective oligodendrocyte death in cortical cultures

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