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. Tacrolimus is associated with similar neurotoxic adverse events. Neurotoxicity may result in serious complications for some patients, particularly recipients of orthotopic liver transplants. Factors that may promote the development of serious complications include advanced liver failure, hypertension, hypocholesterolemia, elevated CsA or tacrolimus blood levels, hypomagnesemia, and methylprednisolone. Occipital white matter appears to be uniquely susceptible to the neurotoxic effects of CsA; injury to both the major and minor vasculature may cause hypoperfusion or ischemia and local secondary toxicity in the white matter. Calcineurin inhibition by CsA and tacrolimus alters sympathetic outflow, which may play a role in the mediation of neurotoxic and hypertensive adverse events. The symptoms of CsA- and tacrolimus-associated neurotoxicity may be reversed in most patients by substantially reducing the dosage of immunosuppressant or discontinuing these drugs. However, some patients have experienced permanent or even fatal neurological damage even after dose reduction or discontinuation. CsA-sparing and tacrolimus-sparing drug regimens that use the immunosuppressant mycophenolate mofetil, which has no neurotoxic effects, may reduce the incidence and severity of neurotoxic adverse events while maintaining an adequate level of immunoisuppression.

https://onlinelibrary.wiley.com/doi/pdf/10.1111/j.1432-2277.2000.tb01004.x

Neurotoxicity of calcineurin inhibitors: impact and clinical management.

We describe severe central nervous system (CNS) toxicity, manifested by confusion, cortical blindness, quadriplegia, seizures, and coma, associated with cyclosporine treatment in three patients undergoing liver transplantation. CT and magnetic resonance studies disclosed a severe, diffuse disorder of the white matter. All side effects and radiographic findings were reversed with discontinuation or a reduction in the dose of cyclosporine. We also observed an inverse association between CNS side effects and total serum cholesterol levels after transplantation. A retrospective analysis of 54 liver transplantations performed in 48 patients revealed that 13 patients had symptoms of CNS toxicity associated with the use of cyclosporine. These patients' total serum cholesterol levels in the first week after transplantation were reduced as compared with those in patients without symptoms (mean +/- SE, 94 +/- 4 mg per deciliter vs. 132 +/- 6, or 2.44 +/- 0.10 mmol per liter vs. 3.43 +/- 0.16). We conclude that cyclosporine therapy for immunosuppression in liver transplantation may cause a syndrome of encephalopathy, seizures, and white-matter changes and that this is most likely to occur in patients with low total serum cholesterol levels after transplantation.

Central Nervous System Toxicity after Liver Transplantation

Cyclosporin A (CsA) induces neurological side effects in up to 40% of patients. A reversible posterior leukoencephalopathy syndrome is the most serious complication. Symptoms include headache, altered mental functioning, seizures, cortical blindness, and other visual disturbances, with hypertension. Neuroimaging studies show white matter changes in the posterior regions of the brain. Other neurological side effects of CsA include tremor, diffuse encephalopathy, cerebellar syndrome, extrapyramidal syndrome, pyramidal weakness, and peripheral neuropathy. Hypertension, hypomagnesemia, hypocholesteremia, and the vasoactive agent endothelin may all play a role in the pathogenesis of CsA neurotoxicty. Neurotoxicity is more frequent with high CsA blood levels, but levels may be within the therapeutic range. Dose reduction or withdrawal of CsA usually results in resolution of clinical symptoms and of neuroimaging abnormalities.

Cyclosporine neurotoxicity: a review.

Experimental traumatic brain injury (TBI) and spinal cord injury (SCI) result in a rapid and significant necrosis of neuronal tissue at the site of injury. In the ensuing hours and days, secondary injury exacerbates the primary damage, resulting in significant neurologic dysfunction. It is believed that alterations in excitatory amino acids (EAA), increased reactive oxygen species (ROS), and the disruption of Ca(2+) homeostasis are major factors contributing to the ensuing neuropathology. Mitochondria serve as the powerhouse of the cell by maintaining ratios of ATP:ADP that thermodynamically favor the hydrolysis of ATP to ADP + P(i), yet a byproduct of this process is the generation of ROS. Proton-pumping by components of the electron transport system (ETS) generates a membrane potential (DeltaPsi) that can then be used to phosphorylate ADP or sequester Ca(2+) out of the cytosol into the mitochondrial matrix. This allows mitochondria to act as cellular Ca(2+) sinks and to be in phase with changes in cytosolic Ca(2+) levels. Under extreme loads of Ca(2+), however, opening of the mitochondrial permeability transition pore (mPTP) results in the extrusion of mitochondrial Ca(2+) and other high- and low-molecular weight components. This catastrophic event discharges DeltaPsi and uncouples the ETS from ATP production. Cyclosporin A (CsA), a potent immunosuppressive drug, inhibits mitochondrial permeability transition (mPT) by binding to matrix cyclophilin D and blocking its binding to the adenine nucleotide translocator. Peripherally administered CsA attenuates mitochondrial dysfunction and neuronal damage in an experimental rodent model of TBI, in a dose-dependent manner. The underlying mechanism of neuroprotection afforded by CsA is most likely via interaction with the mPTP because the immunosuppressant FK506, which has no effect on the mPT, was not neuroprotective. When CsA was administrated after experimental SCI at the same dosage and regimen used TBI paradigms, however, it had no beneficial neuroprotective effects. This review takes a comprehensive and critical look at the evidence supporting the role for mPT in central nervous system (CNS) trauma and highlights the differential responses of CNS mitochondria to mPT induction and the implications this has for therapeutically targeting the mPT in TBI and SCI.

Mitochondrial permeability transition in CNS trauma: cause or effect of neuronal cell death?

Experimental traumatic brain injury (TBI) results in a rapid and significant necrosis of cortical tissue at the site of injury. In the ensuing hours and days, secondary injury exacerbates the original damage, resulting in significant neurological dysfunction. Young adult animals were treated either 5 min before or immediately after a cortical injury with the immunosuppressant cyclosporin A (CsA). All animals treated with CsA demonstrated a significant reduction in the amount of cortical damage 7 days following TBI. The effect was observed in adult rats and in two different strains of adult mice following systemic administration of the drug. Cyclosporin A has known effects on mitochondria by inhibiting the opening of the permeability transition pore and maintaining calcium homeostasis. These results with a clinically approved drug demonstrate an almost 50% reduction in lesion volume and suggest that the mechanisms responsible for tissue necrosis following TBI are amenable to manipulation. Since Cs...

J.H.M. Berden

Papers

Severe central-nervous-system toxicity associated with cyclosporin