It is well known that calcineurin inhibitors (CIs; cyclosporine and tacrolimus) may induce severe neurotoxicity even at therapeutic levels.1 Major central nervous system (CNS) complications induced by CI include headaches, altered mental status (AMS), seizures, cortical blindness, auditory and visual hallucinations, spasticity, paresis, and ataxia. It is interesting that, in their recent article, Besenski et al2 found AMS, headaches, and seizures as the most common symptoms not only in the kidney transplant recipients (KTR) whom they studied, but also in a group of pretransplant patients.
The pathogenesis of CI-induced CNS toxicity remains unclear. It has not been determined whether the clinical symptoms in KTR treated with CI are due to the direct drug toxicity, hypomagnesemia or hypocholesterolemia, hypertension, or a combination of these. Is the mechanism due to demyelination, ischemia mediated by vascular spasm, or hypertension?
It has been suggested in the literature that subcortical edema is the result of a hyperperfusion insult promoted by endothelial damage with breakthrough of autoregulation in the posterior circulation, which has paucity of sympathetic innervation. MR imaging perfusion studies have shown areas of signal intensity abnormality, whereas diffusion studies have been negative. Endothelial cell damage could be responsible for direct injury to the capillary bed and alteration of the blood-brain barrier, as well as the release of potent vasoconstrictors resulting in vasospasm. Injury to the blood-brain barrier may occur and recent reports note brain enhancement in several patients.3
In the series presented by Besenski et al, none of the patients had hypomagnesemia or hypertension, and only 9% had a cholesterol level <120 mg/mL. As the authors stated, this probably contributed to the low incidence of CI CNS toxicity in their study. The authors found posterior reversible encephalopathy syndrome (PRES) in 5% of KTR but also in 4% of the comparison group. It is not clear from this report why the 4% of pretransplant patients had PRES, because they were not hypertensive or taking any neurotoxic medication. PRES can be seen in other conditions such as eclampsia, hypertensive encephalopathy, systemic lupus erythematosus, and thrombotic microagiopathy. Besenski et al’s data suggest that, in KTR, PRES is probably not exclusively caused by direct CI CNS toxicity because the incidence was similar in KTR and in the pretransplant comparison group and in their different groups 1, 2, and 3 (the groups were based on the time interval between transplantation and MR imaging examination). They therefore suggested that the etiology of PRES in KTR is multifactorial and needs further investigation. They did note, however, that statistical power was restricted by the number of patients in their study.
The major finding in this article was that the prevalence of PRES and both acute and chronic changes did not differ significantly in pre- and post-transplant kidney recipients, and, therefore, the authors claimed that their study did not support the previously reported suggestion that those changes were mostly because of CI toxicity because the pretransplant group was not treated with CI. On the other hand, a study by Sheth et al4 of 10 asymptomatic post-transplant patients found no MR imaging abnormalities, and the authors concluded that lesions visible in patients with clinical neurotoxicity were because of cyclosporin effects and not pre-existing coincidental abnormalities. The other major finding in the paper by Besenski et al was that there was no significant difference in the prevalence of brain abnormalities in early compared with late post-transplant periods when exposure to CI is tapered. This also is in contradistinction to what has been previously published where symptoms and imaging findings have been noted to regress rapidly after discontinuation or reduction in dosage of CI and correction of potentiating factors.5
In the future, larger series of cases with appropriate control groups must be studied to obtain statistically significant numbers. Also, further investigation needs to be performed on the mechanism and pathophysiology of CI toxicity, including studies where CI is tapered and serial MR studies are obtained.
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