CNI use (cyclosporine and tacrolimus) is probably the single most frequent cause of neurologic toxicity. The most common manifestations are tremor and burning palmar and plantar dysesthesias. However, headache, depression, confusion, somnolence, and nystagmus may also be observed. Seizures may occur, especially in association with hypomagnesemia, hypertension, hypocholesterolemia, infections, and high blood levels of CNIs.

A unique complication of CNIs is cortical blindness and posterior leukoencephalopathy. This syndrome is known as PRES – posterior reversible encephalopathy syndrome. It is often observed in association with the new onset of hypertension, suggesting that there is cerebral edema due to abnormalities of pressure regulation in the posterior circulation. Many of the radiologic manifestations are similar to those seen in hypertensive encephalopathy. The most common pattern is white matter edema in the posterior circulation, which may or may not persist despite continued use of the drug. Although there are reports to the contrary, most clinicians believe that cyclosporine and tacrolimus are cross-reactive; therefore, substitution of one for the other may not be useful. Newer agents such as sirolimus or mycophenolate mofetil have no known neurological toxicity and may be appropriate substitutes for CNIs. Establishing a successful immunosuppressive regimen in this setting can be quite difficult, and may require persistent use of the offending agent with an effort to maintain excellent blood pressure control.

A frequent complication of the use of CNIs is the development of thrombotic microangiopathy. These microangiopathies are associated with evidence of hemolysis; typically, schistocytes are observed on the blood smear and there is a reduction in haptoglobin. Because of renal vascular involvement, hypertension and azotemia are generally concomitantly observed.

Other less common manifestations of these agents include coma, optic disc edema, aphasia, paralysis, insomnia, somnolence, and rigidity.