Tackling posterior reversible encephalopathy syndrome (pres): a rare case of subtherapeutic tacrolimus causing pres in steroid-resistant nephropathy

SESSION TITLE: Neuro Critical Cases SESSION TYPE: Case Reports PRESENTED ON: 10/19/2022 11:15 am - 12:15 pm INTRODUCTION: Tacrolimus (TAC) is a Calcineurin inhibitor used as an immunosuppressant for solid organ transplants, autoimmune disorders, and an alternative therapy for steroid-resistant nephropathy. TAC may manifest neurotoxicity with a rare syndrome named Posterior Reversible Encephalopathy Syndrome (PRES). PRES is a poorly understood clinical-radiologic syndrome characterized by headache, confusion, seizure, visual disturbances, and posterior focal neurologic deficits. CASE PRESENTATION: A 68 F with hypertension, thrombocytopenia, and nephrotic syndrome with focal segmental glomerulosclerosis (FSGS) commenced treatment with TAC one week prior to admission after failing steroid therapy. She presented to the ED in Status Epilepticus which resolved after 19mg of Lorazepam and was admitted to the ICU. TAC was discontinued due to concern for neurotoxicity despite a sub-therapeutic TAC level of 2.4ng/mL (Normal 5-20ng/mL). Treatment regimen included steroids, anti-epileptics, and anti-hypertensives. After a few days she became more alert, but she developed hallucinations and agitation. Brain MRI revealed vasogenic edema in the occipital and posterior parietal lobes, consistent with PRES. Within one week of conservative management all symptoms resolved, and she was discharged to home. DISCUSSION: Endothelial injury causes disruption of the blood–brain barrier (BBB), leading to extravasation of plasma and macromolecules into the interstitium. The posterior brain is more susceptible due to poor sympathetic innervation in the posterior fossa leading to hyperperfusion.[1] The endothelium may be damaged due to abrupt blood pressure change. Acute hypertension frequently accompanies PRES and treating hypertension results in clinical and radiological resolution.[2] Nephrotic syndrome induces vasogenic edema due to decreased intravascular oncotic pressure, increased capillary permeability, and fluid overload.[3] TAC effects the endothelial production of vasoactive agents that maintain the BBB, such as endothelin and Nitrous Oxide. Currently, the mainstay of treatment is supportive management and discontinuing Tacrolimus. Early suspicion of TAC toxicity is critical and failure to diagnose PRES at an early stage may result in cerebral ischemia and infarction. CONCLUSIONS: Both nephrotic syndrome and supra-therapeutic TAC levels can independently result in PRES. To the best of our knowledge, there is no prior case report of a sub-therapeutic Tacrolimus level induced epilepsy in a patient with membranous nephropathy. Hypertension and endothelial dysfunction occur in patients with nephrotic range proteinuria as well as in patients on TAC. We hypothesize that there is a synergistic risk of Tacrolimus and nephrotic syndrome for the development of PRES. This case highlights that clinicians should be cognizant of this risk and emphasizes the need for novel therapies in steroid-resistant nephrotic syndrome. Reference #1: Fugate JE, Claassen DO, Cloft HJ, et al. Posterior reversible encephalopathy syndrome: associated clinical and radiologic findings. Mayo Clin Proc. 2010;85(5):427-32. Reference #2: Rabinstein AA, Mandrekar J, Merrell R, Kozak OS, Durosaro O, Fugate JE. Blood pressure fluctuations in posterior reversible encephalopathy syndrome. J Stroke Cerebrovasc Dis. 2012;21(4):254-258. Reference #3: Kenji Ishikura1, Masahiro Ikeda et al. Nephrol Dial Transplant (2008) 23: 2531–2536 doi: 10.1093/ndt/gfn013 Advance Access publication 7 February 2008 DISCLOSURES: No relevant relationships by Maria Bernal Riera No relevant relationships by Marvyn Allen Chan No relevant relationships by David Gruen Speaker/Speaker's Bureau relationship with GSK Please note: approx 2016 to now by Michael Mandel, value=Consulting fee