Case Presentation: Four years after kidney transplantation a 65 year-old woman with type 2 diabetes, hypertension, and no psychiatric history is referred to the hospital by her primary care physician to evaluate altered mental status. She was successfully maintained on tacrolimus with stable trough levels. During the preceding three months she had developed progressive symptoms characterized by shuffling gait, disorientation, inappropriate behaviors such as voiding in living spaces, disturbing and vivid dreams, hallucinations, orthostasis, and 25-pound weight loss. Her partner reported these symptoms began with pneumonia that had otherwise responded to treatment. During this decline she was also successfully treated for a urinary tract infection, and found to be Epstein-Barr virus (EBV) seropositive though with no evidence of posttransplant lymphoproliferative disorder.After admission paranoia, delusions, and disorientation progressively worsened. Complete blood count, liver function tests, renal function panel, thyroid studies, and urinalysis were unrevealing. CT and PET/CT imaging was unremarkable, toxicology screen was negative, and ammonia level was within normal limits. Serum EBV on admission was 1097 IU/mL and undetectable before discharge. MRI brain showed mild diffuse pachymeningeal enhancement. Cerebrospinal fluid (CSF) analysis revealed no nucleated cells but elevated total protein (111 mg/dL) and oligoclonal bands. Cultures and viral testing were negative. With no other etiology identified, tacrolimus was changed to cyclosporine and after otherwise negative evaluation she was discharged to a rehabilitation facility. She had nearly complete resolution of her symptoms and return to her baseline functionality in 2 weeks after discontinuing tacrolimus. Two months later she remained at her past baseline mentation and regained 17 pounds.
Discussion: We present a case of subacute progressive neurotoxicity after 4 years of uncomplicated tacrolimus treatment with several unique features. First, neurotoxicity is a common side effect of tacrolimus within a year of induction or maintenance, but is rarely reported after long-term stable dosing. Nevertheless, the rapid improvement following cessation of tacrolimus is strongly suggestive of toxicity. Furthermore, tacrolimus is more likely in the context of elevated trough levels, liver and kidney dysfunction, but our patient had none of these risk factors.Secondly, a range of neurologic complaints are reported with tacrolimus but encephalopathy has generally been acute in onset, and subacute to chronic cognitive impairment with psychotic features is rarely reported. Furthermore, our patient did not have imaging or clinical evidence of posterior reversible encephalopathy syndrome or other abnormalities commonly attributable to tacrolimus toxicity.Finally, our case presents evidence for a possible immunologic basis for tacrolimus’ toxic effect. Elevated protein, inflammatory MRI findings, and oligoclonal bands were not explained by any other factor despite broad infectious testing and extensive imaging studies. Other recent reports highlight this relatively novel mechanism for tacrolimus’ neurotoxic effect (1).
Conclusions: We present an unusual case of reversible subacute progressive encephalopathy suspected to be from a tacrolimus-related toxicity with possible immune etiology. Further research is needed to clarify a possible immune basis for subacute encephalopathy related to tacrolimus therapy.