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Akinetic mutism—a serious complication to tacrolimus-based GVHD prophylaxis

Bone Marrow Transplantation volume 48, pages 157–158 (2013)Cite this article

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Tacrolimus, a heterocyclic macrolide immunosupressive agent that belongs to the calcineurin inhibitor class, works by blocking the production of IL-2, thereby inhibiting proliferation of antigen-specific T lymphocytes.1 It is estimated to be 50–200 times more potent than cyclosporin (CYA) and is now commonly used after allo-SCT to prevent GVHD.1 Although common adverse effects like hypertension, nephrotoxicity and hyperglycemia are manageable without drug discontinuation, serious adverse effects might require discontinuation and change to an immunosuppressive agent from a different class.1 Reported incidence of neurotoxicity from tacrolimus may be as high as 32%.2 Most common neurologic side effects include tremor, insomnia, nightmares, headache, vertigo and mood disturbance. Serious neurologic adverse effects are relatively rare and include: seizures, cortical blindness, coma or encephalopathy.2 Here we present an uncommon but serious neurological complication of tacrolimus: akinetic mutism, mostly described in solid organ transplantation.3, 4, 5, 6, 7, 8 This case documents the occurrence of akinetic mutism after hematopoietic SCT.

A 58-year-old woman without significant medical history except primary refractory AML was admitted to the hospital for a haploidentical stem cell transplant from her son. Conditioning chemotherapy consisted of fludarabine 160 mg/m2, melphalan 140 mg/m2 and thiothepa 10 mg/kg. The patient received post transplant CY 50 mg/m2 on days +3 and +4 for GVHD prophylaxis followed by tacrolimus 0.7 mg intravenous (i.v.) and mycophenolate 2.25 g daily, which started on day 5. The tacrolimus dose was adjusted to 1.4 mg daily, which maintained the serum tacrolimus level in the therapeutic range (6–15 ng/mL). On day 16, the patient started to develop poor motivation to continue her post-transplant recovery and became increasingly withdrawn. She was evaluated by psychiatry and it was appreciated that her symptoms were not related to depression or other psychiatric condition. During the next several days her symptoms worsened. She developed extreme apathy, low energy, poor concentration and somnolence. TSH and free T4 were normal. An Electroencephalogram (EEG) was performed, which showed findings of mild generalized slowing with sleep patterns. Possible sedating medications were discontinued; however, her symptoms continued to worsen. She developed mutism with inability to answer any questions or have spontaneous speech, as well as inability to perform any voluntary movements. She appeared to understand but was unable to communicate or follow commands. No overt metabolic abnormalities were found by laboratory evaluation. Methylphenidate was tried for a short period of time with no improvement. When symptoms started her tacrolimus level was 10.9 ng/mL. She had no focal neurological deficits and an MRI brain showed scattered T2/FLAIR (fluid-attenuated inversion recovery) hyperintensities in the periventricular and deep white matter, and no acute intracranial pathology. A lumbar puncture was performed and the cerebrospinal fluid showed normal WBC count, elevated RBC count at 40/UL (0–0 U/L), elevated glucose at 93 mg/dL (40–70 mg/dL) and elevated protein at 74 mg/dL (15–55 mg/dL). All the bacterial and viral infectious studies were negative. The patient was empirically started on forscarnet for possible viral encephalitis without improvement. Her symptoms persisted, and on day 36 her tacrolimus, which had always been in the therapeutic range, was discontinued, due to possible neurotoxicity. She was started on sirolimus, and the mycophenolate was continued. On day 37 the patient developed tremors, a repeat EEG showed unspecific findings. Because epileptiform waves could not be excluded, she was empirically started on i.v. dilantin for possible non-convulsive status epilepticus requiring intensive care unit admission and intubation for airway protection. Her clinical course was complicated by hypotension and acute kidney injury, and she received hemodyalisis transiently. On day 43 she was extubated, slowly started again to communicate, and become more interactive with spontaneous movements and speech. She had no recollection of previous events. Upon discharge from the hospital, she was fully interactive and had no neurologic deficits.

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Authors and Affiliations

  1. Department of Hematology/Oncology, MD Anderson Cancer Center, Orlando, Orlando, FL, USA

    J E Najera

  2. Department of Internal Medicine, University of Central Florida, College of Medicine, Orlando, FL, USA

    J E Najera

  3. The University of Texas, MD Anderson Cancer Center, Stem Cell Transplantation & Cellular Therapy, Orlando, FL, USA

    A Alousi, M De Lima & S O Ciurea

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Correspondence to J E Najera.

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Najera, J., Alousi, A., De Lima, M. et al. Akinetic mutism—a serious complication to tacrolimus-based GVHD prophylaxis. Bone Marrow Transplant 48, 157–158 (2013). https://doi.org/10.1038/bmt.2012.110

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