Bone Marrow Transplantation (2013) 48, 157–158 & 2013 Macmillan Publishers Limited All rights reserved 0268-3369/13 www.nature.com/bmt

LETTER TO THE EDITOR Akinetic mutism—a serious complication to tacrolimus-based GVHD prophylaxis

Bone Marrow Transplantation (2013) 48, 157–158; doi:10.1038/ 40/UL (0–0 U/L), elevated glucose at 93 mg/dL (40–70 mg/dL) and bmt.2012.110; published online 18 June 2012 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 Tacrolimus, a heterocyclic macrolide immunosupressive agent 36 her tacrolimus, which had always been in the therapeutic that belongs to the calcineurin inhibitor class, works by blocking range, was discontinued, due to possible neurotoxicity. She was the production of IL-2, thereby inhibiting proliferation of antigen- started on sirolimus, and the mycophenolate was continued. specific T lymphocytes.1 It is estimated to be 50–200 times more On day 37 the patient developed tremors, a repeat EEG showed potent than cyclosporin (CYA) and is now commonly used after unspecific findings. Because epileptiform waves could not be allo-SCT to prevent GVHD.1 Although common adverse effects like excluded, she was empirically started on i.v. dilantin for possible hypertension, nephrotoxicity and hyperglycemia are manageable non-convulsive status epilepticus requiring intensive care unit without drug discontinuation, serious adverse effects might admission and intubation for airway protection. Her clinical require discontinuation and change to an immunosuppressive course was complicated by hypotension and acute kidney agent from a different class.1 Reported incidence of neurotoxicity injury, and she received hemodyalisis transiently. On day 43 from tacrolimus may be as high as 32%.2 Most common she was extubated, slowly started again to communicate, and neurologic side effects include tremor, insomnia, nightmares, become more interactive with spontaneous movements and headache, vertigo and mood disturbance. Serious neurologic speech. She had no recollection of previous events. Upon adverse effects are relatively rare and include: seizures, cortical discharge from the hospital, she was fully interactive and had blindness, coma or encephalopathy.2 Here we present an no neurologic deficits. uncommon but serious neurological complication of tacrolimus: Tacrolimus-induced akinetic mutism is an uncommon but akinetic mutism, mostly described in solid organ trans- serious complication, described in solid organ transplant plantation.3–8 This case documents the occurrence of akinetic patients,3–8 and only in one stem cell transplant patient.9 It has mutism after hematopoietic SCT. been shown that this adverse effect can develop even with A 58-year-old woman without significant medical history except therapeutic levels of tacrolimus2,4,6 and can lead to tonic clonic primary refractory AML was admitted to the hospital for a seizures3,5 after mutism has occurred.3 The etiology is unknown, haploidentical stem cell transplant from her son. Conditioning but it is hypothesized that tacrolimus might cause breakdown of chemotherapy consisted of fludarabine 160 mg/m2, melphalan the auto-regulation in the blood–brain barrier by inducing 140 mg/m2 and thiothepa 10 mg/kg. The patient received post vasogenic edema from enhanced nitric oxide production causing transplant CY 50 mg/m2 on days þ 3 and þ 4 for GVHD endothelial damage.7,9 Another theory is that neutoxicity can occur prophylaxis followed by tacrolimus 0.7 mg intravenous (i.v.) and from changes in central nervous system neurotransmitters,2,4,5 as mycophenolate 2.25 g daily, which started on day 5. The tacrolimus can modulate the activity of both excitatory (N-methyl- tacrolimus dose was adjusted to 1.4 mg daily, which maintained D-aspartic acid (NMDA)) and inhibitory (gamma-aminobutyric acid the serum tacrolimus level in the therapeutic range (6–15 ng/mL). (GABA)) aminoacid receptors via calcineurin.1 Abnormalities on On day 16, the patient started to develop poor motivation to imaging are sometimes seen in this disorder. In some cases, MRI continue her post-transplant recovery and became increasingly brain has shown non-specific cerebellar or cerebral white and gray withdrawn. She was evaluated by psychiatry and it was matter changes3,7,8 and in one report, changes were seen on appreciated that her symptoms were not related to depression Positron emission tomography scan4 consisting of decrease FDG or other psychiatric condition. During the next several days her (Fluodeoxyglucose) uptake in the temporal lobes and adjacent symptoms worsened. She developed extreme apathy, low energy, parieto-occipital regions bilaterally. poor concentration and somnolence. TSH and free T4 were The most often used treatment is discontinuation of tacroli- normal. An Electroencephalogram (EEG) was performed, which mus2–5 and replacement with an alternate immunosuppressive showed findings of mild generalized slowing with sleep patterns. agent like mycophenolate mofetil or sirolimus. In one report Possible sedating medications were discontinued; however, her clinical improvement was noted after administration of symptoms continued to worsen. She developed mutism with lorazepam,6 suggesting a possible role for GABA agonists in this inability to answer any questions or have spontaneous speech, as disorder.7 Most patients will have improvement in their symptoms well as inability to perform any voluntary movements. She after tacrolimus removal, whereas some patients might have appeared to understand but was unable to communicate or long-term neurological side effects.2,3,7,10 This case relates to the follow commands. No overt metabolic abnormalities were found importance of having a high level of suspicion for neurological by laboratory evaluation. Methylphenidate was tried for a short side effects related to tacrolimus in patients who develop period of time with no improvement. When symptoms started her unexplained neurologic symptoms in the early post-transplant tacrolimus level was 10.9 ng/mL. She had no focal neurological period and to change this medication before severe or permanent deficits and an MRI brain showed scattered T2/FLAIR (fluid- neurological side effects may develop. attenuated inversion recovery) hyperintensities in the periven- tricular and deep white matter, and no acute intracranial pathology. A lumbar puncture was performed and the cerebro- CONFLICT OF INTEREST spinal fluid showed normal WBC count, elevated RBC count at The authors declare no conflict of interest. Letter to the Editor 158 1,2 3 3 3 JE Najera , A Alousi , M De Lima and SO Ciurea 4 Bronster D, Gurkan A, Buchsbaum M, Sukru E. Tacrolimus-associated mutism after 1 Department of Hematology/Oncology, MD Anderson Cancer Center, orthotopic liver transplantation. Transplantation 2000; 70: 979–982. Orlando, Orlando, FL, USA; 5 Boeve B, Kimmel D, Aronson A, De Groen P. Dysarthria and apraxia of speech 2Department of Internal Medicine, University of Central Florida, associated with FK-506. Mayo Clin Oric 1996; 71: 969–972. College of Medicine, Orlando, FL, USA and 6 Odonnell M, Williams J, Weinrieb R, Denysenko L. Catatonic mutism after 3The University of Texas, MD Anderson Cancer Center, Stem Cell liver transplant rapidly reversed with lorazepam. Gen Hosp Psychiatry 2007; 29: Transplantation & Cellular Therapy, Orlando, FL, USA 280–281. E-mail: [email protected] 7 Sierra F, Matinez A, Moreno S, de Pablo F, Correas E, Ruiz J. Akinetic mutism induced by tracrolimus. Clin Neuropharm 2009; 32: 293–294. 8 Vearrier D, Simpson SE, Greenberg M. Mutism and persistent dysarthria due to tacrolimus-based immunosupression following allogenic liver transplantation. Am REFERENCES JTher2010; 18: e274–e2766. 1 Lee T, Kennedy L. Tacrolimus: an alternative for graft-versus-host disease pre- 9 Ahn K, Lee JW, Hahn ST, Yang DW, Kim PS, Kim HJ et al. Diffusion vention. Ann Pharmacother 2000; 34: 377–381. weighted MRI and ADC mapping in FK506 neurotoxicity. Br J Radiol 2003; 76: 2 Bechstein WO. Neurotoxicity of calcineurin inhibitors: impact and clinical man- 916–919. agement. Transpl Int 2000; 13: 313–326. 10 Chohan R, Vij R, Adkins D, Blum W, Brown R, Tomasson M et al. Long term 3 Sokol DK, Molleston J, Filo RS, Van Valer J, Edwards-Brown M. Tacrolimus induced outcomes of allogenic stem cell transplant recipients after calcineurin inhibitor- mutism after liver transplant. Pediatr Neurol 2003; 28: 156–158. induced neurotoxicity. Br J Haematol 2003; 123: 110–113.

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