Prolonged Pentobarbital-Induced Coma for the Treatment of Severe Seizures Related to Posterior Reversible Encephalopathy Syndrome Elviira Corsi, DO,* Subramanian Sathishkumar, MBBS,‡ Riaz Ali Shah, MD,† Zakiyah Kadry, MD, FACS,† Patrick M. McQuillan, MD,* Sonia J. Vaida, MD,* and Dmitri S. Bezinover, MD, PhD* In this report, we describe a case of posterior reversible encephalopathy syndrome in a female patient after deceased donor liver transplantation. She developed posterior reversible encephalopathy syndrome on postoperative day 3 and did not improve despite adjustments in immunosuppressive therapy. The patient had symptoms of severe brain edema requiring maximal therapy, which included cooling, mannitol, 3% saline, and a pentobarbital infusion. Attempts to lighten the level of sedation failed because of recurring intractable seizure activity. Reductions in therapeutic support were ultimately successful after 62 days of continuous pentobarbital therapy. The patient awoke neurologically intact and was discharged to a rehabilitation center in good condition.  (A&A Case Reports. 2014;3:149–52.)

P

osterior reversible encephalopathy syndrome (PRES) is a rare disorder related to various conditions, such as exposure to toxic agents, severe infection or sepsis, eclampsia, hypertension, and autoimmune diseases. In particular, PRES occurs after organ transplantation. Usually, PRES responds promptly to medication adjustments. If the condition is not quickly recognized and appropriately treated, it can lead to fatal complications, including cerebral herniation. We report a case of PRES after liver transplantation complicated by status epilepticus treated with prolonged barbiturate-induced coma after conventional antiseizure therapy was unsuccessful. Informed written consent and permission for publication were obtained from the patient before the preparation of this report.

CASE PRESENTATION

A 26-year-old woman with an unremarkable medical history presented to the medical center with fulminant hepatic failure secondary to amatoxin mushroom toxicity. Despite intensive treatment, her condition continued to deteriorate, and she was listed for liver transplantation. On hospital day 6, her trachea was intubated because of worsening encephalopathy. Magnetic resonance imaging (MRI) performed the same day did not reveal any signs of intracranial hemorrhage, increased intracranial pressure, or brain edema. Because of the patient’s small size (weight 46 kg, body mass index 18 kg/m2), donor options were limited. On hospital day 7, the patient received a blood group From the *Department of Anesthesiology, †Department of Transplant Surgery, Penn State University, College of Medicine, Hershey Medical Center, Hershey, Pennsylvania; and ‡Department of Anesthesiology, University of Michigan, Ann Arbor, Michigan. Accepted for publication May 21, 2014.

Funding: The study did not receive any funding. The authors declare no conflicts of interest. Address correspondence to Dmitri S. Bezinover, MD, PhD, Department of Anesthesiology, Penn State University, College of Medicine, Hershey Medical Center, H187, 500 University Dr., P.O. Box 850, Hershey, PA 17033. Address e-mail to [email protected]. Copyright © 2014 International Anesthesia Research Society DOI: 10.1213/XAA.0000000000000093

unmatched pediatric deceased donor (donation after brain death) liver transplant. Before transplantation, IV immunoglobulin (IVIG), rituximab, and high-dose mycophenolate mofetil were administered because the surgical team was concerned about the high risk of antibody-mediated rejection, particularly because of the presence of recipient anti-A isoagglutinins. The transplantation procedure was uneventful, and the patient was returned to the surgical intensive care unit tracheally intubated and sedated. On postoperative day 2, while the sedation level was being reduced, the patient developed severe hypertension and agitation and would no longer follow commands. Sedation was restarted, and her hypertension was treated with intermittent hydralazine. A complete neurologic evaluation was difficult to perform because of the patient’s condition; however, a computed tomography scan of the head suggested cerebral edema. On postoperative day 3, during another attempt to discontinue sedation, the patient developed repeated generalized tonic-clonic seizures, each lasting about 30 seconds. These were treated with lorazepam and levetiracetam. MRI of the brain demonstrated worsening cerebral edema and subtle crowding of the sulci, suggesting increased intracranial pressure. Other radiologic findings included a small area of restricted diffusion within the left frontal lobe corresponding to a small left frontal intraparenchymal hemorrhage, and a subcortical white matter signal abnormality involving both frontal lobes and occipital lobes consistent with PRES (Figs. 1 and 2). PRES was initially diagnosed by a neuroradiologist and confirmed by the neurology consultant to the transplant service. Immunosuppressive therpy was immediately adjusted by discontinuing tacrolimus and reducing the dose of mycophenolate mofetil. Methylprednisolone was continued. Intracranial pressure monitoring was considered but was not recommended by the neurosurgical team due to significant coagulopathy (laboratory results at this time were: partial thromboplastin time 33.7 seconds, international normalized ratio 3.19, alanine aminotransferase (ALT) 913 u/L, aspartate aminotransferase (AST) 730 u/L, bilirubin 9.2 mg/dL, and ammonia 43 μmol/L. Transcranial Doppler performed on

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Figure 1. Subcortical hyperintensities—T2 Fluid Attenuated Inversion Recovery (FLAIR) sequence.

Figure 2. Subcortical hyperintensities—T2 weighted sequence.

the same day demonstrated normal blood flow velocities and flow patterns in all major cranial arteries (pulsatility index was 0.70–0.83 on the right side and 0.98–0.53 on the left). Because of clinical signs and radiological evidence of increased intracranial pressure, the patient was cooled and treated with mannitol and 3% saline. Despite this intensive therapy, the patient had multiple recurring seizures culminating in status epilepticus. Liver function improved after transplantation. On postoperative day 4, significant increases in ALT (2982 u/L) and AST (7262 u/L) were noted. Ultrasonography of the liver graft and a mesenteric arteriogram showed excellent arterial and venous flow in the hepatic artery and portal vein. Because of concern that the seizure activity might

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be contributing to the transaminase increases, and also because of the ineffectiveness of anticonvulsive therapy, a pentobarbital infusion was initiated at 1 mg/kg/h and the electroencephalogram (EEG) was continuously monitored. Pentobarbital was intermittently titrated for optimal burst suppression (1 to 2 spikes per 10-second interval). Twentyfour hours after pentobarbital administration began, the patient’s ALT and AST levels began decreasing. On postoperative day 14, the patient underwent a tracheostomy because she needed prolonged ventilator support. Throughout the postoperative period, the patient was hemodynamically stable without vasoactive support and had normal liver and kidney function. All attempts to reduce the level of sedation failed because of intractable seizure activity. After 1 month of therapy, radiography indicated recovery from PRES. Repeated imaging demonstrated almost complete resolution of cerebral edema and no other intracranial abnormality. Nonetheless, pentobarbital infusion was maintained because her EEG continued to be suspicious for seizure activity. During this period, other possible causes for seizures (metabolic, infectious, vascular, and neurologic) were evaluated and excluded. One month postoperatively, there was a transient increase of the patient’s serum ammonia level (to 96 μmol/L) despite normal liver enzyme levels and coagulation. An amino acid profile was performed to exclude an undiagnosed amino acid metabolism disorder in the graft. The donor had been a 6-year-old child who suffered a severe brain injury in a motor vehicle accident. In the setting of a significantly increased serum ammonia level with normal liver and kidney function, an underlying urea cycle disorder had to be considered. In patients who are heterozygous for this mutation, the clinical presentation of disease might manifest itself only in adulthood. However, the patient’s amino acid profile was within normal limits and the ammonia level improved over the next 14 days. Pentobarbital therapy was successfully tapered over 62 days. The patient awoke and followed commands, and there was no EEG evidence of seizures. Ventilator support was discontinued 4 days later, and the patient was discharged to a rehabilitation center in stable condition. Two years after transplantation, the patient is doing well. Her current immunosuppressive therapy consists of prednisone, mycophenolate mofetil, and sirolimus. She is also receiving levetiracetam and phenytoin for seizure prophylaxis. The patient has no residual neurologic deficits and continues to have normal liver function.

DISCUSSION

PRES is a rare condition that occasionally arises after organ transplantation. In this circumstance, PRES is most frequently associated with the use of calcineurin inhibitor immunosuppressive drugs such as tacrolimus or cyclosporine.1–3 Other immunosuppressive medications, such as mycophenolate mofetil, rituximab, and IVIG, have also been implicated in the development of PRES. The reported incidence of PRES after solid organ transplantation is 0.49%.1 The most common clinical findings include headache, altered mental status, visual abnormalities, and seizures.2 Classic neurological imaging features include cortical or subcortical edema of the parietal or occipital lobes.1

A & A case reports

The onset of PRES frequently occurs within the first 2 months after liver transplantation and initiation of immunosuppression. Its onset is usually later after kidney transplantation.4 The underlying etiology of PRES is not completely understood, but the effects of vasogenic and cytotoxic edema secondary to immunosuppressive therapy are frequently cited as causes. One proposed mechanism involves impaired cerebral autoregulation resulting from endothelial dysfunction leading to cerebral hypoperfusion.4 Prompt recognition of the syndrome and dose reductions or even complete cessation of calcineurin therapy usually lead to recovery. However, if PRES is not diagnosed and treated in a timely manner, the injury pattern may progress to include ischemic infarctions and, less commonly, intracranial hemorrhage.5,6 In severe cases, PRES can lead to cerebral herniation.4 In this case, the calcineurin inhibitor (tacrolimus) was discontinued, and the dose of mycophenolate mofetil was significantly reduced. The incidence of PRES related to mycophenolate mofetil administration is unknown but must be very low considering the paucity of reported cases.7 Mycophenolate mofetil is also most often used as an alternative immunosuppressive in the case of calcineurin inhibitor-related PRES.8 Other medications potentially responsible for the development of PRES (IVIG and rituximab) were administered in high doses only before transplantation to compensate for graft ABO incompatibility and were not used postoperatively. Unfortunately, this modulation of therapy did not lead to either improvement in the patient’s condition or termination of seizures, even after the radiographic resolution of PRES. Seizures are among the most frequent manifestations of PRES, occurring in up to 90% of patients.9 Up to 13% of patients develop status epilepticus.10 Kastrup et al.11 reviewed the records of 38 patents with seizures associated with PRES and found that the overall prognosis was favorable after appropriate treatment and resolution of PRES. Normalization of the EEG pattern usually occurred 3 to 20 days after therapy was initiated. Symptom-free recovery was recorded between 1 to 6 months after the initial diagnosis. Previous publications have described prolonged or chronic seizures presenting even after radiographically documented improvement of PRES.12,13 This is probably related to the necessity of continuing immunosuppressive therapy, or to structural brain damage caused by recurrent epileptic episodes, or both. Epileptic activity can be associated with significant increases in AST and ALT production even after a single seizure.14 Our patient had significantly increased plasma levels of these enzymes, without any signs of rejection or graft hypoperfusion, with an AST/ALT ratio of 2.4. This substantial increase in the level of transaminases, with an AST/ ALT ratio >2, is a pattern typically seen after a seizure. It is probably related to the loss of cellular integrity in skeletal muscle and does not represent hepatic injury. Enzyme levels rapidly returned to normal after the seizures were treated. Current recommendations regarding antiepileptic therapy for patients with PRES are based on the severity of seizures and are not significantly different from recommendations regarding the treatment of epilepsy due to other conditions. Apart from causal management, monotherapy with benzodiazepines is commonly used for mild cases, and combination

therapy is frequently used for more severe cases.4 For intractable seizures, continuous IV barbiturate infusion has been recommended.4 The effectiveness of barbiturates is based on their modulation of γ-aminobutyric acid receptors and possibly their inhibition of N-methyl-d-aspartate receptors.15 These interactions are thought to inhibit lipid peroxidation and reduce glutamine release in the brain.16,17 Barbiturate-induced coma has been used for a variety of neurological conditions including intractable seizures and increased intracranial pressure. It is usually maintained for 24 to 96 hours; however, several reports describe a positive effect of longer-term barbiturate-induced coma,18,19 with coma in 1 pediatric patient lasting 146 days. However, in none of these patients was neurological recovery complete. There is 1 case report of an adult treated with barbiturate coma therapy for 50 days to control status epilepticus, but neurologic recovery was also incomplete.20 The incidence of withdrawal seizures after discontinuation or dose reduction of barbiturates is relatively high (about 43%).21 Because this patient had seizures, even after radiological evidence of PRES resolved, the possibility that the seizures were due to barbiturate withdrawal had to be considered. This would presume, however, that our patient had 2 separate causes for her seizures: the first as a result of PRES and the second due to barbiturate withdrawal. Long-term consequences of therapy to suppress refractory seizure activity can occur. Fugate et al.22 described 2 cases of long-term isoflurane administration for refractory status epilepticus. Both patients developed MRI abnormalities in the thalamus and cerebellum. These abnormalities improved after discontinuing isoflurane, but neither patient had a favorable outcome. It is important to note that our patient had no structural abnormality of the brain described on follow-up MRI. In comparison to other therapeutic modalities, barbiturate-induced coma is likely not associated with neurotoxicity. In our case, barbiturate-induced coma was maintained for 62 days followed by complete neurologic recovery being to our knowledge one of the longest reported such cases with a complete eventual recovery. E REFERENCES 1. Bartynski WS, Tan HP, Boardman JF, Shapiro R, Marsh JW. Posterior reversible encephalopathy syndrome after solid organ transplantation. AJNR Am J Neuroradiol 2008;29:924–30 2. Singh N, Bonham A, Fukui M. Immunosuppressive-associated leukoencephalopathy in organ transplant recipients. Transplantation 2000;69:467–72 3. Shepard PW, St Louis EK. Seizure treatment in transplant patients. Curr Treat Options Neurol 2012;14:332–47 4. Legriel S, Pico F, Azoulay E. Understanding posterior encephalopathy syndrome. In: Vincent JL, ed. Annual Update in Intensive Care and Emergency Medicine. Berlin: Springer, 2011:631–53. 5. Heidenhain C, Puhl G, Neuhaus P. Late fulminant posterior reversible encephalopathy syndrome after liver transplant. Exp Clin Transplant 2009;7:180–3 6. Striano P, Striano S, Tortora F, De Robertis E, Palumbo D, Elefante A, Servillo G. Clinical spectrum and critical care management of Posterior Reversible Encephalopathy Syndrome (PRES). Med Sci Monit 2005;11:CR549–53 7. Alparslan M, Bora U, Hüseyin K, Ayhan D, Gültekin S. Posterior reversible encephalopathy syndrome in a renal transplanted patient. Am J Case Rep 2013;14:241–4 8. Cruz RJ Jr, DiMartini A, Akhavanheidari M, Iacovoni N, Boardman JF, Donaldson J, Humar A, Bartynski WS. Posterior

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reversible encephalopathy syndrome in liver transplant patients: clinical presentation, risk factors and initial management. Am J Transplant 2012;12:2228–36 9. Lee VH, Wijdicks EF, Manno EM, Rabinstein AA. Clinical spectrum of reversible posterior leukoencephalopathy syndrome. Arch Neurol 2008;65:205–10 10. Kozak OS, Wijdicks EF, Manno EM, Miley JT, Rabinstein AA. Status epilepticus as initial manifestation of posterior reversible encephalopathy syndrome. Neurology 2007;69:894–7 11. Kastrup O, Gerwig M, Frings M, Diener HC. Posterior reversible encephalopathy syndrome (PRES): electroencephalographic findings and seizure patterns. J Neurol 2012;259:1383–9 12. Rashkin MC, Youngs C, Penovich P. Pentobarbital treatment of refractory status epilepticus. Neurology 1987;37:500–3 13. Baldini M, Bartolini E, Gori S, Bonanni E, Cosottini M, Iudice A, Murri L. Epilepsy after neuroimaging normalization in a woman with tacrolimus-related posterior reversible encephalopathy syndrome. Epilepsy Behav 2010;17:558–60 14. Nathwani RA, Pais S, Reynolds TB, Kaplowitz N. Serum alanine aminotransferase in skeletal muscle diseases. Hepatology 2005;41:380–2 15. Rossetti AO, Lowenstein DH. Management of refractory status epilepticus in adults: still more questions than answers. Lancet Neurol 2011;10:922–30

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16. Okutomi T, Nomoto K, Nakamura K, Goto F. Autogenous production of hydroxyl radicals from thiopental. Acta Anaesthesiol Scand 1995;39:338–42 17. Qu H, Faerø E, Jørgensen P, Dale O, Gisvold SE, Unsgård G, Sonnewald U. Decreased glutamate metabolism in cultured astrocytes in the presence of thiopental. Biochem Pharmacol 1999;58:1075–80 18. Kim YI, Park SW, Nam TK, Park YS, Min BK, Hwang SN. The effect of barbiturate coma therapy for the patients with severe intracranial hypertension: a 10-year experience. J Korean Neurosurg Soc 2008;44:141–5 19. Sahin M, Menache CC, Holmes GL, Riviello JJ. Outcome of severe refractory status epilepticus in children. Epilepsia 2001;42: 1461–7 20. Dara SI, Tungpalan LA, Manno EM, Lee VH, Moder KG, Keegan MT, Fulgham JR, Brown DR, Berge KH, Whalen FX, Roy TK. Prolonged coma from refractory status epilepticus. Neurocrit Care 2006;4:140–2 21. Claassen J, Hirsch LJ, Emerson RG, Mayer SA. Treatment of refractory status epilepticus with pentobarbital, propofol, or midazolam: a systematic review. Epilepsia 2002;43:146–53 22. Fugate JE, Burns JD, Wijdicks EF, Warner DO, Jankowski CJ, Rabinstein AA. Prolonged high-dose isoflurane for refractory status epilepticus: is it safe? Anesth Analg 2010;111:1520–4

A & A case reports

Prolonged pentobarbital-induced coma for the treatment of severe seizures related to posterior reversible encephalopathy syndrome.

In this report, we describe a case of posterior reversible encephalopathy syndrome in a female patient after deceased donor liver transplantation. She...
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