Pediatr Transplantation 2014: 18: E120–E123

© 2014 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd

Pediatric Transplantation DOI: 10.1111/petr.12255

Central pontine myelinolysis following pediatric living donor liver transplantation: A case report and review of literature Uchida H, Sakamoto S, Sasaki K, Hamano I, Shigeta T, Kanazawa H, Fukuda A, Nosaka S, Kubota M, Kasahara M. Central pontine myelinolysis following pediatric living donor liver transplantation: A case report and review of literature.

Hajime Uchida1, Seisuke Sakamoto1, Kengo Sasaki1, Ikumi Hamano1, Takanobu Shigeta1, Hiroyuki Kanazawa1, Akinari Fukuda1, Shunsuke Nosaka2, Masaya Kubota3 and Mureo Kasahara1

Abstract: CPM is one of the most serious neurological complications that can occur after OLT and is characterized by symmetrical demyelinization in the basis pontis. The etiology of CPM remains unclear, although the rapid correction of the serum sodium and CNI concentrations may be associated with the development of CPM. With recent advances in MRI technology, early diagnosis of CPM has become possible. Here, we present the case of a five-yr-old female who developed CNI-associated CPM after undergoing LDLT. A decreased level of consciousness and dysphasia was noted one wk after LDLT, and MRI revealed findings compatible with a diagnosis of CPM. The patient fully recovered from the neurological deficits related to CPM following the switch from the CNI to sirolimus. We propose MRI to be promptly considered for patients with abnormal neurological findings, together with the substitution of CNI with an mTOR inhibitor as a management regimen for CNI-related CPM.

1

Transplantation Center, National Center for Child Health and Development, Tokyo, Japan, 2Division of Radiology, National Center for Child Health and Development, Tokyo, Japan, 3Division of Neurology, National Center for Child Health and Development, Tokyo, Japan Key words: sirolimus – neurological complications – pediatric liver transplantation – living donor liver transplantation – calcineurin inhibitors Hajime Uchida, National Center of Child Health and Development, Transplantation Center, 2-10-1 Okura, Setagaya, Tokyo, 157-8535, Japan Tel.: +81 3 3416 0181 Fax: +81 3 3416 2222 E-mail: [email protected] Accepted for publication 24 February 2014

The development of CPM following OLT was first reported by Starzl et al. (1). CPM is considered to be the most serious neurological complication of OLT, with a risk of early mortality (2). Although most previously reported cases of CPM were diagnosed at autopsy, recent advances in MRI technology now allow for the early diagnosis of CPM (3, 4). It has been reported that electrolyte imbalances, the rapid correction of the serum sodium concentration and the administration of immunosuppressive agents are associated with the development of CPM following organ transplantation (5, 6). Abbreviations: ADC, apparent diffusion coefficient; CNI, calcineurin inhibitor; CPM, central pontine myelinolysis; CT, computed tomography; DWI, diffusion-weighted image; FLAIR, fluid-attenuated inversion recovery; LDLT, living donor liver transplantation; LT, liver transplantation; MRI, magnetic resonance imaging; mTOR, mammalian target of rapamycin; OLT, orthotopic liver transplantation; POD, post-operative day; PRES, posterior reversible encephalopathy syndrome.

E120

Previous reports have focused on adult liver transplant patients with CPM, and there are few case reports of pediatric CPM patients. We herein present the case of pediatric patient who developed CNI-associated CPM after LDLT, whose neurological symptoms exhibited a complete reversal following a switch from the CNI to an mTOR inhibitor. Case report

A five-yr-old female was transferred to our institution due to fulminant hepatic failure of unknown etiology. On admission, she presented with jaundice, coagulopathy and hepatic encephalopathy. Brain CT did not show any cerebral edema. Despite the administration of intensive medical treatment, the liver atrophy rapidly progressed with sustained liver dysfunction. Consequently, the patient underwent LDLT with a partial liver from her ABO blood type compatible father. Standard LDLT technique was employed for the operation.

Central pontine myelinolysis after liver transplantation

The post-operative immunosuppressive regimen consisted of tacrolimus and low-dose steroids. The patient was fully alert and underwent extubation on POD 7. However, her level of consciousness gradually worsened and she developed swallowing dysfunction. Laboratory parameters, including the serum level of sodium (135– 144 mEq/L) and the trough level of tacrolimus (6.4–12.2 ng/mL), were maintained within acceptable ranges. Brain MRI images obtained on POD 13 revealed an increased signal on DWIs and a decreased signal on ADC images in the pons (Fig. 1). These observations were compatible with the findings of CPM. Neurological symptoms, including dysphagia, a weak cough and increased patellar tendon reflexes, were identified. Despite the replacement of tacrolimus by cyclosporine (due to the possibility of tacrolimus-induced encephalopathy), the patient’s neurological symptoms did not dramatically improve. Brain MRI performed on POD 23 revealed progressed neuroradiological findings, including new abnormal T2 hyperintensity in the middle cerebellar peduncle to the pons (Fig. 2). Following the introduction of sirolimus and the complete cessation of the CNI, the patient’s neurological symptoms disappeared. She was discharged three and a half months after LDLT. Follow-up brain MRI did not show any abnormal findings (Fig. 3). Throughout the one-yr follow-up, her liver function tests remained excellent on sirolimus monotherapy. Discussion

CPM is a neurological disorder characterized by symmetrical demyelinization and severe damage of the myelin sheath of nerve cells in the basis pontis (2). A late diagnosis of CPM often results in a high mortality rate owing to the development of irreversible brain damage (7). Recently, however, CPM can be detected much earlier by paying particular attention to the rapid changes

Fig. 2. (a) T2-weighted images showing hyperintensity in the middle cerebellar peduncle to the pons (arrowhead). (b) DWI sequence clearly showing an increased signal in the pons (arrowhead).

Fig. 3. (a) Improved findings in the pons on T2-weighted images, as evidenced by the slightly hyperintense area (arrowhead). (b) ADC map showing almost normal findings.

in electrolytes, together with the timely MRI (4, 8–10). To the best of our knowledge, 10 cases of CPM after pediatric LT were reported worldwide between 1989 and 2012 (Table 1) (3, 8–12). Five patients died, and they were only diagnosed with

Fig. 1. (a) T2-weighted images showing normal findings in the pons. (b) DWI showing an increased signal in the pons due to restricted water diffusion (arrowhead). (c) ADC map showing a decreased signal in the pons (arrowhead).

E121

Uchida et al. Table 1. Patients with CPM following pediatric LT Reference (issue year)

Age (yr), sex

Indication for LT

Onset (day)

HE

3 (1989)

4, F 8, F 18, M 8, F

BA FHF CAH FHF

NA NA NA 1

NA NA NA Yes

16, F 17, F 0.8, M 15, F 11, M

CAH WD BA BA PSC

38 NA NA NA 9

No No Yes Yes Yes

FHF

8

Yes

8, 9 (1991)

10 (2000) 11 (2002) 12 (2012) The presented case

5, F

Neurological manifestation

Risk factor(s)

Diagnostic approach

Treatment

Outcome

Neurological impairment

Seizure NA NA Decreased LOC Seizure None None None Decreased LOC Decreased LOC

CNI (CsA) CNI (CsA) Hyponatremia NA

Autopsy Autopsy Autopsy Autopsy

NA NA NA NA

Died Died Died Died

NA NA NA NA

NA CNI (CsA) CNI (Tac) CNI (Tac) Hyponatremia, CNI (Tac) CNI (Tac, CsA)

Autopsy MRI MRI MRI MRI

NA None None None Conversion from Tac to SRL Conversion from CNI to SRL

Died Alive Alive Alive Alive

NA No No No Yes

Alive

No

MRI

BA, biliary atresia; CAH, chronic active hepatitis; CsA, cyclosporine; F, female; FHF, fulminant hepatic failure; HE, hepatic encephalopathy; LOC, level of consciousness; M, male; NA, not available; Tac, tacrolimus; PSC, primary sclerosing cholangitis; SRL, sirolimus; WD, Wilson’s disease.

CPM at autopsy. On the other hand, five patients survived, providing an overall survival rate similar to that of adult patients (6). Among the five survivors, three patients without any neurological symptoms were incidentally found with CPM on the imaging follow-up of LT. The other two survivors, including the present case, revealed neurological symptoms at onset, and then, they were diagnosed with CPM. The present case was the only patient to have exhibited a complete neurological recovery. To the contrary, the other patient, who displayed hyponatremia and cerebral edema before LT, suffered from neurological sequelae (10). The pre-existing condition might have caused neurological sequelae (5, 6). Although there are several initial symptoms of CPM, including stupor, dementia, dysarthria and dysphagia, none of these is specifically associated with pontine lesions (8, 9). Diagnosing CPM based on clinical manifestations can be difficult, as the signs and symptoms of CPM are often absent or masked by other neurological abnormalities unrelated to the pontine lesions (13). In our case, the occurrence of hepatic encephalopathy before LT due to fulminant hepatic failure complicated the diagnosis process, although Erol et al. reported that the presence of encephalopathy before LT is not a risk factor for neurological complications in pediatric patients (14). The underlying mechanisms of the development of CPM remain largely unknown. However, some cases of CNI-related CPM have been reported (2, 5, 10). The occurrence of CNIrelated neurotoxicity after LT, including CPM and PRES, is observed in 1–10% of patients (10, 14). Recently, CNI-related neurotoxic side effects have been reported to be relatively common in E122

pediatric recipients (14). In pediatric patients, PRES is a rare neurological complication that can occur after LT in association with the administration of CNIs, such as tacrolimus and cyclosporine; however, this condition should be distinguished from CPM. Brain MRI demonstrates characteristic PRES findings that can be used to differentiate between CPM and PRES. ADC mapping of PRES patients shows increased diffusion in areas that exhibit high signal intensity on FLAIR images, whereas ADC mapping of CPM patients demonstrates decreased diffusion, as observed in this case. Sirolimus, an inhibitor of mTOR, is known to be an effective immunosuppressant for the prevention of acute rejection in renal transplant recipients (15). In spite of that, there is a lack of reports on the use of mTOR inhibitors as the primary immunosuppressants in LT patients (16, 17). Currently, mTOR inhibitors are mainly used to treat steroid-resistant rejection in children who underwent LT (18). Sirolimus does not usually cause neurotoxicity in LT recipients, which may be attributed to the different mechanism of action of mTOR inhibitors compared with that of CNIs. CNIs bind to immunophilin, forming a ternary complex with calcineurin, which constitutes more than 1% of the total protein in the central nervous system (CNS), while mTOR inhibitors bind the same immunophilin as tacrolimus. However, mTOR inhibitors act downstream by blocking the activation of a cell cycle kinase, mTOR, which has a negligible impact on the CNS (15, 19). To date, there are several reports that suggest a switch from CNI to an mTOR inhibitor may improve the neurological prognosis of LT patients with CNI-related neurotoxicity (10, 20). Despite the withdrawal of the CNI at an early

Central pontine myelinolysis after liver transplantation

phase after LT, our patient achieved the desired outcome through sirolimus monotherapy without any complications such as acute rejection, drug-related effects or neurological sequelae. In summary, making an early diagnosis is crucial in patients with neurological manifestations after LT. The importance of using promptly to facilitate the early diagnosis of CPM cannot be overstated. We also suggest the switching from CNI to an mTOR inhibitor as a potentially feasible approach to treating CNI-related CPM.

6.

7. 8.

9.

10.

Acknowledgments This work was supported by the Grant from the National Center for Child Health and Development (25-6). We would like to thank Dr. Julian Tang from the Department of Education for Clinical Research, National Center for Child Health and Development, for proofreading and editing this manuscript.

11.

12.

13.

Authors’ contributions H.U.: study design, writing of the paper; S.S. and M.K.: study design and critical revision of the article for clinical content; K.S., I.H., H.K., A.F. and T.S.: collection of the data; S.N.: critical revision of the article for radiological content; and M.K.: critical revision of the article for neurological content.

14.

15.

16.

References 1. STARZL TE, SCHNECK SA, MAZZONI G, et al. Acute neurologic complications after liver transplantation with particular reference to intraoperative cerebral air embolus. Ann Surg 1978: 187: 236–240. 2. YU J, ZHENG SS, LIANG TB, SHEN Y, WANG WL, KE QH. Possible causes of central pontine myelinolysis after liver transplantation. World J Gastroenterol 2004: 10: 2540–2543. 3. HALL WA, MARTINEZ AJ. Neuropathology of pediatric liver transplantation. Pediatr Neurosci 1989: 15: 269–275. 4. ESTOL CJ, FARIS AA, MARTINEZ AJ, AHDAB-BARMADA M. Central pontine myelinolysis after liver transplantation. Neurology 1989: 39: 493–498. 5. FUKAZAWA K, NISHIDA S, AGUINA L, PRETTO EJR. Central pontine myelinolysis (CPM) associated with tacrolimus

17.

18.

19.

20.

(FK506) after liver transplantation. Ann Transplant 2011: 16: 139–142. LEE ME, KANG JK, YUN SC, et al. Risk factors for central pontine and extrapontine myelinolysis following orthotopic liver transplantation. Eur Neurol 2009: 62: 362–368. MEDANA IM, ESIRI MM. Axonal damage: A key predictor of outcome in human CNS disease. Brain 2003: 126: 515–530. BOON AP, CAREY MP, ADAMS DH, BUCKELS J, MCMASTER P. Central pontine myelinolysis in liver transplantation. J Clin Pathol 1991: 44: 909–914. KATO T, HATTORI H, NAGATO M, et al. Subclinical central pontine myelinolysis following liver transplantation. Brain Dev 2002: 24: 179–182. CUI R, FAYEK S, RAND EB, FEYGIN T, KHRICHENKO D, SHAKED A. Central pontine myelinolysis: A case report and clinicalpathological review. Pediatr Transplant 2012: 16: 251–256. BOON AP, CAREY MP, SALMON MV. Central pontine myelinolysis not associated with rapid correction of hyponatremia. Lancet 1988: 2: 458. LUI CC, CHEN CL, CHANG YF, LEE TY, CHUANG YC, HSU SP. Subclinical central pontine myelinolysis after liver transplantation. Transplant Proc 2000: 32: 2215–2216. PEARCE JM. Central pontine myelinolysis. Eur Neurol 2009: 61: 59–62. EROL I, ALEHAN F, OZCAY F, CANAN O, HABERAL M. Neurological complications of liver transplantation in pediatric patients: A single center experience. Pediatr Transplant 2007: 11: 152–159. MORATH C, ARNS W, SCHWENGER V, et al. Sirolimus in renal transplantation. Nephrol Dial Transplant 2007: 22(Suppl 8): viii61–viii65. VIVARELLI M, VETRONE G, ZANELLO M, et al. Sirolimus as the main immunosuppressant in the early portoperative period following liver transplantation: A report of six cases and review of the literatures. Transpl Int 2006: 19: 1022–1025. CHANG GJ, MAHANTY HD, QUAN D, et al. Experience with the use of sirolimus in liver transplantation–use in patients for whom calcineurin inhibitors are contraindication. Liver Transpl 2000: 6: 734–740. BASSO MS, SUBRAMANIAM P, TREDGER M, et al. Sirolimus as renal and immunological rescue agent in pediatric liver transplantation recipients. Pediatr Transplant 2011: 15: 722–727. MARAMATTOM BV, WIJDICKS EF. Sirolimus may not cause neurotoxicity in kidney and liver transplant recipients. Neurology 2004: 63: 1958–1959. FORGACS B, MERHAV HJ, LAPPIN J, MIELES L. Successful conversion to rapamycin for calcineurin inhibitor-related neurotoxicity following liver transplantation. Transplant Proc 2005: 37: 1912–1914.

E123

Central pontine myelinolysis following pediatric living donor liver transplantation: a case report and review of literature.

CPM is one of the most serious neurological complications that can occur after OLT and is characterized by symmetrical demyelinization in the basis po...
120KB Sizes 0 Downloads 5 Views