SUBMITTED 30 JAN 23 1 REVISION REQ. 19 MAR 23; REVISIONS RECD. 23 MAR 23 2 ACCEPTED 4 APR 23 3 ONLINE-FIRST: MAY 2023 4 DOI: https://doi.org/10.18295/squmj.5.2023.023 5 6 Longitudinal Extensive Transverse Myelitis (LETM) in a Four-year-old 7 Boy Liver Transplant Recipient 8 *Roshan Koul,1 Shalini Thapar,2 Rajeev Khanna,3 Seema Alam3 9 10 Departments of 1Neurology, 2Radiology and 3Pediatric Hepatology, Institute of liver and 11 biliary sciences, New Delhi, India 12 *Corresponding Author’s e-mail: koulroshan@gmail.com 13 14 Acute transverse myelitis (ATM) is defined as acute onset quadriplegia or paraplegia with 15 sensory and autonomic involvement progressing in three to four days’ time. 1 If the myelitis 16 involves more than three consecutive vertebral segments on magnetic resonance imaging 17 (MRI), it is called longitudinal extensive transverse myelitis (LETM). 1 On Google and 18 PubMed search only, one adult case of transverse myelitis was seen in a liver transplant (LT) 19 recipient.2 This is the first case of LETM to be reported in a child who had LT. 20 21 Introduction 22 Four years eight months old boy diagnosed with biliary atresia at neonatal period, underwent 23 living liver donor transplantation at the age of one year and five months. He was third child in 24 the family with no family history of liver disease. He had tubercular lymphadenitis soon after 25 transplant which was treated appropriately. He also had prolonged unprovoked seizure in 26 November 2020, which was treated with levetiracetam. He developed Epstein-Barr virus 27 (EBV) infection and was treated with ganciclovir. He had graft dysfunction due to hepatitis E 28 infection which settled of its own. Two years and ten months after transplant (June 2022) he 29 developed right mandibular mass. Positron emission tomography (PET) computerized 30 tomography (CT) scan showed fluoro-deoxy glucose (FDG) avid irregular mass involving 31 right maxillary sinus, retro-orbital region, and ethmoid sinus with lytic destruction of maxilla. 32 Histopathology revealed Burkett’s lymphoma stage IV. Bone marrow and cerebro spinal fluid 33 (CSF) were normal. He was started on rituximab, cyclophosphamide, hydroxydaunorubicin, 34 vincristine, prednisolone (R-CHOP) chemotherapy along with intrathecal methotrexate. By 35 end of August 23, 2022 he had received 3 cycles of CHOP with intrathecal methotrexate and 36 5th pulse of rituximab. On September 5th 2022 he was admitted with progressive weakness of 37 all four limbs which started in the left arm first and completely paralyzed him below neck in 38 three days’ time. His cranial nerves and sensorium were normal. MRI brain was normal and 39 MRI spine revealed almost whole length spinal cord myelitis [Figure 1]. CSF examination 40 was normal. No malignant cells were seen. Viral studies were negative. Aquaporin antibody 41 test was not done as the facility to test this, was not available in the hospital. He was treated 42 with pulse methylprednisolone 30mg/kg/day for five days followed by oral steroids for four 43 weeks and IVIG 400mg/kg/day for five days. He started improvement in his weakness after 44 ten days of treatment. Currently he has grade three power (medical research council grading) 45 in right upper limb, grade 2 to 3 in lower limbs and grade 1 in left upper limb. Sensory 46 examination was normal all over. He received repeat chemotherapy on 29th November 2022, 47 including intrathecal methotrexate. There was no worsening of his weakness after intrathecal 48 methotrexate. During the hospital stay he had recurrence of seizures which evolved into 49 status epilepticus requiring four anti-epileptic drugs (midazolam, levetiracetam, phenytoin 50 sodium, lacosamide and phenobarbital) to control. 51 52 Comment 53 There are many neurological complications seen in liver transplant recipients. 3 These may 54 be related to the transplant or immunosuppressants used in the treatment. 3 ATM is the rarest 55 of all complications. Only few reports are in the literature. 2 Most of the ATM in children 56 are of unknown etiology, believed to be some form of nervous system demyelinating illness 57 in response to varied etiology. 1,4 A thorough workup is required in ATM to rule out 58 infectious, autoimmune disorders or infiltrations. 1,4 In a single case of ATM reported in an 59 adult liver transplant recipient, it was correlated to the high levels of tacrolimus.2 This patient 60 was a 39 years old male, with chronic liver disease due to Budd-Chiari syndrome. He 61 underwent deceased liver transplant and was put on tacrolimus. He developed weakness of all 62 four limbs on day five post operation. Blood tacrolimus level was normal. MRI brain was 63 normal and MRI spine revealed whole length spinal cord demyelination. No underlying 64 etiology was found on investigation. Immunoglobulins did not improve the weakness. 65 Cyclosporine was added in the treatment and tacrolimus was stopped. This change of 66 immunosuppressant resulted in improvement of his weakness. 2 Our patient had not received 67 tacrolimus, and CSF study was normal. Intrathecal methotrexate is widely used and there are 68 few reports in literature about association of ATM and intrathecal methotrexate. 5 However 69 our patient had received three doses previously and the weakness developed after thirteen 70 days of the third dose. Further he was given fourth dose on 29th November 2022, without 71 worsening of his neuro status. This observation rules out methotrexate induced ATM. Our 72 patient is the first case of LETM seen in a liver transplant recipient. ATM is uncommon in 73 children.1,6 LETM presentation in our patient is possible due to his medical condition, 74 making him more prone to various autoimmune conditions or coincidental. Several 75 cofounders in setting of LT, it is difficult to pinpoint what predisposed this boy to LETM. A 76 repeat follow up MRI spine and clinical monitoring will determine his long-term therapy for 77 the LETM. 78 79 Authors’ contribution 80 RoK, SA and RaK managed the patient. RoK provided the diagnosis. ST provided the 81 radiological images. RoK drafted the manuscript and SA edited the manuscript. All authors 82 approved the final version of the manuscript. 83 84 References 85 1. Wolf VL, Lupo PJ, Lotze TE. Pediatric Acute Transverse Myelitis. Overview and 86 Differential diagnosis. J child Neurol 2012;27:1426-87 1436.doi:10.1177/0883073812452916 88 2. Aksoy F, Dundar HZ, Demir AB, Kiyici M, Kaya E. .Myelitis After Liver 89 Transplant: A case Report. Experimental and Clinical Transplantation. 2021; 1-3. 90 Doi:10.6002/ect.2020.0278 91 3. Weiss N, Thabut D. Neurological Complications Occurring After Liver 92 Transplantation: Role of Risk Factors, Hepatic Encephalopathy and Acute (on 93 Chronic) Brain Injury. Liver Transplantation.2019;25:469-487 94 https://doi.org/10.1002/lt.25420 95 4. Scott TE, Frohman EM, De Seze J, Gronseth GS, Weinshenker BG. Evidence based 96 guidline: clinical evaluation and treatment of transverse myelitis: report of the 97 Therapeutics and Technology Assessment Subcommittee of the American Academy 98 of Neurology. Neurology 2011; 77:2128-2134. 99 5. Castillo-Torres SA, Soto-Rincón CA, Villarreal-Montemayor HJ, Chávez-Luévanos 100 B. Case of neuromyelitis optica: bilateral sensorineural hearing loss 101 https://pubmed.ncbi.nlm.nih.gov/32300035/ and transverse myelopathy following intrathecal chemotherapy. BMJ Case Rep. 2020 102 Apr 15; 13(4):e234076. doi: 10.1136/bcr-2019-234076 103 6. Koul R, AlFutaisi A, Mani R, AbdelRahim R, Sankhla DK, AlAzri FM. Longitudinal 104 extensive transverse myelitis in children from Oman. Neurosciences (Riyadh) 105 2017;22:127-130, doi.10.17712/nsj.2017.2.20160352 106 107 108 Figure 1:MRI short tau inversion recovery (STIR) sagittal image of spine, A shows cervical 109 1to dorsal 7 vertebra hyper-intense lesion, B shows dorsal 8 to conus medullaris lumbar 1 110 vertebra hyper-intense lesion (Whole spine could not come in single image due to mild 111 scoliosis). C. STIR sagittal image spine as control shows normal appearance of the spinal 112 cord. 113 https://pubmed.ncbi.nlm.nih.gov/32300035/