- Email: [email protected]
Epilepsy surgery in a liver-transplanted girl with temporal lobe epilepsy and hippocampal sclerosis following PRES with status epilepticus
Accepted Manuscript Epilepsy surgery in a liver-transplanted girl with temporal lobe epilepsy and hippocampal sclerosis following PRES with status epilepticus Robertino Dilena, Gabriella Nebbia, Lorenzo Fiorica, Marcello Farallo, Irene Degrassi, Francesca Gozzo, Veronica Pelliccia, Sergio Barbieri, Massimo Cossu, Laura Tassi PII:
S1090-3798(16)30011-3
DOI:
10.1016/j.ejpn.2016.04.007
Reference:
YEJPN 2042
To appear in:
European Journal of Paediatric Neurology
Received Date: 25 December 2015 Revised Date:
7 April 2016
Accepted Date: 7 April 2016
Please cite this article as: Dilena R, Nebbia G, Fiorica L, Farallo M, Degrassi I, Gozzo F, Pelliccia V, Barbieri S, Cossu M, Tassi L, Epilepsy surgery in a liver-transplanted girl with temporal lobe epilepsy and hippocampal sclerosis following PRES with status epilepticus, European Journal of Paediatric Neurology (2016), doi: 10.1016/j.ejpn.2016.04.007. This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.
ACCEPTED MANUSCRIPT Epilepsy surgery in a liver-transplanted girl with temporal lobe epilepsy and hippocampal sclerosis following PRES with status epilepticus Robertino Dilena
a,*
, Gabriella Nebbia b, Lorenzo Fiorica b , Marcello Farallo b, Irene Degrassi
b
,
Francesca Gozzo c , Veronica Pelliccia c , Sergio Barbieri a, Massimo Cossu c , Laura Tassi c
a
RI PT
Affiliations
Service of Paediatric Epileptology – Unit of Clinical Neurophysiology, Department of
Neuroscience and Mental Health, Fondazione IRCCS Ca’ Granda, Ospedale Maggiore Policlinico,
b
Service of Paediatric Hepatology, Department of Paediatrics, Fondazione IRCCS Ca’ Granda,
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Ospedale Maggiore Policlinico, Milan, Italy C
SC
Milan, Italy
“Claudio Munari” Epilepsy Surgery Centre, Niguarda Hospital, Milan, Italy
Abbreviations: EEG, electroencephalogram; AED, antiepileptic drugs; PRES, posterior reversible
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encephalopathy syndrome; HS, hippocampal sclerosis; LDH, Lactate dehydrogenase enzyme; SUDEP, sudden unexpected death of epileptic patients.
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Keywords: liver transplant; posterior reversible encephalopathy syndrome; temporal lobe epilepsy;
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refractory epilepsy; hippocampal sclerosis; epilepsy surgery
*Corresponding author: Robertino Dilena
Fondazione IRCCS Ca’ Granda, Ospedale Maggiore Policlinico, Servizio di Epilettologia e Neurofisiopatologia pediatrica, Clinica Mangiagalli, via Commenda 12, 20122, Milan, Italy, Tel: +390255032406; Fax: +390255032155 Email adress: [email protected]
ACCEPTED MANUSCRIPT Abstract Introduction. Posterior reversible encephalopathy syndrome (PRES) with status epilepticus may occur after liver transplant. This may rarely lead to refractory epilepsy and hippocampal sclerosis (HS).
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Case description. We report the first case of epilepsy surgery in a liver-transplanted patient with refractory temporal lobe epilepsy. A 3-year-old girl underwent liver transplant for congenital biliary atresia. Four days after transplant she manifested PRES with status epilepticus, but she recovered
SC
within a couple of weeks. At the age of 5 years she started presenting complex partial seizures, that became refractory to antiepileptic drugs (AED), worsening psychosocial performances. The pre-
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surgical work-up identified a left HS and temporal pole alterations. A left antero-mesial temporal lobectomy was performed, leading to epilepsy remission and allowing AED withdrawal. Conclusion. Drug-resistant temporal lobe epilepsy and HS may occur as sequelae of PRES with status epilepticus related to liver transplant and cyclosporine use. In this setting early epilepsy
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surgery may reduce the time of chronic exposure to AED and severe illness due to repeated seizures. This option might have additional advantages in the subgroup of epileptic patients with liver transplant, preserving the liver from the potential damage due to multiple AED trials and their
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EP
interaction with commonly used immunosuppressant drugs.
ACCEPTED MANUSCRIPT 1. Introduction Neurological complications are a significant cause of morbidity and mortality in patients undergoing liver transplantation (up to one-third of liver-transplanted patients). 1-2 Among acute neurological complications occurring in the post-transplant period, seizures are the 1
No reliable epidemiological data about long-term neurological complications are
available. Focal drug-resistant epilepsy has been rarely reported. 2
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most frequent.
In liver-transplanted patients neurological problems can originate from acute brain injuries related
SC
to liver transplantation and immunosuppressant drugs, to chronic liver disease, or be incidentally associated. Among the post-transplant complications there is posterior reversible encephalopathy
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syndrome (PRES). 3-4 PRES refers to a disorder of reversible subcortical vasogenic brain oedema in patients with acute neurological symptoms (seizures, encephalopathy, headache, and visual disturbances) in different situations like cytotoxic or immunosuppressant drug use, transplantation, renal failure, blood pressure fluctuations, autoimmune disorders, and pre-eclampsia or eclampsia.
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Brain imaging usually reveals vasogenic oedema involving predominantly (but not only) parietooccipital regions. PRES seems caused by endothelial injury related to abrupt blood pressure changes or direct effects of cytokines on the endothelium, which leads to breakdown of the blood–brain
EP
barrier. The posterior brain regions can be particularly susceptible to hyperperfusion, because little sympathetic innervation exists in the posterior fossa.3 Despite the name “reversible”, persistent
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neurological sequelae are reported in 10–20% of patients with PRES.3 Among them, epilepsy and hippocampal sclerosis (HS) have been rarely reported.5 They seem linked to complications of PRES like haemorrhage or cytotoxic oedema3,5 or related to consequences of PRES-associated status epilepticus. Indeed epilepsy and HS has been described as possible consequence of status epilepticus, 6 as mesial temporal lobe areas are more susceptible to this injury. In this article we show the sequential occurrence of these pathological events in a liver transplanted girl, describe the importance to prevent them and report for the first time in this setting the possibility to successfully treat refractory focal epilepsy by surgery.
ACCEPTED MANUSCRIPT
2. Case study 2.1 Liver disease and transplantation A female infant, born after a normal pregnancy and delivery, presented in the neonatal period with
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jaundice, dark urine ad pale stools. Blood examinations showed hyperbilirubinemia associated with high gamma-glutamyl transferase and alkaline phosphatase serum levels. A laparotomy performed at the age of three months showed extrahepatic biliary atresia, requiring a portoenterostomy (Kasai
transplantation waiting list at the age of 5 months.
SC
I). This procedure did not improve symptoms and the patient was therefore included in the liver
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In the first two years neurological examination showed generalized hypotonia with motor delay ascribed to the metabolic derangement. A brain MRI yielded normal findings. While the patient was on the waiting list, the hepatic function deteriorated due to cirrhosis associated with portal hypertension, esophageal varices and splenomegaly.
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At the age of 3 years, the patient was transplanted with left-liver technique. A primary liver dysfunction acutely occurred and a second transplantation was performed 8 days later. Immunosuppressive treatment with cyclosporine was started at 1,5 mg/kg/die for one week. Four
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days after re-transplantation the patient had recurrent focal seizures characterized by right-sided clonic jerks and left head deviation with impairment of awareness which persisted between the
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seizures consistent with focal status epilepticus. She also developed arterial hypertension, moderate renal impairment and respiratory failure associated with pneumonia. Liver enzymes were decreasing (almost normal levels), while dehydrogenase (LDH) levels were high (around 900 UI/L). She was admitted to the intensive care unit, where after lack of response to diazepam she was treated with intravenous phenobarbital, repeated boluses of thiopentone and antibiotic therapy. Excessively high cyclosporine blood levels (479 ng/mL; target therapeutic level: 200 ng/mL) initially required drug reduction to 1 mg/kg and subsequent switching to tacrolimus (4 mg daily). Brain CT showed right occipito-parietal, left occipito-temporal and left frontal hypodensities
ACCEPTED MANUSCRIPT without contrast enhancement compatible with PRES. The electroencephalogram (EEG) showed diffuse slow activity and focal paroxysmal activity in the left fronto-temporal and right parietooccipital leads. One week after onset of the neurological complication complete control of seizures was achieved. Ten days after onset MRI showed only occipito-temporal alterations (appearing as
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hyperintensities on T2-weighted sequences), decreasing in extent compared with the acute brain CT. Clinical recovery and EEG normalization occurred in about two weeks after onset. The patient was discharged on phenobarbital (4 mg/kg/day), slowly tapered and then withdrawn 10 months
SC
later, whereas immunosuppressive therapy with tacrolimus was continued.
In the following years no signs of liver rejection or other transplant complications were observed
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and the patient on low dose tacrolimus maintained normal liver function tests. 2.2 Epilepsy history
At the age of 5 years the patient presented with focal seizures with impairment of awareness. They were characterized by staring (no subjective feeling was referred), unresponsiveness, oral and left
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upper limb automatisms, dystonic posture of the right hand, left head and eyes deviation, post-ictal aphasia. Secondary tonic-clonic generalization sometimes occurred. Interictal EEG showed focal slow waves and sharp waves, localized over the left temporal lobe. Brain MRI was initially reported
EP
as unremarkable, but at that time the temporal region was not specifically studied. Several therapeutic trials with antiepileptic drugs (AED) like oxcarbazepine, vigabatrin, levetiracetam,
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topiramate, valproate, lacosamide, phenobarbital, as monotherapies or in combination gave some benefit, but failed to ensure a persistent seizure control. Phenobarbital was associated with liver side effects (transaminase increase) and was soon withdrawn. Seizure frequency slowly increased over years, from one per week to one-two per day, and some episodes of focal non convulsive status epilepticus were also reported. The girl was increasingly disabled by her epileptic condition, with severe social isolation and school difficulties. The neuropsychological evaluation (WISC-R) performed at the age of 15 years disclosed a significant cognitive impairment (total IQ of 41, verbal IQ 51 and performance IQ 45).
ACCEPTED MANUSCRIPT 2.3 Presurgical evaluation At the age of 15 years, when the patient’s family asked for a second epileptological opinion, she was immediately sent to the epilepsy surgery center. At that time she had 3 focal seizures per week, approximately 2 secondarily generalized seizures per month and at least 1 dense cluster of seizures
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lasting 2 days per month, often configuring a true non-convulsive status epilepticus. The neurological examination was normal. The neuropsychological investigation showed impaired capacity in word generation and long-term memory for visual/verbal materials and faces. She also
SC
had difficulties in visuospatial construction, praxic functions, reasoning and problem solving, although her global learning capacity had a good potential. She also had high levels of anxiety and
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depression and difficulties in social adaptation.
A long-term video-EEG monitoring showed slow and spike-waves localized in left temporal lobe during wakefulness, increasing during sleep (Fig. 1, A). A typical seizure was recorded, showing a left temporal lobe rhythmic theta activity (Figure 1, B). Brain 1.5T MRI demonstrated a left HS,
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associated with a slight hypoplasia and poor gray-white matter demarcation (blurring) of the left temporal pole (Fig.1, D). On the basis of these clear-cut anatomo-electro-clinical correlations the
2.4 Histopathology
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patient underwent a left antero-mesial temporal lobectomy (Fig 1, C).
Surgical specimens were obtained from the temporal pole, from the mesial structures including the
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hippocampus tail, and from the anterior portions of the first, second, third and fourth temporal gyri (antero-mesial temporal lobectomy). The histological examination confirmed an ILAE type 2 hippocampal sclerosis, with loss of pyramidal neurons in CA1, with neuronal preservation in CA2-CA4 and end-folium. A Chaslin gliosis in all the surgical neocortical specimens including the temporal pole was observed. 2.5 Five-year outcome After surgery AED have been progressively decreased and two years later stopped, without seizure relapse. The patient quality of life has markedly improved.
ACCEPTED MANUSCRIPT The neuropsychological evaluation performed 2 years after surgery did not indicate significant changes of her cognitive abilities with small differences consisting in some improvement in selective visual attention and praxic functions. Her emotional and behavioral difficulties had
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improved. Five years after surgery the patient is still completely seizure-free.
3. Discussion
Efficacy of surgery in temporal lobe epilepsy is well known, 7 but this is the first case reported in a
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liver transplant patient. She developed drug-resistant epilepsy of the left temporal lobe after a posttransplant PRES. Presurgical EEG showed intercritical and critical left temporal activity. In the
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seizure semiology the typical initial temporal aura (déjà vu or olfactory sensations) was not reported, but the other signs were typical of electrical spreading from the mesial temporal lobe (staring, unresponsivess, oral and left upper limb automatism, dystonic posture, postictal aphasia). This could be related to a possible fast electrical discharge spreading, possibly related to a more
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extensive temporal alteration proved at the MRI by presence of not only left HS, but also left temporal pole slight hypoplasia and gray-white matter blurring and at the histology by gliosis in the temporal specimens. We think that these lesions might represent the sequelae of PRES with status
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epilepticus suffered by the patient.
It is known that PRES can occur after liver transplantation triggered by immunosuppressant drugs 3-6
but also hypertension, renal failure, and homeostatic derangement determined
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like cyclosporine,
by transplant-related rapid liver function changes. Status epilepticus and cytotoxic injury in PRES have been already associated with HIS and chronic epilepsy.5-6 This is why all treatable risk factors need to be checked and managed as better as possible. Large case-control studies focused on PRES and epilepsy occurrence in the population of liver transplant patients are needed to better study risk factors and the possibility to prevent irreversible lesions. A better identification of biomarkers of PRES could help to identify patients at high risk to develop PRES with major severity. Recently an increased serum level of dehydrogenase (LDH), which plays an essential role in endothelial injury,
ACCEPTED MANUSCRIPT has been described as a potential risk factor for the development of oedema in PRES particularly in cancer patients.
8
In our patient we had increased LDH levels, but we also know that this is a
nonspecific finding, which need to be studied in the large population of transplanted patients to make correct conclusions.
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The presented case also highlights the additional advantages of early epilepsy surgery in the subgroup of epileptic patients with liver transplantation. Temporal lobe epilepsy associated with HIS is often drug-resistant, but it is surgically remediable with an excellent outcome. The most
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recent definition of refractory epilepsy is failure of adequate trials of two tolerated, appropriately chosen and used AED schedules to achieve sustained seizure freedom.
9
Refractory epilepsy
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increases the risk of cognitive and psychosocial dysfunction and sudden unexpected death of epileptic patients (SUDEP).10 Surgical outcome is less satisfactory as duration of epilepsy or age at surgery increase, thus suggesting a progressive disorder.10
Cognitive impairment found in our patient is probably multifactorial. Given the harmonic global
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cognitive deficits found, we think that the PRES-related status epilepticus and the underlying cerebral injury associated with liver dysfunction before the first three years had a major etiological role than refractory focal epilepsy. A slightly lower intellectual functioning is found among all
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children with liver transplantation compared to matched siblings and it seems related to cerebral effects of pre-transplant liver dysfunction. 11
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Anyway the patient was unfortunately referred late to surgery. When the patient received a second epileptological opinion, she was immediately sent to the surgery centre and operated with epilepsy resolution and drug withdrawal after two years. The history highlights the importance to early consider the surgical option to reduce the time of illness and of chronic exposure to drugs. In our population of operated patients with hippocampal sclerosis there is a 1-2% percentage of breakthrough seizures after drug withdrawal. The risk is highest during the first year following the suspension and then decreases.
ACCEPTED MANUSCRIPT Worries about the possible injury due the use of AED in liver transplanted patients exist. 12 In our patient one of AED (phenobarbital) was withdrawn because of liver side effects (transaminase increase). Early epilepsy surgery and drug withdrawal, when possible, may be even more advantageous in the subgroup of drug-resistant epileptic patients with liver transplant, as they might
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immunosuppressant drugs commonly used in these patients.
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preserve the liver from the potential damage due to multiple AED trials and their interaction with
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Conflict of interest
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The authors declared no potential conflict of interest and no financial support for this article.
ACCEPTED MANUSCRIPT References 1. Lee YJ, Yum MS, Kim EH, Choi HW, Oh SH, Kim DY, Kim KM, Ko TS. Risk factors for neurological complications and their correlation with survival following pediatric liver transplantation. Pediatr Transplant. 2014 Mar;18:177-84.
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2. 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 Mar;11:152-9.
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3. Fugate JE, Rabinstein AA. Posterior reversible encephalopathy syndrome: clinical and radiological manifestations, pathophysiology, and outstanding questions. Lancet Neurol.
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2015 Sep;14:914-25.
4. Santos MM, Tannuri AC, Gibelli NE, Ayoub AA, Maksoud-Filho JG, Andrade WC, Velhote MC, Silva MM, Pinho ML, Miyatani HT, Susuki L, Tannuri U. Posterior reversible encephalopathy syndrome after liver transplantation in children: a rare complication related
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to calcineurin inhibitor effects. Pediatr Transplant. 2011 Mar;15(2):157-60. 5. Heo K, Cho KH, Lee MK, Chung SJ, Cho YJ, Lee BI. Development of epilepsy after posterior reversible encephalopathy syndrome. Seizure. 2016 Jan;34:90-4.
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6. Walker M. Hippocampal Sclerosis: Causes and Prevention. Semin Neurol. 2015 Jun;35(3):193-200.
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7. Tassi L, Meroni A, Deleo F, Villani F, Mai R, Russo GL, Colombo N, Avanzini G, Falcone C, Bramerio M, Citterio A, Garbelli R, Spreafico R. Temporal lobe epilepsy: neuropathological and clinical correlations in 243 surgically treated patients. Epileptic Disord. 2009 Dec;11:281-92. 8. Gao B, Liu FL, Zhao B. Association of degree and type of edema in posterior reversible encephalopathy syndrome with serum lactate dehydrogenase level: initial experience. Eur J Radiol. 2012 Oct;8:2844-7.
ACCEPTED MANUSCRIPT 9. Kwan P, Arzimanoglou A, Berg AT, et al. Definition of drug resistant epilepsy: consensus proposal by the ad hoc Task Force of the ILAE Commission on Therapeutic Strategies. Epilepsia 2010;51:1069–1077.
antiepileptic drug. J Epilepsy Res. 2014 Jun 30;4:1-6.
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10. Lee SK. Treatment strategy for the patient with hippocampal sclerosis who failed to the first
11. Reed-Knight B, Lee JL, Cousins LA, Mee LL. Intellectual and academic performance in children undergoing solid organ pretransplant evaluation. Pediatr
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Transplant. 2015 Mar;19(2):229-3
Neurol. 2012 Aug;14(4):332-47.
Fig. 1: EEG and MRI
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12. Shepard PW, St Louis E. Seizure treatment in transplant patients. Curr Treat Options
A: intercritical EEG, showing sharp waves in the left temporal leads (dotted square); B: critical
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EEG, showing theta rhythmic activity on the left temporal leads (dotted squares) that stops at the end of the seizure, and delta slow activity on the left hemisphere; C: MRI images (upper part),
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showing the temporo-polar hypoplasia and blurring and the hippocampal sclerosis (arrow) before surgery. D:
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MRI images (lower part), showing the antero-mesial left temporal cortectomy (arrow) after surgery.
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ACCEPTED MANUSCRIPT
ACCEPTED MANUSCRIPT Highlights
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SC
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PRES with status epilepticus may occur after liver transplantation Risk factors in this setting are immunosuppressant, hypertension, renal failure We report a transplanted girl with refractory epilepsy and hippocampal sclerosis Epilepsy surgery led to seizure remission and antiepileptic drug withdrawal Antiepileptic drug withdrawal is a major advantage in liver-transplanted patients
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• • • • •
S1090-3798(16)30011-3
DOI:
10.1016/j.ejpn.2016.04.007
Reference:
YEJPN 2042
To appear in:
European Journal of Paediatric Neurology
Received Date: 25 December 2015 Revised Date:
7 April 2016
Accepted Date: 7 April 2016
Please cite this article as: Dilena R, Nebbia G, Fiorica L, Farallo M, Degrassi I, Gozzo F, Pelliccia V, Barbieri S, Cossu M, Tassi L, Epilepsy surgery in a liver-transplanted girl with temporal lobe epilepsy and hippocampal sclerosis following PRES with status epilepticus, European Journal of Paediatric Neurology (2016), doi: 10.1016/j.ejpn.2016.04.007. This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.
ACCEPTED MANUSCRIPT Epilepsy surgery in a liver-transplanted girl with temporal lobe epilepsy and hippocampal sclerosis following PRES with status epilepticus Robertino Dilena
a,*
, Gabriella Nebbia b, Lorenzo Fiorica b , Marcello Farallo b, Irene Degrassi
b
,
Francesca Gozzo c , Veronica Pelliccia c , Sergio Barbieri a, Massimo Cossu c , Laura Tassi c
a
RI PT
Affiliations
Service of Paediatric Epileptology – Unit of Clinical Neurophysiology, Department of
Neuroscience and Mental Health, Fondazione IRCCS Ca’ Granda, Ospedale Maggiore Policlinico,
b
Service of Paediatric Hepatology, Department of Paediatrics, Fondazione IRCCS Ca’ Granda,
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Ospedale Maggiore Policlinico, Milan, Italy C
SC
Milan, Italy
“Claudio Munari” Epilepsy Surgery Centre, Niguarda Hospital, Milan, Italy
Abbreviations: EEG, electroencephalogram; AED, antiepileptic drugs; PRES, posterior reversible
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encephalopathy syndrome; HS, hippocampal sclerosis; LDH, Lactate dehydrogenase enzyme; SUDEP, sudden unexpected death of epileptic patients.
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Keywords: liver transplant; posterior reversible encephalopathy syndrome; temporal lobe epilepsy;
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refractory epilepsy; hippocampal sclerosis; epilepsy surgery
*Corresponding author: Robertino Dilena
Fondazione IRCCS Ca’ Granda, Ospedale Maggiore Policlinico, Servizio di Epilettologia e Neurofisiopatologia pediatrica, Clinica Mangiagalli, via Commenda 12, 20122, Milan, Italy, Tel: +390255032406; Fax: +390255032155 Email adress: [email protected]
ACCEPTED MANUSCRIPT Abstract Introduction. Posterior reversible encephalopathy syndrome (PRES) with status epilepticus may occur after liver transplant. This may rarely lead to refractory epilepsy and hippocampal sclerosis (HS).
RI PT
Case description. We report the first case of epilepsy surgery in a liver-transplanted patient with refractory temporal lobe epilepsy. A 3-year-old girl underwent liver transplant for congenital biliary atresia. Four days after transplant she manifested PRES with status epilepticus, but she recovered
SC
within a couple of weeks. At the age of 5 years she started presenting complex partial seizures, that became refractory to antiepileptic drugs (AED), worsening psychosocial performances. The pre-
M AN U
surgical work-up identified a left HS and temporal pole alterations. A left antero-mesial temporal lobectomy was performed, leading to epilepsy remission and allowing AED withdrawal. Conclusion. Drug-resistant temporal lobe epilepsy and HS may occur as sequelae of PRES with status epilepticus related to liver transplant and cyclosporine use. In this setting early epilepsy
TE D
surgery may reduce the time of chronic exposure to AED and severe illness due to repeated seizures. This option might have additional advantages in the subgroup of epileptic patients with liver transplant, preserving the liver from the potential damage due to multiple AED trials and their
AC C
EP
interaction with commonly used immunosuppressant drugs.
ACCEPTED MANUSCRIPT 1. Introduction Neurological complications are a significant cause of morbidity and mortality in patients undergoing liver transplantation (up to one-third of liver-transplanted patients). 1-2 Among acute neurological complications occurring in the post-transplant period, seizures are the 1
No reliable epidemiological data about long-term neurological complications are
available. Focal drug-resistant epilepsy has been rarely reported. 2
RI PT
most frequent.
In liver-transplanted patients neurological problems can originate from acute brain injuries related
SC
to liver transplantation and immunosuppressant drugs, to chronic liver disease, or be incidentally associated. Among the post-transplant complications there is posterior reversible encephalopathy
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syndrome (PRES). 3-4 PRES refers to a disorder of reversible subcortical vasogenic brain oedema in patients with acute neurological symptoms (seizures, encephalopathy, headache, and visual disturbances) in different situations like cytotoxic or immunosuppressant drug use, transplantation, renal failure, blood pressure fluctuations, autoimmune disorders, and pre-eclampsia or eclampsia.
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Brain imaging usually reveals vasogenic oedema involving predominantly (but not only) parietooccipital regions. PRES seems caused by endothelial injury related to abrupt blood pressure changes or direct effects of cytokines on the endothelium, which leads to breakdown of the blood–brain
EP
barrier. The posterior brain regions can be particularly susceptible to hyperperfusion, because little sympathetic innervation exists in the posterior fossa.3 Despite the name “reversible”, persistent
AC C
neurological sequelae are reported in 10–20% of patients with PRES.3 Among them, epilepsy and hippocampal sclerosis (HS) have been rarely reported.5 They seem linked to complications of PRES like haemorrhage or cytotoxic oedema3,5 or related to consequences of PRES-associated status epilepticus. Indeed epilepsy and HS has been described as possible consequence of status epilepticus, 6 as mesial temporal lobe areas are more susceptible to this injury. In this article we show the sequential occurrence of these pathological events in a liver transplanted girl, describe the importance to prevent them and report for the first time in this setting the possibility to successfully treat refractory focal epilepsy by surgery.
ACCEPTED MANUSCRIPT
2. Case study 2.1 Liver disease and transplantation A female infant, born after a normal pregnancy and delivery, presented in the neonatal period with
RI PT
jaundice, dark urine ad pale stools. Blood examinations showed hyperbilirubinemia associated with high gamma-glutamyl transferase and alkaline phosphatase serum levels. A laparotomy performed at the age of three months showed extrahepatic biliary atresia, requiring a portoenterostomy (Kasai
transplantation waiting list at the age of 5 months.
SC
I). This procedure did not improve symptoms and the patient was therefore included in the liver
M AN U
In the first two years neurological examination showed generalized hypotonia with motor delay ascribed to the metabolic derangement. A brain MRI yielded normal findings. While the patient was on the waiting list, the hepatic function deteriorated due to cirrhosis associated with portal hypertension, esophageal varices and splenomegaly.
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At the age of 3 years, the patient was transplanted with left-liver technique. A primary liver dysfunction acutely occurred and a second transplantation was performed 8 days later. Immunosuppressive treatment with cyclosporine was started at 1,5 mg/kg/die for one week. Four
EP
days after re-transplantation the patient had recurrent focal seizures characterized by right-sided clonic jerks and left head deviation with impairment of awareness which persisted between the
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seizures consistent with focal status epilepticus. She also developed arterial hypertension, moderate renal impairment and respiratory failure associated with pneumonia. Liver enzymes were decreasing (almost normal levels), while dehydrogenase (LDH) levels were high (around 900 UI/L). She was admitted to the intensive care unit, where after lack of response to diazepam she was treated with intravenous phenobarbital, repeated boluses of thiopentone and antibiotic therapy. Excessively high cyclosporine blood levels (479 ng/mL; target therapeutic level: 200 ng/mL) initially required drug reduction to 1 mg/kg and subsequent switching to tacrolimus (4 mg daily). Brain CT showed right occipito-parietal, left occipito-temporal and left frontal hypodensities
ACCEPTED MANUSCRIPT without contrast enhancement compatible with PRES. The electroencephalogram (EEG) showed diffuse slow activity and focal paroxysmal activity in the left fronto-temporal and right parietooccipital leads. One week after onset of the neurological complication complete control of seizures was achieved. Ten days after onset MRI showed only occipito-temporal alterations (appearing as
RI PT
hyperintensities on T2-weighted sequences), decreasing in extent compared with the acute brain CT. Clinical recovery and EEG normalization occurred in about two weeks after onset. The patient was discharged on phenobarbital (4 mg/kg/day), slowly tapered and then withdrawn 10 months
SC
later, whereas immunosuppressive therapy with tacrolimus was continued.
In the following years no signs of liver rejection or other transplant complications were observed
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and the patient on low dose tacrolimus maintained normal liver function tests. 2.2 Epilepsy history
At the age of 5 years the patient presented with focal seizures with impairment of awareness. They were characterized by staring (no subjective feeling was referred), unresponsiveness, oral and left
TE D
upper limb automatisms, dystonic posture of the right hand, left head and eyes deviation, post-ictal aphasia. Secondary tonic-clonic generalization sometimes occurred. Interictal EEG showed focal slow waves and sharp waves, localized over the left temporal lobe. Brain MRI was initially reported
EP
as unremarkable, but at that time the temporal region was not specifically studied. Several therapeutic trials with antiepileptic drugs (AED) like oxcarbazepine, vigabatrin, levetiracetam,
AC C
topiramate, valproate, lacosamide, phenobarbital, as monotherapies or in combination gave some benefit, but failed to ensure a persistent seizure control. Phenobarbital was associated with liver side effects (transaminase increase) and was soon withdrawn. Seizure frequency slowly increased over years, from one per week to one-two per day, and some episodes of focal non convulsive status epilepticus were also reported. The girl was increasingly disabled by her epileptic condition, with severe social isolation and school difficulties. The neuropsychological evaluation (WISC-R) performed at the age of 15 years disclosed a significant cognitive impairment (total IQ of 41, verbal IQ 51 and performance IQ 45).
ACCEPTED MANUSCRIPT 2.3 Presurgical evaluation At the age of 15 years, when the patient’s family asked for a second epileptological opinion, she was immediately sent to the epilepsy surgery center. At that time she had 3 focal seizures per week, approximately 2 secondarily generalized seizures per month and at least 1 dense cluster of seizures
RI PT
lasting 2 days per month, often configuring a true non-convulsive status epilepticus. The neurological examination was normal. The neuropsychological investigation showed impaired capacity in word generation and long-term memory for visual/verbal materials and faces. She also
SC
had difficulties in visuospatial construction, praxic functions, reasoning and problem solving, although her global learning capacity had a good potential. She also had high levels of anxiety and
M AN U
depression and difficulties in social adaptation.
A long-term video-EEG monitoring showed slow and spike-waves localized in left temporal lobe during wakefulness, increasing during sleep (Fig. 1, A). A typical seizure was recorded, showing a left temporal lobe rhythmic theta activity (Figure 1, B). Brain 1.5T MRI demonstrated a left HS,
TE D
associated with a slight hypoplasia and poor gray-white matter demarcation (blurring) of the left temporal pole (Fig.1, D). On the basis of these clear-cut anatomo-electro-clinical correlations the
2.4 Histopathology
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patient underwent a left antero-mesial temporal lobectomy (Fig 1, C).
Surgical specimens were obtained from the temporal pole, from the mesial structures including the
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hippocampus tail, and from the anterior portions of the first, second, third and fourth temporal gyri (antero-mesial temporal lobectomy). The histological examination confirmed an ILAE type 2 hippocampal sclerosis, with loss of pyramidal neurons in CA1, with neuronal preservation in CA2-CA4 and end-folium. A Chaslin gliosis in all the surgical neocortical specimens including the temporal pole was observed. 2.5 Five-year outcome After surgery AED have been progressively decreased and two years later stopped, without seizure relapse. The patient quality of life has markedly improved.
ACCEPTED MANUSCRIPT The neuropsychological evaluation performed 2 years after surgery did not indicate significant changes of her cognitive abilities with small differences consisting in some improvement in selective visual attention and praxic functions. Her emotional and behavioral difficulties had
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improved. Five years after surgery the patient is still completely seizure-free.
3. Discussion
Efficacy of surgery in temporal lobe epilepsy is well known, 7 but this is the first case reported in a
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liver transplant patient. She developed drug-resistant epilepsy of the left temporal lobe after a posttransplant PRES. Presurgical EEG showed intercritical and critical left temporal activity. In the
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seizure semiology the typical initial temporal aura (déjà vu or olfactory sensations) was not reported, but the other signs were typical of electrical spreading from the mesial temporal lobe (staring, unresponsivess, oral and left upper limb automatism, dystonic posture, postictal aphasia). This could be related to a possible fast electrical discharge spreading, possibly related to a more
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extensive temporal alteration proved at the MRI by presence of not only left HS, but also left temporal pole slight hypoplasia and gray-white matter blurring and at the histology by gliosis in the temporal specimens. We think that these lesions might represent the sequelae of PRES with status
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epilepticus suffered by the patient.
It is known that PRES can occur after liver transplantation triggered by immunosuppressant drugs 3-6
but also hypertension, renal failure, and homeostatic derangement determined
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like cyclosporine,
by transplant-related rapid liver function changes. Status epilepticus and cytotoxic injury in PRES have been already associated with HIS and chronic epilepsy.5-6 This is why all treatable risk factors need to be checked and managed as better as possible. Large case-control studies focused on PRES and epilepsy occurrence in the population of liver transplant patients are needed to better study risk factors and the possibility to prevent irreversible lesions. A better identification of biomarkers of PRES could help to identify patients at high risk to develop PRES with major severity. Recently an increased serum level of dehydrogenase (LDH), which plays an essential role in endothelial injury,
ACCEPTED MANUSCRIPT has been described as a potential risk factor for the development of oedema in PRES particularly in cancer patients.
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In our patient we had increased LDH levels, but we also know that this is a
nonspecific finding, which need to be studied in the large population of transplanted patients to make correct conclusions.
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The presented case also highlights the additional advantages of early epilepsy surgery in the subgroup of epileptic patients with liver transplantation. Temporal lobe epilepsy associated with HIS is often drug-resistant, but it is surgically remediable with an excellent outcome. The most
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recent definition of refractory epilepsy is failure of adequate trials of two tolerated, appropriately chosen and used AED schedules to achieve sustained seizure freedom.
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Refractory epilepsy
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increases the risk of cognitive and psychosocial dysfunction and sudden unexpected death of epileptic patients (SUDEP).10 Surgical outcome is less satisfactory as duration of epilepsy or age at surgery increase, thus suggesting a progressive disorder.10
Cognitive impairment found in our patient is probably multifactorial. Given the harmonic global
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cognitive deficits found, we think that the PRES-related status epilepticus and the underlying cerebral injury associated with liver dysfunction before the first three years had a major etiological role than refractory focal epilepsy. A slightly lower intellectual functioning is found among all
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children with liver transplantation compared to matched siblings and it seems related to cerebral effects of pre-transplant liver dysfunction. 11
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Anyway the patient was unfortunately referred late to surgery. When the patient received a second epileptological opinion, she was immediately sent to the surgery centre and operated with epilepsy resolution and drug withdrawal after two years. The history highlights the importance to early consider the surgical option to reduce the time of illness and of chronic exposure to drugs. In our population of operated patients with hippocampal sclerosis there is a 1-2% percentage of breakthrough seizures after drug withdrawal. The risk is highest during the first year following the suspension and then decreases.
ACCEPTED MANUSCRIPT Worries about the possible injury due the use of AED in liver transplanted patients exist. 12 In our patient one of AED (phenobarbital) was withdrawn because of liver side effects (transaminase increase). Early epilepsy surgery and drug withdrawal, when possible, may be even more advantageous in the subgroup of drug-resistant epileptic patients with liver transplant, as they might
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immunosuppressant drugs commonly used in these patients.
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preserve the liver from the potential damage due to multiple AED trials and their interaction with
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Conflict of interest
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The authors declared no potential conflict of interest and no financial support for this article.
ACCEPTED MANUSCRIPT References 1. Lee YJ, Yum MS, Kim EH, Choi HW, Oh SH, Kim DY, Kim KM, Ko TS. Risk factors for neurological complications and their correlation with survival following pediatric liver transplantation. Pediatr Transplant. 2014 Mar;18:177-84.
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2. 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 Mar;11:152-9.
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3. Fugate JE, Rabinstein AA. Posterior reversible encephalopathy syndrome: clinical and radiological manifestations, pathophysiology, and outstanding questions. Lancet Neurol.
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2015 Sep;14:914-25.
4. Santos MM, Tannuri AC, Gibelli NE, Ayoub AA, Maksoud-Filho JG, Andrade WC, Velhote MC, Silva MM, Pinho ML, Miyatani HT, Susuki L, Tannuri U. Posterior reversible encephalopathy syndrome after liver transplantation in children: a rare complication related
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to calcineurin inhibitor effects. Pediatr Transplant. 2011 Mar;15(2):157-60. 5. Heo K, Cho KH, Lee MK, Chung SJ, Cho YJ, Lee BI. Development of epilepsy after posterior reversible encephalopathy syndrome. Seizure. 2016 Jan;34:90-4.
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6. Walker M. Hippocampal Sclerosis: Causes and Prevention. Semin Neurol. 2015 Jun;35(3):193-200.
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7. Tassi L, Meroni A, Deleo F, Villani F, Mai R, Russo GL, Colombo N, Avanzini G, Falcone C, Bramerio M, Citterio A, Garbelli R, Spreafico R. Temporal lobe epilepsy: neuropathological and clinical correlations in 243 surgically treated patients. Epileptic Disord. 2009 Dec;11:281-92. 8. Gao B, Liu FL, Zhao B. Association of degree and type of edema in posterior reversible encephalopathy syndrome with serum lactate dehydrogenase level: initial experience. Eur J Radiol. 2012 Oct;8:2844-7.
ACCEPTED MANUSCRIPT 9. Kwan P, Arzimanoglou A, Berg AT, et al. Definition of drug resistant epilepsy: consensus proposal by the ad hoc Task Force of the ILAE Commission on Therapeutic Strategies. Epilepsia 2010;51:1069–1077.
antiepileptic drug. J Epilepsy Res. 2014 Jun 30;4:1-6.
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10. Lee SK. Treatment strategy for the patient with hippocampal sclerosis who failed to the first
11. Reed-Knight B, Lee JL, Cousins LA, Mee LL. Intellectual and academic performance in children undergoing solid organ pretransplant evaluation. Pediatr
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Transplant. 2015 Mar;19(2):229-3
Neurol. 2012 Aug;14(4):332-47.
Fig. 1: EEG and MRI
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12. Shepard PW, St Louis E. Seizure treatment in transplant patients. Curr Treat Options
A: intercritical EEG, showing sharp waves in the left temporal leads (dotted square); B: critical
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EEG, showing theta rhythmic activity on the left temporal leads (dotted squares) that stops at the end of the seizure, and delta slow activity on the left hemisphere; C: MRI images (upper part),
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showing the temporo-polar hypoplasia and blurring and the hippocampal sclerosis (arrow) before surgery. D:
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MRI images (lower part), showing the antero-mesial left temporal cortectomy (arrow) after surgery.
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ACCEPTED MANUSCRIPT Highlights
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PRES with status epilepticus may occur after liver transplantation Risk factors in this setting are immunosuppressant, hypertension, renal failure We report a transplanted girl with refractory epilepsy and hippocampal sclerosis Epilepsy surgery led to seizure remission and antiepileptic drug withdrawal Antiepileptic drug withdrawal is a major advantage in liver-transplanted patients
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