Liver transplantation in neurological Wilson’s disease in children: Where do we stand?

Abstract

Wilson’s disease (WD) is a genetic disorder caused by a mutation in the gene ATP7B. It results in the pathological deposition of copper mainly in the liver and the brain leading to hepatic and neurological manifestations. Medical management is effective in most patients (approximately 85%). It includes chelators (D-penicillamine and trientine), which are the mainstay of treatment, and zinc salts, which are used to inhibit the gastrointestinal absorption of copper. However, in cases of WD with neurological manifestations, patients take longer time to improve and sometimes have persistent clinical symptoms, and a few develop irreversible neurological damage despite adequate chelation. Generally, liver transplantation (LT) is indicated in acute fulminant hepatic failure or decompensated liver cirrhosis (despite adequate chelation). However, LT is still debatable for severe neurologic WD because of advanced or irreversible brain damage. There is a dearth of literature on the role of LT in neurological WD. This study aims to review the current literature concerning indications, contraindications, and outcomes of liver transplantation among children with neurological WD.

Key Words: ATP7B protein; Liver transplantation; Wilson’s disease; Hepato-neurologic; Children

Core Tip: Liver transplantation (LT) is indicated in Wilson’s disease (WD) in acute fulminant hepatic failure or decompensated liver cirrhosis. However, LT is still debatable for neurologic WD because of advanced or irreversible brain damage. This review aims to study the current literature concerning indications, contraindications, timing and outcomes of LT among children with neurological WD.

INTRODUCTION

Wilson’s disease (WD) is an autosomal recessive inherited disorder of copper metabolism, caused by a mutation in the ATP7B gene, located on chromosome 13. The ATP7B gene codes for a P-type adenosine triphosphatase (ATPase), which mediates the incorporation of dietary copper into ceruloplasmin for copper transport into peripheral tissues and mediates copper excretion into the biliary canaliculi in copper loaded condition. In absence of this ATPase, there is copper overload mainly in the liver and brain and various organs such as eyes, kidneys and muscles. Recent studies have shown the prevalence of WD to vary from 1:29000 to 1:40000[1]. The majority of children present with hepatic manifestations ranging from asymptomatic elevation of transaminases, chronic liver disease to acute liver failure. Common neurologic manifestations are dysphagia, drooling of saliva, abnormal gait, tremors, personality change and deterioration in school performance[2]. Forty to sixty percent of patients present with a hepatic presentation in the second decade of life, around 34% and 10% present with neurologic and psychiatric manifestations respectively[3]. The mean age of presentation with neurologic symptoms varies from 12.7 years to 18.9 years[2,4,5]. Chelation of copper is the mainstay of treatment. Liver function improves in over 90% of patients, usually within 2-6 months, while clinical neurological improvement is seen in approximately 50%-60% of patients which takes longer time i.e., 1-3 years to improve[6]. The current guidelines recommend liver transplantation (LT) in patients with decompensated WD or progressive disease with end-stage liver disease unresponsive to adequate chelation, or acute liver failure (presenting with intravascular hemolysis) or rarely in a case of unresectable hepatocellular carcinoma without vascular invasion[7]. The role of LT in patients with neurological manifestations is controversial. It is not yet recommended for pure neurological indication[7,8]. While, it is only recently that the European Association for the Study of the Liver has recommended that LT can be considered in patients with neurological worsening (despite 6-months of optimum chelation), on a case-to-case basis[6]. Here, we have presented a narrative review of the case series/reports, retrospective studies focusing on the patient selection, indications of LT in neurologic WD, and post-LT neurologic outcomes; the scarce and retrospective data pose a major limitation.

The earliest reports of LT for neurological WD dates back to 1993[9]. Recently, there has been increase in LT in patients with neurological manifestations and various studies have shown neurological improvement[10]. Although in most of these studies the primary indication of LT was hepatic, patients also had significant neurological symptoms. A systematic review of outcomes of LT of 302 patients with neurological symptoms showed major improvement in 215 (71.2%) cases, no change in the neurological status in 21 (6.9%) and immunosuppression related de novo neurological worsening in 24 (7.9%) cases[10]. Neurological manifestations such as dystonia, dysphagia can contribute to significant morbidity in the post-operative period and pose risks of aspiration pneumonia, prolonged hospitalization and have difficulty with compliance to the immunosuppressive medications[10,11]. Till date, the impact of LT on the progress of neurological manifestations of WD is controversial. Herein, we present a review of LT in pediatric neurologic WD.

LT IN NEUROLOGIC WD: PATHOPHYSIOLOGY, TIMING AND DONOR CONSIDERATIONS

Mechanism

The hypothesis is that the abnormal deposition of copper is due to the low ceruloplasmin level, which normalizes after LT and the copper deposition in the extrahepatic organs is prevented by the cupriuresis caused by the transplanted liver[12-14]. It has also been shown that children had a faster neurological improvement compared to adults[15]. Normally, the ATP7B gene expresses a P-type ATPase in the hepatocytes, which transports the dietary copper across the trans-Golgi network and mediates its incorporation into apoceruloplasmin, leading to the formation of holoceruloplasmin, which then transports copper to the periphery. In copper-overload states, ATP7B also mediates biliary excretion of excess copper. In the absence of this ATPase, free “non-ceruloplasmin bound copper” accumulates in the cells, causing hepatocyte damage and when it exceeds the storage capacity of the liver, it is released into the peripheral blood stream and deposits in various organs such as brain, eyes, and kidneys[16]. Brain expresses both ATPases (ATP7A and ATP7B) transporters, predominantlyATP7A[17]. Reversal of neurological symptoms and magnetic resonance imaging (MRI) changes post-LT points to a reversal of copper overload in the brain, possibly due to the compensation for ATP7B by ATP7A in a brain that is not subject to excess copper overload because of hepatic dysfunction[17]. Occasionally, the neurological manifestations may persist, owing to the irreversible brain damage or slow mobilization of extrahepatic copper. In patients with persistent neurological symptoms post-LT, D-penicillamine has been used to expedite the mobilization of copper from the central nervous system and has shown reversal of neurological symptoms[18-20].

Timing of LT

Regarding the timing of LT, Poujois et al[18] presented a retrospective data of 18 WD (including 15 pediatric) patients, who underwent LT as a rescue therapy for neurological indications and showed a significant neurological improvement (78% patients gained physical independence) and fairly good post-LT survival outcomes comparable to previous studies[11,21]. In this cohort, the authors have specifically reported the median time between neurologic worsening and LT, which has a bearing on deciding the timing of LT in addition to the time from WD diagnosis to LT. Neurological worsening was defined objectively using Unified WD Rating Scale (UWDRS) score and modified Rankin Scale (mRS) score. The entire cohort of 18 patients was grouped into two: Primary neurological worsening and neurological worsening due to poor drug adherence. In the patients with primary neurological worsening, the median time between neurologic worsening and LT was 6.7 (5.3-14.5) months and the median (interquartile range) time form diagnosis to LT was 6.7 (5.3-14.5) months. In those with secondary worsening due to poor drug compliance, the median time between the diagnosis of WD and LT was 84 (24-181) months whereas the median interval between neurological aggravation and LT was 7 (5-7) months, which is much shorter than in older studies[18]. In the study by Guillaud et al[21] where patients with neuropsychiatric manifestations had poor outcomes (with seven patients undergoing LT for neurological indication), the median interval between diagnosis to LT was 2.1 years (range: 0.6-20.5 years) and time between neurological worsening and LT was not mentioned. Neurological symptoms take years to improve with chelation, hence, to decide the timing of LT in this subset, it is vital to select patients when they start deteriorating neurologically while on chelation. Hence, the duration from neurological deterioration to LT is more important than duration between the disease diagnosis and LT, so that patients could be considered for LT before irreversible brain damage sets in.

Additionally, before a decision of LT is made, it is important to understand the natural history of neurological WD and paradoxical neurological worsening related to chelators. Chelation-related paradoxical neurological deterioration has been categorized into two: Early deterioration, defined as neurological deterioration within 6 months of starting chelators, and late deterioration is usually beyond 6 months of treatment[22]. It is challenging to differentiate neurological worsening due to disease progression from chelator-related paradoxical neurological worsening. The dose and compliance to chelators may help in differentiating between the two. In the recent studies, around 11.1%-26.1% patients developed paradoxical neurological worsening on chelators; the majority improved on drug withdrawal, around a third of patients remained the same or worsened[23,24]. Litwin et al[23] in a study of 143 patients of WD (with or without neurological involvement), showed that early neurological worsening was seen in 11.1% (16/143) patients, only in those who had neurological signs at diagnosis. It was completely reversible in 53% (8/15) and partially reversible in 13% (2/15) of patients over 9.2 ± 5.2 months, three died of complications arising out of immobilization, two remained severely disabled, and one was lost to follow-up[23]. Thus, it is prudent to rule out paradoxical neurological worsening and allow time for recovery on drug withdrawal. At the same time, it may be argued that the patients who didn’t improve on drug-withdrawal, had irreversible brain damage and probably might have benefitted from earlier treatment initiation (and consideration for LT if medical therapy failed). The challenge is to identify these patients before irreversible brain damage. This challenge may be abrogated by the use of WD brain MRI severity scale, which can differentiate between acute copper-induced brain damage (paradoxical neurological worsening) from the chronic irreversible changes[22,25,26].

Studies have shown that chronic damage score correlated well with UWDRS and serum neuro-filament light chain (a biomarker of brain injury)[22,25-27]. Thus, brain MRI can aid in selecting the ideal transplant candidates who do not have irreversible MRI changes. Contrary to this, a study performed in six children with neurological symptoms [three patients had stable liver function test (LFT) and underwent transplant for neurological symptoms] showed that all patients improved symptomatically, however, the pattern of T2-weighted hyperintensities did not correlate with neurological outcomes, suggesting that these changes do not necessarily represent irreversible clinical damage[28]. Similar findings were shown by Aksoy et al[29]. Brain MRI T2-weighted changes are thought to represent copper toxicity, cytotoxic edema and myelinolysis in the initial stages and gliosis, demyelination and cystic degeneration later on[28]. In the pediatric study stated above, the T2 hyperintensities were likely due to acute changes such as edema and cytotoxicity, which improved post-LT. So, it may be said that brain MRI can aid in decision of LT and needs more long-term studies for validating the post-LT MRI changes and their clinical correlation. Tang et al[30] compared post-LT neurological improvement in 18 patients to long-term chelation in 20 patients and showed that neurological symptoms and signs, serum copper and serum ceruloplasmin were improved in the operative group compared to non-operative group. It is possible that LT is more effective than chelator in mobilizing copper from the central nervous system, as the liver dysfunction is taken care of by the transplanted liver, hence, a patient should not be denied of LT if he/she has persistent severe neurological symptoms even after adequate chelation.

Donor considerations

Initial liver transplant studies on neurologic WD were deceased donor LT. Increasing number of living donor LT (LDLT) in WD led to the consideration of parents as the most common donors[31]. There were initial speculations whether parents, being heterozygote carriers, could be considered as safe liver donors. Around 20% heterozygote carriers may have low ceruloplasmin and their copper metabolisms may be sub-normal, however, this did not have a clinical impact on the children who had their parents as donors[31-33]. Asonuma et al[31] reported that when WD was ruled out in the parents, with their ceruloplasmin levels ranging from 15.6 mg/dL to 24.5 mg/dL, the short-term (range 7-75 months) outcomes were good and none had recurrence of WD. Additionally, Yoshitoshi et al[34] who presented the long-term follow-up data of LDLT among 32 (24 pediatric) patients with parents as donors in 29/32 cases, showed that none of the survivors had disease recurrence during the mean follow-up time of 6.7 ± 4.0 years (range: 0.04-15.0 years). The post-transplant ceruloplasmin improved and urinary copper excretion decreased in all the recipients, even when the donors had sub-optimal levels. Thus, children who received livers from their parents had good post-LT clinical outcomes with marked reduction in their urinary copper excretion with only mildly abnormal copper balance post-LT[31,34]. Hence, it is prudent to measure ceruloplasmin and screen the donors for WD and consider LDLT once WD is ruled out in the donor[6,31,35].

NEUROLOGICAL OUTCOMES POST-LT IN NEUROLOGICAL WD

Evolution of evidence over the years

The first case report of LT in WD dates back to 1971 when an eleven-year-old boy underwent LT for hepatic decompensation and improved post-LT[36]. Thereafter, in 1973, Groth et al[12] presented two cases of LT in children with WD, one of them was a 14-year-old boy with decompensated liver disease with crippling dysarthria and choreo-athetosis and showed partial improvement in neurological status at 17 months post LT[14,37]. Thereafter, there were a few case reports of patients with mixed hepatic and neurological symptoms (who underwent LT primarily for hepatic decompensation) had good neurological outcomes[13,38-41]. For the first time, Mason et al[9] performed LT in a young adult, who had crippling neurologic manifestations without any hepatic involvement, and showed partial improvement 3 weeks post-surgery (although the patient died ultimately due to a ruptured splenic artery aneurysm). Similar case was reported in a 14-year-old boy, who was operated for purely neurological indications and showed dramatic response within 9 weeks of transplant[42]. In the early 1990s, Schilsky et al[19] reviewed 55 patients of WD who underwent LT; among them seven had neuro-hepatic WD and one had purely neurological indication (described earlier by Mason et al[9]). Among these 7 patients, 5 showed significant neurological improvement (one of them had persistence of mild tremors, necessitating D-penicillamine post-LT) and the remaining two died of an unrelated cause. Similarly, Schumacher et al[15] presented a single-center retrospective analysis of 21 patients (operated from 1988 to 2000) based on the indications of LT (acute liver failure/end-stage liver cirrhosis/neurological manifestations with stable liver function). Overall, 9 patients had neurological manifestations and four of them had only neurological impairment with stable LFTs. Among the 4 patients with purely neurological indication, one completely improved, and the other 3 showed improvement in the first 6 months to 1.5 years after which only mild residual symptoms persisted, rest of the 5 patients of mixed neuro-hepatic WD also showed improvement. It was also noted that the younger patients were quicker to show improvement[15]. A Chinese study of 18 LDLTs, showed that 7/18 patients with mixed hepatic and neurological symptoms had complete resolution of their neurological symptoms post-LT[43]. Marin et al[44] showed neurological improvement in 3 out of 4 patients who underwent LT for primary neurological deterioration and had only Child A cirrhosis. The neurological improvement has also been shown to corroborate with the regression in white matter and grey matter changes on neuroimaging and KF ring on slit lamp examination[45,46]. Towards the end of the first decade of the 21^st century, there were larger studies and increase in the number of LDLTs which led to a better understanding of post-transplant long-term neurological outcomes. In a Chinese study, where LDLT was performed for liver failure (fulminant hepatic failure, or chronic liver disease) in 22 (19 pediatric) patients, with nine patients having mixed hepatic and neurological impairment, it was shown that the neurological impairment improved significantly in 6/8 patients (one of them died due to rejection) at a mean follow-up of 18.5 months[47]. Three of them had crippling disability with inability to walk pre-LT. A further distinction between the outcomes of neurologic symptoms was shown by Cheng et al[35] (indication of LT was hepatic in all) who classified neurological involvement using Medici’s scoring system into mild, moderate and severe neurological involvement. In their review of 36 patients (with mixed hepatic and neurological symptoms in 15 patients), who underwent transplant for hepatic indications, United Network for Organ Sharing status, model for end-stage liver disease (MELD) score and the presence of neurologic symptoms affected the survival. The survival was slightly better in those with only hepatic manifestations compared to those with mild to moderate neurologic impairment, although not statistically significant. However, when compared to those with severe neurologic impairment, survival was statistically better in patients with only hepatic manifestations[35]. Six out of nine patients who died at a mean follow-up period of 21.7 ± 18.3 months, had mixed hepatic and neurological presentation[35]. The most common cause of death was sepsis, which was more common in neurologically debilitated patients, which is similar to other studies[11,21,35]. In one of the largest series of 107 WD patients, in which all patients underwent LT for hepatic indications, Lankarani et al[48] showed yet again that among 60 patients with mixed hepatic and neuropsychiatric symptoms, the majority showed neurologic improvement; 66.7% had neurologic improvement, 3.3% had no change and 30% had some exacerbations in neuropsychiatric symptoms related to immunosuppressant drugs (tremors) and a psychologic reaction to a major surgery (anxiety, depression). Similar outcomes were shown by Yagci et al[49] in a younger set of patients, median age 19 years (range 10 to 25). In this study, among 8 patients with mixed neuro-hepatic manifestations, they reported neurological improvement in 7/8 patients (87.5%), and psychiatric improvement in 5/8 (67.5%) patients. Neurologic symptom progression was seen in one (attributed to post-operative ischemic stroke) and psychiatric worsening in two patients post-transplant. Neurologic worsening has been reported occasionally, and is usually unrelated to the primary condition in most of the studies[21,48-51]. Over the years, studies have used objective scoring systems to assess the neurologic symptoms, and shown neuropsychiatric improvement post-LT[18,47,49,52].

On the contrary, there were a few studies which showed that not all patients with neurological impairments improve. Guarino et al[50] showed that there was no neurological improvement 5 years post-LT in a patient who had advanced liver disease and had undergone LT mainly for neurological manifestations (although the post-operative course was compounded by a concomitant diagnosis of cyclosporine neurotoxicity and central pontine and extra-pontine myelinolysis). The authors attributed the poor outcome to irreversible damage in the basal ganglia. Kassam et al[53] reported a patient who underwent LT for severe neurologic and psychiatric manifestations (with only mild hepatic disease), had noncompliance to medications due to his persisting psychiatric issues and committed suicide 3.5 years post-LT. In a multi-center Italian study, Medici et al[11] used a scoring system to objectively show neurological improvement in transplanted patients. They compared post-transplant outcomes in WD with pure hepatic and mixed neuro-hepatic symptoms. Among a total of 37 patients, ten had neuropsychiatric manifestations (mixed neurological and psychiatric symptoms in six, neurological symptoms alone in three, and psychiatric symptoms alone in one). Of the 10 patients, six improved in the first 6 months, three showed neurological worsening, and the those with psychiatric symptoms didn’t improve. They postulated that psychiatric manifestations interfered with the drug compliance post-LT, delayed identification of patient complaints and that the severe neurologic symptoms such as dysphagia, dystonia led to prolonged hospitalization predisposing to sepsis and therefore, the overall survival in mixed neuro-hepatic WD was far less compared to those with only hepatic involvement. Similar findings were presented by Guillaud et al[21] in a large cohort of 121 patients of WD. Total nineteen patients had neurologic symptoms, of which, seven were transplanted for pure neurological indication. Among the seven patients transplanted for purely neurological indication (median age: 21.5 years), follow-up data was available for six patients, three improved significantly; however, three patients died in the follow-up due to infection. They showed that neurological indication was associated with poor survival outcomes.

By the end of the first decade of the 21^st century, there was enough evidence supporting significant neurological improvement in those who had mixed hepatic and neurological symptoms and underwent LT for hepatic indications vs LT for a purely neurological indication[54,55]. There might have been a publication bias i.e., the patients with neurological WD who improved might have been published while those who deteriorated were less commonly published; nonetheless, the improvement shown in these studies could not be undermined. In the last 10 years, there has been an increase in LT performed for pure neurological indication with Child A cirrhosis and stable liver function. Mocchegiani et al[56] reported reversal of severe neurologic impairment after LT in a 19-year-old man with normal liver function and Child A cirrhosis (MELD score 7) along with reversal of MRI changes over four years. Poujois et al[18] studied the post-LT outcomes of patients who underwent LT for purely neurological indication from 1994 to 2016. They included only those who had constant neurologic worsening over a maximum of 18 months and despite a minimum of 2 months of appropriate copper chelation and had severe neurologic impairment with an mRS score ≥ 4 (moderately severe disability with inability to walk or attend to bodily functions without assistance). Post-transplant outcomes were measured objectively using the UWDRS score, the mRS score for disability, LFT, MELD score, together with the presence of a Kayser-Fleischer ring, brain MRI scores, and copper balance. Fourteen out of a total of 18 patients [median age 18.5 years (range 16-20.8 years)], were alive at a median follow-up of 40.9 [interquartile range (18.1-93.2)] months]; eight patients (44.4%) had major improvement, four (22.2%) had moderate improvement and two (11.1%) had stable neurological function as measured by UWDRS. Couchonnal et al[57] in a pediatric study of 182 patients of WD, reported six patients of WD who underwent LT for neurologic indication; four had a mean decrease of 77% in UWDRS and two had a decrease of 41% in the UDWRS, of the latter two patients, one had persistent behavioural issues.

Litwin et al[10] presented the first systematic review of 48 studies (up to April 2021) and analyzed the post-transplant outcomes of 302 patients of WD with neurologic symptoms (both mixed neuro-hepatic and pure neurologic WD) with the majority having a hepatic indication of LT (acute liver failure or cirrhosis). Major neurologic improvement was found in 215 cases (71.2%), no improvement was seen in 21 cases (6.9%) and there was de-novo (mostly immunosuppression related) neurologic worsening in 24 cases (7.9%). Turgut et al[58] performed a systematic review of articles published until November 2018, and studied the post-LT outcomes of 791 patients, 36.4% had neurologic symptoms prior to LT, and 74.2% of them showed some neurologic improvement. Wang et al[59] performed a systematic review and meta-analysis on post-LT outcomes in WD (until July 2023), they reported 22 studies in which neuropsychiatric outcomes in both pure neurological and mixed form of WD were analyzed; they showed that general improvement in neurologic features ranged from 22% to100%. In another single-center experience of WD (with 106 LTs performed among 98 children (median age 10.8 years) and 8 adults (median age 33.1 years), mainly for hepatic indications (97.9%), neurological symptoms improved to varying degrees in all seven patients with pre-existing neurological symptoms[60]. Recently, Poujois et al[51] systematically reviewed all 368 patients of WD from January 1973 to January 2024. They classified patients based on their indication of LT into two groups, neurological deterioration (n = 89) and end-stage liver disease (n = 279) to compare their post-transplant outcomes. Neurological improvement at 1-year post-transplant was similar in either group (neurological indication: 86.3% vs hepatic indication: 79.7%). In the neurologic group, of the 73 survivors beyond 1-year follow-up, neurologic improvement was seen in 63 (86.3%) patients at a mean follow-up of 3.7 ± 2.6 years. The improvement was major in 47 (69.1%) patients, moderate in 13 (20.6%) patients and unspecified in 3 patients. Follow-up MRI brain was reported in 38 patients; improvement was seen in (28/38) 73.7% patients with complete regression in 13.2%. Hence, they concluded that LT is a viable option for neurological deterioration as a rescue therapy in case of non-response to medical therapy. American Association for the Study of Liver Diseases guidelines didn’t list severe neurologic symptoms as an indication for LT as there were not sufficient evidence to support LT for neurologic improvement[7]. However, the recent European Reference Network-European Association for the Study of the Liver guideline has aptly recommended that LT should not be contraindicated in patients of WD with neurologic symptoms and that, LT may be considered for severe neurologic symptoms on case-to-case basis if there is no response to chelation therapy[6].

Post-LT outcomes: Post-operative morbidity, survival and neurologic deterioration

Post-operative morbidity and survival: Among the initial studies of LT for hepatic failure due to WD, Medici et al[11] presented the outcomes of 37 patients operated between 1985 and 2000, patient survival at 12 months, 5 years, and 10 years after transplantation were 89.1%, 75.6%, and 58.8%, respectively. The post-LT survival in WD was comparable to other causes of liver disease, however, the survival of patients with mixed hepatic and neuropsychiatric involvement was significantly lower than those with liver disease alone. Cheng et al[35] in their single center study of LDLT in 36 patients of WD with 15/36 patients having neurologic manifestations, showed a similar post-LT survival of 91.7%, 83.3%, 75%, at 1, 3, and 5 years, respectively. Pre-transplant intensive care unit (ICU)-bound, neurologic involvement and MELD score were significantly associated with poor survival on univariate analysis, however, on multivariate analysis, pre-LT ICU bound and MELD score were found to be independent predictors of patient survival. Long-term post-LT outcomes of 121 patients (75 adults and 46 children) operated between 1985 and 2009, with a median follow-up of 72 months (range: 0-276) after LT, were studied by Guillaud et al[21]. They showed a better survival; the overall cumulative patient survival rates post-transplant were 89% at 1 year, and 87% at 5, 10, 15, and 20 years, respectively. Overall, there were 15 deaths, with most deaths occurring in the early post-transplant period (≤ 45 days), the commonest cause of death being sepsis. Follow-up data was available for 6 out of 7 patients operated for neurologic indication; three of them died of sepsis and three survived with persistent neurologic symptoms. They showed that male gender, pre-transplant renal insufficiency, non-elective procedure, and neurological indication were significantly associated with poorer survival rate on univariate analysis, however, on multivariate analysis, only period of LT (prior to 2000) was associated with poor prognosis[21]. This might be attributed to the improved ICU care and better availability of transplant facilities. Also, there were no significant difference in post-LT survival among children and adults in WD[21,61]. Various studies[48,59] have similar and even better survival outcomes compared to the study by Guillaud et al[21]. Overall survival rates have improved and it has been shown that post-transplant survival rate is comparable to LT for other etiologies[11,48]. In the unique study by Poujois et al[18] in which post-LT outcomes of 18 highly dependent with severe neurologic disabilities (who underwent LT for neurologic symptoms) were studied, the cumulated survival rates were 88.8% at 1 year and 72.2% at 3- and 5-years post-LT, which is comparable to older studies[11,35]. Severe sepsis and ICU admission before LT were significantly associated with death. They showed that elective procedure for patients with swallowing difficulties e.g., gastro/jejunostomy improved the transplant outcomes. In a study conducted in the United States and Canada, Ismail et al[62] showed a 47% reduction in graft failure with every 10-year increase from 1987-2016. They showed survival rates of 90.5%, 89.7%, and 86.5% patients, at 3-, 5- and 10-year post-LT, respectively, among pediatric patients. They also showed that there is no difference in graft-survival in WD and non-WD pediatric patients. Younger age, male gender, elevated creatinine (≥ 0.8 mg/dL in children < 3 years old and ≥ 1.0 mg/dL in children ≥ 3 years old) and obesity were risk-factors associated with poor post-LT survival among children[62].

In the systematic review of LTs performed in 302 patients of WD with neurologic presentation, Litwin et al[10] showed a cumulative survival rate of 90.4% at the end of follow-up of all included studies and found that survival outcomes were better in the LT performed post-2000, similar findings were shown in recently published studies[60]. Poujois et al[51] systematically reviewed all 368 patients of WD who had neurological symptoms and categorized them into two groups; neurological indication (n = 89) and end-stage liver disease (n = 279), based on their indication of LT. They showed that survival was similar in both the groups (82 % vs 86.6 % in neurological vs hepatic indication, at a mean follow-up of 3.7 ± 2.6 years and 4.7 ± 3.1 years, respectively) and the most common cause of death was sepsis in either group. Recently, Beyzaei et al[60] presented a single-center post-LT outcomes of 98 pediatric patients with WD (only five had mixed symptoms) and showed survival rates of 97.0%, 96%, and 94.5% at 6 months, 1 year, and 3 years, respectively, which is still better than previous studies.

Neurologic deterioration after LT in neurologic WD: Post-LT neurologic symptoms in WD are most commonly related to immunosuppression and dyselectrolytemia. In neurological WD (neuro-hepatic or pure neurological WD), some authors have reported neurological deterioration post-LT. These are mainly related to drugs (seizures, chorea, tremors related to immunosuppressants (calcineurin inhibitors)[60,63-65], metabolic derangement (central pontine myelinolysis[11,34,50], depression and anxiety related to the surgical procedure and the long-term follow-up[48] and rarely recurrence of neurological symptoms[20,66,67]. Xu et al[66] reported an adolescent girl who underwent LT for acute liver failure, presented 10 months post-LT with new-onset dysphagia, dysarthria, salivation, and gait instability and was found to have low ceruloplasmin levels along with worsening brain MRI showing visible metal deposition in the lenticular nucleus. This patient was started on D-penicillamine and dimercapto succinic acid, but she didn’t show any neurological improvement in the next four years; authors attributed this to sub-normal ceruloplasmin post-LT and direct deposition of free copper in the brain. Similarly, Ni et al[20] presented a series of 8 patients (six patients were aged < 18 years) with two patients transplanted for disabling neurological symptoms, both the patients deteriorated 1-month post-LT, one of them improved partially on restarting D-penicillamine. Among the other six patients transplanted for hepatic indications, two patients had new-onset extrapyramidal symptoms which improved on D-penicillamine, zinc and low-copper diet; the authors concluded that chelation therapy and low-copper diet may be used to alleviate neurological worsening post-LT once tacrolimus toxicity and graft rejection have been ruled out. The low ceruloplasmin levels, elevated urine copper excretion and the neurologic improvement on restarting chelation with normal/low tacrolimus points towards transient liver dysfunction, which could be due to liver rejection or massive release of copper just before or during LT as reported by Litwin et al[67]. Poujois et al[18] also continued chelation in 5/18 patients operated for neurological indication in view of persistence of elevated 24-hour urine copper excretion. However, European Association for the Study of the Liver guidelines do not recommend this, as literature is scarce[6]. Poujois et al[51] in their systematic review, reported that over 13% experienced either a worsening of pre-LT neurological symptoms or the onset of new neurological symptoms after LT in those who were operated for end-stage liver disease group, compared to only 2.7% in those who underwent LT for neurological deterioration. Hence, it is likely that immunosuppression-related neurologic worsening post-LT is a predominant cause. As the LT techniques, ICU care, and outcomes have improved significantly in the last 10 years, we performed a PubMed search with Medical Subject Headings terms “Wilson’s disease” and “liver transplantation” between January 2014 and October 2024 and found 436 articles. We included only those studies (n = 13) which included pediatric patients with neurologic manifestations, and had detailed information on indications of LT and post-LT follow-up (Figure 1). We have summarized the studies in Table 1[18,26,29,48,49,52,56,57,60,65,68-70]. We acknowledge that the data is heterogeneous, making it difficult to draw conclusions.

Figure 1 Literature search strategy for studies (published in the last 10 years) describing the outcomes of liver transplantation in neurological Wilson’s disease among children. LT: Liver transplantation.

Table 1 Recent studies (published in last 10 years) reporting neurological outcomes of liver transplantation in Wilson’s disease.

Ref.	Number of patients enrolled in the studies with their ages at LT	Number of transplanted patients with neurological manifestations	Indication of LT (n, %)	Outcome among pediatric patients with neurologic involvement: Neurologic improvement or death	NW/new-onset neurological symptoms	Mean/median (interquartile range) follow-up
Beyzaei et al[60], 2025	Total n = 106; pediatric, n = 98, (median pediatric age: 10.8 years)	n = 5/98 (P), all neuro-hepatic; n = 2/8 (A), neurologic	Hepatic, n = 93/98 (94.9%); neuro-hepatic, n = 5/98 (5.1%)	NI: 5/5; deaths: 11/98, 11.2% (neurological issue in one)	New-onset neurological symptoms in those without any pre-existing neurologic symptoms: n = 7	21 ± 1.8 months
Isa HM et al[68], 2024	Total n = 8; pediatric, n = 7	n = 1/7	Neurologic and hepatic	None	No neurological improvement	NA
Aksoy et al[29], 2022	Total n = 24 (including adults); mean age: 34, range: 14-57 years	n = 7, all neuro-hepatic; age NA	Hepatic: n = 24 (100%)	NI, n = 6/7; no improvement in one patient who had a brain lesion unrelated to WD	None	Up to 10 years
Couchonnal et al[57], 2021	Total n = 39, all pediatric	n = 6, neurologic	Hepatic, n = 33; neurologic, n = 6	NI, n = 6, one had persistent behavioral abnormalities after LT	None	4.3 ± 2.5 years
Poujois et al[18], 2020	Total n = 18 (including adults) (median age: 18.5 years)	n = 18; n = 13, neurologic; n = 5: Neuro-hepatic; age at LT for individual patient NA	Neurologic: n = 18, 100%	Overall NI: n = 14/18; death: n = 4 (pulmonary infection)	None	Median 40.9 (18.1-93.2) months
Öcal et al[65], 2020	Total: n = 15; pediatric: Nil; mean age: 35.2 years	n = 4, all neuro-hepatic	NA	NI, n = 4	New-onset neurological symptoms in those without any pre-existing neurologic symptoms: n = 1	NA
Moguilevitch and Straker[69], 2020	Total n = 1; age: 15 years	n = 1, neuro-hepatic	Neurologic and hepatic	NI, n = 1	None	12 months
Laurencin et al[52], 2017	Total n = 4 (including adults); age range: 15-23 years	n = 2, neuro-hepatic; n = 2, neurologic	Hepatic: n = 2 (50%); neurologic: n = 2 (50%)	NI, n = 4; death: None	Transient NW, improved on D-penicillamine: n = 1	1-4 years
Lankarani et al[48], 2016	Total n = 107 (including adults; age range: 5-59 years)	n = 60/107, all neuro-hepatic (adults included)	Hepatic: 107 (100%)	NI, n = 40/60 (66.67%); stable disease, n = 2/60 (3.3%); death: 16/107	NW: n = 18/60 (30%); new onset neurological symptoms: n = 4	4015 days
Yagci et al[49], 2015	Total n = 9 (including adults); pediatric, n = 4; median age: 19 (range: 10-25) years	n = 9, all neuro-hepatic	Hepatic: 9 (100%)	NI, n = 7/8 (87.5%); one patient had post-operative acute ischemic stroke, hence, excluded from analysis	NW, n = 1/8	36.6 months
Sutariya et al[70], 2015	n = 1, age: 14 years	n = 1, neurologic	Neurologic: 1	NI, n = 1; death after 1 year of LT due to discontinuation of immunosuppression leading to rejection	None	12 months
Guillaud et al[21], 2014	Total n = 121; pediatric, n = 46, median (range) age: 14 years (7-17)	n (adult + pediatric) = 26; mixed neuro-hepatic, n = 19; pure neurologic: n = 7	Hepatic: n = 104/121, (94.2%); pure neurologic: 7/121 (5.8%)	NI, n = 11/26; stable disease, n = 1/26; death, n = 4/26 (3 were due to sepsis); data NA, n = 9/26	NW: n = 1 (in mixed neuro-hepatic)	Median post-transplant follow-up: 72 months (0-23.5)
Mocchegiani et al[56], 2014	n = 1, age: 19 years	n = 1, neurologic	Neurologic: 1	NI, n = 1	None	4 years

LT: Liver transplantation; NW: Neurological worsening; A: Adults; P: Pediatric; NI: Neurological improvement; NA: Not available; WD: Wilson’s disease.

In the recent studies, LT when performed for pure neurologic symptoms, has shown significant improvement even in patients with severe neurologic symptoms. With the improvement in the ICU care and LT techniques, there has been improvement in the survival rates in neurologic WD, which is comparable to that of LT performed for end-stage liver disease of other etiologies. Neurologic symptoms take years to improve on chelation; careful clinical follow-up (preferably using objective neurologic scores) is required to identify those who do not show improvement or show secondary progressive deterioration, so that LT may be considered before irreversible brain damage sets in.

Future perspectives: The diagnosis of neurological manifestation needs to be more objective to assess the progress of neurological deterioration over time. The tools for assessment include, UWDRS, mRS, brain MRI severity score, magnetic resonance spectroscopy etc. which needs prospective validation. Precise monitoring on treatment is vital to differentiate paradoxical neurological deterioration from disease progression. Neurologic WD takes years to improve; nonetheless, the trend of the neurologic symptoms i.e., neurologic worsening despite being on adequate chelation, is paramount for early identification of patients with refractory symptoms so that they may be considered for LT before irreversible brain changes occur. It is challenging to obtain an organ in the deceased donor LT setting for a neurologic manifestation as this is not an indication for routine LT, LDLT may be useful in this setting, good outcomes have been reported with LDLT.

CONCLUSION

Neurologic WD is not uncommon; the usage of chelators has significantly improved survival. However, there are no clear recommendations for LT in neurologic WD. Recent studies have reported improved overall survival, improvement in neurological manifestations, and even lower incidence of de novo neurological worsening in post-LT period compared to patients with pure hepatic indication. Differentiation of chelator-related paradoxical neurologic worsening from disease progression is important; history, dug compliance and brain MRI can be helpful in differentiating them. Timing of LT needs careful attention; time from neurologic deterioration (despite adequate chelation) to LT is a vital parameter to be considered. For example, if an adolescent presents with progressive neurological worsening, the first step is to ensure the drug compliance and rule out paradoxical worsening, which calls for reduction in drug dosage. Once paradoxical worsening has been ruled out and progressive neurological worsening has been documented despite adequate chelation, radiological imaging should be obtained and an attempt should be made to differentiate acute brain damage from irreversible changes using WD brain MRI severity scale. If there are no irreversible changes in brain MRI, and neurological worsening has been documented despite optimized medical management over 6-12 months (as shown by Poujois et al[18]), LT should be kept in mind and family should be screened for WD, to search for potential donors. Post-LT graft dysfunction can pose a risk for worsening, which needs careful graft selection and peri-operative management. Still, there remain gaps in the knowledge and understanding of the pathogenesis of neurological manifestations and the impact of LT on the natural history of the disease.