EXPERIMENTAL AND CLINICAL TRANSPLANTATION

Wilson disease (WD) is a potentially treatable, inherited disorder of copper metabolism characterized by pathological copper deposition caused by mutations of the ATP7B gene. This results in an abnormality of transmembrane copper-carrying ATPase, which leads to copper overload in the liver, brain, and other organs.¹ It is a multisystemic disease, but the manifestation in each system usually depends on the age of the patient at presentation. In children and young adults with WD, hepatic symptoms predominate, whereas neurological WD is less common before puberty.² The clinical course of WD can vary in severity, but progressive liver disease is a common feature.³ Diagnosis of WD is based on diagnostic algorithms that include clinical symptoms and signs, copper metabolism measu-rements, and DNA analysis.⁴ Neurological findings of WD reflect the disproportionate involvement of caudate nucleus, putamen, cerebral cortex, and cerebellum. Neurological signs include resting or postural tremor, choreiform movements of the limbs, facial grimace, rigidity, hypokinesia, dysarthria, dysphagia, abnormal (flexed) posture, and ataxia. Seizures may also occur. Psychological disorders in WD include dementia, characterized by mental slowness, poor concentration, and memory impair-ment; disorders of affect, behavior, or personality; and (rarely) psychosis with hallucinations. With WD, there is a tendency for a dystonic or parkinsonian picture with hyperreflexia and extensor plantar responses to predominate when the disease begins in patients younger than 20 years; for older patients, WD is exhibited as wild tremor, chorea, or ballismus. Symptoms may progress rapidly, especially in younger patients, but more often develop gradually with intermittent periods of remission and exacerbation.⁵ Current treatment options include chelators and zinc salts, which can reverse copper overload by various mechanisms. Orthotopic liver transplant (OLT) is one of the treatment options for WD⁶s and represents the ultimate treatment when routine medical treatment fails.⁷ The OLT spectrum of indications is controversial, especially for mixed phenotypes or solely neuropsychiatric phenotypes in patients with WD.⁸ It is not clear whether the neurological symptoms associated with liver failure, which may lead to functional deterioration over time, improve with OLT.⁹ In this study, we aimed to investigate the changes in neurological symptoms after OLT versus the preoperative period in patients with WD and cirrhosis as assessed with established scoring systems.

Materials and Methods

This is a single-center, retrospective observational study approved by the local clinical ethics committee (approval No. 2021-4/22). The patients included in the study were those with both neurological and hepatic involvement who were definitively diagnosed with WD as assessed by clinical, biochemical, and/or histopathological parameters⁹ and who were resistant to standard medical therapy. They were evaluated by the same neurologist and the same gastroenterologist before and after transplant. Follow-ups were done by the same team in a single center; patients who were followed up outside the center were excluded from the study. The study was carried out retrospectively in accordance with the Declaration of Helsinki after approval by the ethics committee and acquisition of consent from each participant. The New Wilson Index for Predicting Mortality¹⁰ and Model for End-Stage Liver Disease (MELD) score were calculated immediately before transplant. Neurological examination, neuropsychometric examination (Mini-Mental State Examination, MMSE), and neuroimaging by cranial magnetic resonance imaging (MRI) were performed for these patients, and neurophysiological examinations such as electro-encephalography were applied to patients when deemed necessary. After the transplant, neurological evaluation and follow-up were performed by the same neurologist, and advanced examinations (such as MMSE and electroencephalography) were also performed. Patients were evaluated while on the wait list before transplant and then reevaluated after LT at 1 year, 5 years, and 10 years of follow-up. Neurological symptoms were evaluated with the Medici Scoring System (MSS),¹¹ which consisted of 2 parts. The elements of rigidity, bradykinesia, ataxia, tremor, dyskinesia, and dystonia were evaluated in the first part. In the second part, 4 main elements of daily life were evaluated, which were walking, eating, talking, and daily activities. There was a maximum score of 3 for each element of the MSS (3, no impairment; 2, mild impairment; 1, moderate impairment; and 0, severe impairment), and the maximum total score for the MSS was 30. The MMSE test was used to evaluate neuropsy-chiatric complaints and mental capacities before and after transplant. The test results at 1 year, 5 years, and 10 years were compared.Postoperative intensive care unit stay and total hospital stay of each patient were determined. The postoperative outpatient clinic follow-ups of the patients were performed at 1 month, 3 months, and 6 months, then annually thereafter. An immunosup-pression regimen including steroid, calcineurin inhibitor, and mycophenolate mofetil was applied as standard to all patients in the early period.Post-LT graft and patient survival rates were reviewed until the last available follow-up period or February 2021, which determined the causes of any death or graft loss. In addition, postoperative liver-related and non-liver-related complications were also collected, as well as the length of stay after OLT.Statistical tests were performed with SPSS software for Windows (version 16.00). The 95% confidence intervals were calculated with associated estimated standard deviation. P < .05 was considered significant.

Twenty-four patients (13 female, and 11 male) who underwent deceased donor OLT for liver cirrhosis due to WD were included in the study. The age range of the evaluated patients was 14 to 57 years, with a mean age of 34 years. The OLT surgeries were performed in the same university hospital by a single team with a similar surgical technique. There were no patients in the study who underwent transplant only for neurological involvement. One of these patients had been diagnosed with hypergammaglobulinemia since the age of 2 years and presented with liver cirrhosis secondary to WD. The patient underwent transplant under emergency conditions with acute-on-chronic liver failure and was then followed up in the intensive care unit after the transplant. However, 2 months later, this patient died from pneumosepsis after prolonged intensive care stay in the postoperative period. The mean MELD score of the patients included in the study was 24.9 (range, 15-41; SD 8). The mean preoperative New Wilson Index for Predicting Mortality of the patients was 7 (range, 1-16; SD 4.4). Preoperative laboratory findings were also determined (Table 1). Postoperative complications were seen in 58.3% (14/24) of the patients. The most common posto-perative complications were gastrointestinal side effects due to immunosuppression (12.5%), biliary stricture (12.5%), and pulmonary complications (12.5%). Two patients (8.3%) developed COVID-19 infection, and they survived. Postoperative comp-lications are shown in (Table 2). The neurological examination scores according to MSS are shown in (Table 3), for pretransplant and for 1 year, 5 years, and 10 years after OLT. The values for posttransplant neurological symptoms at 1 year, 5 years, and 10 years were statistically significant compared with the pretransplant period. Statistics related to the comparison of neurological examination scores are presented in (Table 4). According to MSS, 16 patients’ scores before the LT were from 28/30 to 30/30 points, and these patients’ scores were normal after the operation (patients with 28 and 29 points were patients who had tremors in the hands and sometimes in the head, but these did not cause difficulties in daily life). Improvement was also observed in the scores of 6 of 7 patients (Table 5). The remaining 1 patient (case 1) had a central nervous system lesion independent of WD preoperatively, and the sequelae of right spastic hemiparesis continued. All patients required help in their daily lives (such as eating, dressing, bathing) before OLT, as assessed by these examinations. After OLT, there were significant improvements in the tremor symptoms and other complaints of the patients, and the patients became more independent in their daily lives. No worsening of neurological findings was observed in any of the patients evaluated within the scope of the study. Neuropsychometric tests were applied to the patients before and after OLT. There was mild-moderate mental disability in 3 patients (cases 2, 3, and 10), which was absent in the other 21 patients. The MMSE score of these 3 patients before transplant was 22/30. Although the MMSE score improved in these 3 patients in the posttransplant period, this was not statistically significant. Pretransplant MRI was not available for 5 of 24 patients. Imaging was within normal limits in 12 of 19 patients, and bilateral and symmetrical abnormal hyperintensity was observed in 3 patients. One patient had a lesion in the left periventricular region that did not retain contrast material and was being followed up. Findings in the other 3 patients were high signal intensities involving the thalami, midbrain, and pons; and increased intensity in bilateral lentiform nuclei and caudate nuclei atrophy of both cerebral pedicles, mesencephalon, pons, and cerebellum. Significant improvement in neurological symptoms was observed in 6 of 7 patients with MRI changes (Table 5). Posttransplant neuroimaging was performed in all 23 patients. There was no change in the MRI findings in the posttransplant period of 12 patients whose MRI was normal in the pretransplant period. Pathological MRI findings were present in the pretransplant period in 6 patients whose neurological symptoms improved after transplant. There was no change in the control MRI performed in the post-OLT period.

Wilson disease is an autosomal-recessive condition with hepatic, neurologic, psychiatric, and systemic manifestations.¹² It is caused by mutations in the ATP7B gene, which encodes a transmembrane copper ATPase that excretes copper into bile for synthesis of ceruloplasmin, a major copper-transporting protein in the blood.¹³ This defect results in hepatic copper overload and oxidative damage of hepatocytes, which in turn leads to copper being released into circulation and its accumulation in extrahepatic organs.¹³ Liver diseases range from asymptomatic hepatomegaly or transaminitis to decompensated cirrhosis and acute liver failure.¹⁴ Unlike many neurogenetic metabolic diseases, WD can be treated very effectively in the acute and chronic stages of the disease.¹⁵ Although chelation agents and zinc are used in medical treatment, OLT should be considered in patients with neurological symptoms resistant to this treatment who develop chronic liver disease or who develop acute liver failure.¹⁶ Nine patients with chronic presentation had neurological symptomatology in a series of 24 patients by Sevmis and colleagues. Speech disturbances and dysarthria were the most common neurological features, present with diverse severity in 3 patients. Gross tremor was described in 6 patients. One patient had severe neurological disorders manifesting as Parkinson-like symptoms, including gait disturbances, tremor, severe dysarthria, and dysphagia . Schumacher and colleagues¹⁷ have reported that patients with severe neurological symptoms could benefit from OLT, but the scoring system in their study was not based on objective criteria. According to the study by Weiss and colleagues,¹⁸ although it was thought that neurological symptoms improved in patients who underwent OLT due to WD, statistical significance could not be determined. Within the scope of the present study, patients were objectively evaluated by the same neurologist and according to standard neurological scoring systems in the pretransplant and posttransplant periods and were supported by pretransplant and posttransplant imaging methods. Thus, we have clearly demonst-rated that there is a significant improvement in the long-term follow-up of the patients. In many studies on OLT, the prognosis is very good in patients who present only with hepatic symptoms, and very good results have been reported in patients with Wilson disease who have neurological involvement. Weiss and colleagues reported improvement in 88 (62%) of 143 patients with neurological symptoms at 4-year follow-up.¹⁹ It is predicted that the damage of unbound free copper to the central nervous system can be prevented with the initiation of chelator and supportive treatment, but they concluded that, since effect at the cellular level was unknown, a clear interpretation could not be made.²⁰ At the same time, the longest follow-up period was determined as 4 years in these studies, and in our study we showed that some patients had an improvement in the 10-year follow-up results. In a study by Erol and colleagues, none of the patients who presented with fulminant liver failure had a history of neurological symptoms, whereas 6 of the patients presenting with chronic liver failure had a history of liver encephalopathy and 5 patients had stage 1 or stage 2 hepatic encephalopathy at the time of LT.²¹ Preexisting hepatic encephalopathy resolved in all patients in the immediate posto-perative period. In our study, however, none of the patients had a history of hepatic encephalopathy, but it was not present in our case with posttransplant neurological complications. Poujois and colleagues conducted a retrospective study from 1994 to 2016 with 18 patients who underwent OLT therapy when neurological deteri-oration continued despite a minimum of 2 months of chelation therapy. The patients were followed up with the Unified Wilson Disease Rating Scale (UWDRS) and modified Rankin score, and the scores improved after transplant. Four patients died during follow-up, from pulmonary failure, hepatic failure, and sepsis. Of the 14 patients, 8 had major improvement (78% reduction in UWDRS), 4 had moderate improvement (41% reduction in UWDRS), and 2 had mild improvement (8.1%).³ In our study, neurological examination findings in the preoperative period were evaluated with a scoring system (MSS) and by a single neurologist, and significant impro-vement was observed in 6 patients. At the same time, these patients showed significant improvement in activities of daily living and demonstrated greater independence. In the long-term follow-up of these patients, it was observed that their complaints continued to decrease. Statistically, there were significant results despite the small number of patients. In the study of Lankarani and colleagues, 60 of 107 transplant patients had neuropsychiatric complaints (such as tremor, dystonia, dysarthria, rigidity, school performance disorder, seizures, ataxia, anxiety, and depression), and posttransplant improvement was observed in 40 patients. In addition, new-onset dysarthria, rigidity, and ataxia were noted in 4 cases.²¹ In our study, it was a homogeneous group that developed WD-induced liver cirrhosis and was resistant to medical therapy. It was observed that most of these patients did not have neurological involvement in the preoperative period. It was determined that the most common symptoms of tremor, bradykinesia, dystonia, and rigidity were observed in patients with neurological involvement and that the complaints of these patients decreased significantly in the follow-up period. Diffuse brain atrophy and focal nonspecific abnormalities in the lenticular, thalamic, and caudate nuclei, as well as in the white matter and brain stem, may be visible in cranial MRI results. Although some studies have shown a correlation between imaging findings and neurological symptoms,²² this correlation was not found in other studies.²³ The most common abnormality observed in MRI is increased signal intensity in the lenticular, thalamic, and caudate nuclei, as well as in the white matter on T2-weighted images.²⁴ Generally, the findings are bilateral.²⁵ Histological studies showed swelling, gliosis, demyelination, and edema in capillary endothelium in white matter,²⁶ which explains the signal changes in the MRI results. In the literature, it has been shown that signal intensities, especially in the basal ganglia, are lost after treatment in patients with movement disorders. In patients with a predominant complaint of tremor, a loss of intensity was observed in the thalamus and red nuclei.²⁴ Peedikayil and colleagues, in the single-center experience published in 2013, stated that neuroimaging findings and symptoms of the patients showed significant improvement in 4 patients, but no scoring system was used.²⁷ In a case series from Ocal and colleagues from 2020, 4 (26.6%) patients had tremor and 1 patient had tremor and dystonia before LT. Only 3 patients with tremor had regression after transplant, and no change in MRI findings was shown before and after LT. The patient symptoms of tremor and dystonia were also regressed. In the posttransplant period, tremor started in 1 patient.²⁸ In our study, routine MRI was used as the tool for neuroimaging. Preoperative MRI was considered normal in the vast majority of patients included in the study. The MRI results were normal in most of the patients in the preoperative period. Pathological MRI findings were detected in all patients with neurological symptoms. There was no change in the control MRI performed during the follow-up period after transplant; therefore, we concluded that LT did not cause a significant change in regression in MRI findings in patients with WD. In a study of postoperative complications in patients undergoing LT for WD, effects were generally seen secondary to the immunosuppression regimen. Accordingly, tremor and seizure were reported as the most common postoperative complications.²⁹ With regard to surgical complications, another study reported that primary nonfunction was observed in 1 patient, and acute respiratory distress syndrome developed in another patient. Five of the 24 patients died within 4 months of surgery.³⁰ In our patient series, the most common side effects were gastrointestinal system effects, for which the reason was determined to be the immunosuppression regimen. Although retransplant was performed secondary to hepatic artery thrombosis in 1 patient, 1 patient died due to pneumosepsis. The pathogenesis of WD with neurological involvement is not clear. When copper released into the circulation increases, the central nervous system is most affected. Two proteins are associated with neurodegenerative disease. The first is the amyloid precursor protein (APP), which is the copper-binding domain (CuBD). The other is the prion protein (PrP). These proteins and copper accumulation cause the neurological impairment and neurodegenerative insufficiency in WD.³¹ We suggest that improvements in the neuropsychiatric findings, especially post-transplant neuropsychiatric findings, in our patients may be caused by the decrease in the effects of protein and copper toxicity over time. A similar study has mentioned that the neurological symptoms improved in 14 of 45 patients after transplant.³² Although it is known in the literature that OLT is a successful treatment for WD with isolated neurological involvement, studies on the degree of improvement of neurological symptoms are limited. Patients included in our study were evaluated by the same neurologist in the preoperative period and were followed up in the long-term postoperatively and evaluated with a scoring system based on neurological symptoms, which facilitated a more objective assessment of the improvement of neurological symptoms.

In our study, we showed that neurological symptoms partially improved for WD with neurological involvement in patients after LT. We emphasize that a significant improvement in the quality of life of these patients was observed even after OLT, as a result of these partial improvements in neurological symptoms. Important limitations of this study, in terms of homogeneous formation of the groups, were (1) all patients had end-stage liver disease and (2) all patients had deceased donor OLT. Although the option of OLT for WD with only neurological involvement but without end-stage liver disease remains unclear in the literature, our study shows that neurological symptoms have sustained positive effects in the long-term.

Volume: 20 Issue: 11 November 2022

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