Early neurological deterioration in Wilson’s disease: a systematic literature review and meta-analysis

Introduction Neurological deterioration, soon after anti-copper treatment initiation, is problematic in the management of Wilson’s disease (WD) and yet reports in the literature are limited. The aim of our study was to systematically assess the data according to early neurological deteriorations in WD, its outcome and risk factors. Methods Using PRISMA guidelines, a systematic review of available data on early neurological deteriorations was performed by searching the PubMed database and reference lists. Random effects meta-analytic models summarized cases of neurological deterioration by disease phenotype. Results Across the 32 included articles, 217 cases of early neurological deterioration occurred in 1512 WD patients (frequency 14.3%), most commonly in patients with neurological WD (21.8%; 167/763), rarely in hepatic disease (1.3%; 5/377), and with no cases among asymptomatic individuals. Most neurological deterioration occurred in patients treated with d-penicillamine (70.5%; 153/217), trientine (14.2%; 31/217) or zinc salts (6.9%; 15/217); the data did not allow to determine if that reflects how often treatments were chosen as first line therapy or if the risk of deterioration differed with therapy. Symptoms completely resolved in 24.2% of patients (31/128), resolved partially in 27.3% (35/128), did not improve in 39.8% (51/128), with 11 patients lost to follow-up. Conclusions Given its occurrence in up to 21.8% of patients with neurological WD in this meta-analysis of small studies, there is a need for further investigations to distinguish the natural time course of WD from treatment-related early deterioration and to develop a standard definition for treatment-induced effects. Supplementary information The online version contains supplementary material available at 10.1007/s10072-023-06895-6.


Introduction
Wilson's disease (WD) is an inherited disorder of copper metabolism with pathological copper accumulation, which can result in clinical symptoms in affected organs, particularly hepatic and/or neuropsychiatric manifestations [1][2][3][4]. As the disease is caused by copper overload, WD treatment is based on drugs promoting negative copper balance including (1) copper chelators (d-penicillamine [DPA], trientine [TN] or dimercaptopropane sulfonic acid [DMPS] used in China) which mainly increase urinary copper excretion; (2) drugs which inhibit copper absorption from the digestive tract (zinc salts [ZS]); or (3) drugs complexing copper into insoluble complexes, leading to increase biliary copper excretion, as well as decrease copper absorption (e.g. molybdenum salts in clinical trials) [5].
Despite acknowledgement of the severe and even lifethreatening consequences of early neurological deterioration, which is also a problem in the development of new WD treatments, there remains a lack of comprehensive studies on frequency and predictors. Numerous retrospective analyses of large national WD cohorts have assessed the frequency of neurological deterioration as part of secondary analyses; however, most did not use objective neurological scales [6][7][8]. Only a small number of studies and case reports have specifically analysed the phenomenon and investigated predictors [27,28,35,43].
The aim of our study was to perform a systematic review and meta-analysis of published studies on early neurological deterioration, as well as discuss its definition and summarize risk factors.

Methods
This systematic review was performed in concordance with internationally accepted criteria of the Preferred Reporting Items for Systematic Reviews and Meta-analyses (PRISMA) statement [46].

Search strategy and eligibility criteria
We searched the PubMed database (up to 15 September 2022) for original studies (prospective and retrospective), as well as case and series reports analyzing early neurological deterioration, its frequency, risk factors and outcomes in patients with WD. Search terms included: ("Wilson's disease"/ "Wilson disease" and "early neurological worsening"), ("Wilson disease"/ "Wilson disease" and "early neurological deterioration"), ("Wilson's disease"/ "Wilson disease" and "neurological deterioration") and ("Wilson's disease"/ "Wilson disease" and "neurological worsening"). Studies eligible for further analysis were (1) human studies; (2) original studies (prospective or retrospective); (3) case and series reports of pregnant WD patients; and (4) those published in English. The reference lists of extracted publications were also searched. For the purpose of this study, we defined neurological deterioration as worsening in the 6-month period after treatment introduction.
Initially, the titles and abstracts of papers retrieved by the search terms were screened independently by all authors and duplicate records were removed. Reviews, editorial, commentaries, as well as overlapped studies were excluded after assessment and revisions. Then the full text of initially eligible articles was screened. Again, incomplete reports, reviews, editorials, commentaries, conference proceedings, discussions and overlapped studies were excluded. Finally, all identified studies were analyzed and verified independently by all authors to confirm the inclusion criteria and were grouped as (1) prospective studies that aimed to analyze early neurological deterioration; (2) retrospective studies mostly presenting data from country WD registries with additional analyses of early neurological deterioration; (3) retrospective analyses focused on the early neurological deterioration phenomenon; 4) series reports and (5) case reports describing patients who deteriorated shortly after decoppering treatment initiation; and 6) diagnosis of early neurological deterioration established based on objective neurological examination (preferably using neurological scales). Only WD drug naive patients were analyzed, also the analysis according to WD phenotypic presentation if available was summarized separately. For each publication, the number of patients involved, the definition of early neurological deterioration used (if any), the phenotype of WD, the risk factors of deterioration, the treatment type and the outcome were recorded, where available.

Meta-analysis methodology
A random effects meta-analysis was used to estimate the risk of an early neurological deterioration among patients with the neurological form at diagnosis because deteriorations after treatment initiation almost never occur in other patients with WD. Heterogeneity was assessed with I2 and the chi-squared test for the Cochrane's Q statistic. The Baujat plot was used to find studies with the greatest contribution to heterogeneity; a sensitivity analysis was carried out after the exclusion of these studies.

Results
The publications search and selection process is presented in Fig. 1.
The 32 publications included 1512 WD patients in whom 217 cases of early neurological deterioration were described, indicating a frequency of 14.3%. In available analysis (excluding the papers without detailed phenotypic presentation) [42], the early neurological deterioration occurred mostly in patients with the neurological phenotype (21.8% [167/763]; see Fig. 2A shows studies in WD patients with neurological symptoms; Fig. 2B shows studies after the exclusion of studies with the greatest contribution to heterogeneity [28,36,44]  The main risk factor for neurological deterioration in WD patients was neurological phenotype (21.8% risk vs 1.3% risk in hepatic WD phenotype). Other risk factor was the initial high dose treatment with high DPA (7/16 (43.7%) reported in case reports [12, 15-17, 19, 24, 26]. Other welldocumented risk factors of early neurological deterioration were (1) initial severity of neurological disease WD scored in clinical scales, in brain magnetic resonance imaging (MRI) semiquantitative scale (or lesions in pons), as initial serum concentration of neurofilaments (sNfL) [27]; (2) severity of liver disease [45] or (3) concomitant drugs blocking dopaminergic neurotransmission [35].

Discussion
This is the first systematic review of the literature focused on early neurological deterioration in WD patients. Based on our previous papers [27,35], we defined early neurological deterioration as worsening up to 6 months of anti-copper treatment initiation to verify the available results and present more homogenous data. We documented that early neurological deterioration in WD occurred in about 14% of all WD patients and 21.8% of patients with neurological symptom. These data show that this phenomenon may currently occur less frequently than reported previously, particularly in some older review studies, which cited frequency up to 50% [15][16][17][18]24]. A potential reason for this difference is that DPA was the first drug introduced as a WD treatment and initial reports of early neurological deterioration were mostly describing DPA-treated patients. The longest experience with WD treatment as well as adverse drug reactions relates to DPA and next to chelators (mostly used to treat symptomatic WD patients), which affected the assessment of the frequency of neurological deterioration. Since the link between early neurological deterioration and full-dose DPA was made, clinicians have adopted a "start low and go slow" approach to dosing, which has contributed to decreased frequency. Moreover, current WD treatment recommendations emphasize the DPA dose titration during treatment initiation [1]. However, retrospective studies and national registries still included older cases in analysis [4][5][6][7][8], which could have affected our results. But due to mostly summarized results of these studies, the separate analysis of such cases (apart from case reports [12, 15-17, 19, 24, 26] were not available. It is noteworthy that the most often cited article reporting the high frequency of neurological deterioration after DPA was published in 1987 [15] and was based on a questionnaire filled in by patients or their families. Out of 54 patients, 28 completed the questionnaire and 3 patients did not have neurological presentation, so only 25 patients were analyzed (45% of initial group), of which neurological worsening occurred in 13 (52%) patients. However, in 3 cases, worsening occurred between 6 and 12 months after DPA introduction and after re-analyzing their results, they calculated a frequency of 18.5% for neurological deteriorations (10/54), not using objective neurological scales.
Our study additionally verified the irreversibility of early neurological deteriorations. Based on our systematic review, we found complete or partial recovery in around half of the patients, which is higher than previously reported [35], but the lack of improvement in other patients highlights the severe nature of the phenomenon. Indeed, these neurological complications have contributed to the search for new anti-copper drugs, such as TN or molybdate salts.
Additionally, we found that most early neurological deteriorations occurred in WD patients initially diagnosed with the neurological phenotype of the disease. Ziemssen et al. [27] found that early neurological deterioration was related to sNfL levels (as a marker of severity of neuroaxonal injury), the severity of neurological disease scored on the Unified Wilson Disease Rating Scale (UWDRS) and the chronic damage score subscale in brain semiquantitative MRI scale [27]. The semiquantitative brain MRI scale in WD consists of an acute damage score (which reflects oedema, demyelination -potentially acute -"fresh" reversible changes) and a chronic damage score (which reflects necrosis, brain atrophy as well as iron accumulation secondary to neuronal necrosis -the irreversible changes) [27]. The finding that only the chronic damage score predicts neurological worsening may suggest that in some patients who neurologically deteriorate, there are irreversible advanced neurodegenerative processes that cannot be stopped by drugs -they present with natural progression and not early neurological deterioration. Other, proposed in the available literature, risk factors for early neurological worsening include the use of concomitant drugs blocking dopaminergic neurotransmission, lesions located in the pons and thalamus, which again indicate advanced neurological disease [35], and advanced liver disease (e.g.. evidence of chronic liver disease, splenomegaly, leukopenia, thrombocytopenia and drooling) [43].
Taken together, these observations indicate a need to distinguish the natural course of the disease from treatmentrelated early neurological deteriorations and additionally lead to discussions about how to establish the diagnosis and a definition of early neurological deterioration in neurologically symptomatic patients, which are currently lacking. As part of these studies, the so-called "therapeutic lag" effect [50] could be investigated, which is seen in other neurological disorders, like multiple sclerosis. After the introduction of anti-copper drugs in WD, the expected time to effects on liver function tests and liver symptoms is 4-6 months, but data on neurological symptoms are more limited and they may take longer to improve [1]. It would be interesting to conduct studies in WD to establish the expected time course of neurological symptoms regression, including initial brain MRI changes as well as biomarkers of nervous system injury [4,27,45].

Study limitations
Our study has some limitations. Studies were heterogenous, particularly regarding the treatment. In line with current recommendations [1] most of the symptomatic WD patients were treated with chelators (mostly DPA). Therefore, we were not able to conduct a meta-analyses comparing deterioration risk between different treatments regarding the type of anti-copper treatment and neurological deterioration. Some of the studies included only [28,44] neurological or mostly hepatological WD patients [36]. The meta-analysis was limited by substantial heterogeneity, but the estimate was stable after excluding the studies with the greatest contribution to heterogeneity [28,36.44] (Supplementary Fig. 1 and Fig. 2B). Further, some studies included patients switched from other anti-copper drugs and/or receiving combination treatments. We tried to control for this with our inclusion criteria. Additionally, the definition of neurological worsening differed, although we tried to standardize this to a degree with our inclusion of cases within the first 6 months of treatment. Details were missing for some cases of neurological worsening in retrospective WD long-term follow-up studies and these were not included [6-8, 29, 51-65].

Conclusions
The early neurological deteriorations in WD occur less frequently than previously reported; however, it is still present in around 14% of WD patients and almost one quarter of patients with initial neurological phenotype of WD. Further studies are required to distinguish the natural progression of the disease from an early neurological deterioration, including considerations of "therapeutic lag" [47] as well as brain MRI studies [66], and biomarkers of central nervous system involvement [66]. Results of such studies may help develop an evidence-based definition for an early neurological deterioration.

Declarations
Consent for publication This manuscript has been approved for publication by all authors.

Human and animal rights
This article is based on previously conducted studies and does not contain any new studies with human participants or animals performed by any of the authors.

Conflict of interest The authors declare no conflict of interest.
Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http:// creat iveco mmons. org/ licen ses/ by/4. 0/.