This retrospective study analyzed 277 neurologically predominant WD patients undergoing DMPS therapy at the First Affiliated Hospital of Anhui University of Chinese Medicine (Sept 2021–Oct 2023). The inclusion criteria were as follows: (a) Satisfaction with the Leipzig scoring system diagnostic criteria for WD, the Leipzig score ≥4 (8); (b) Neurological symptoms as the initial presentation, neurological score ≥ 1 regarded as neurological WD (9, 10); (c) The clinical data were complete. The exclusion criteria were as follows: (a) Severe hepatic or renal dysfunction; (b) Switching of chelation agents during treatment; (c) Undergoing splenectomy or splenic artery embolization during treatment; (d) Severe psychiatric disorders encompassing severe depressive episodes (with psychomotor impairment), bipolar affective disorder (manic or mixed episodes), and profound cognitive impairment that significantly impacted daily functioning (11); (e)Forced cessation of chelation due to significant disease exacerbation during treatment; (f) Allergy to the trial medicine.

This study was designed as case–control study and was approved by the Ethics Committee of the First Affiliated Hospital of Anhui University of Chinese Medicine (Approval No.: 2021AH-60).

The clinical characteristics and laboratory biochemical indicators of patients were retrospectively collected using the Hospital Information System (HIS) system of the Information Center. These included age, weight, gender, duration of illness, Kayser-Fleischer (K-F) ring, serum ceruloplasmin (CER), alanine aminotransferase (ALT), aspartate aminotransferase (AST), blood urea nitrogen (BUN), serum creatinine (Scr), albumin (ALB), 24-h urinary copper, lactate, and homocysteine (HCY). Additionally, electronic medical records regarding clinical symptoms, signs, medication history, imaging data, and disease progression before and after treatment were also recorded.

In this study, we conducted a follow-up assessment of the recovery of patients with neurological deterioration. The follow-up began after the patients were discharged and lasted for 6 months, with assessments conducted every 3 months. Data were collected through telephone interviews, video calls via WeChat, and outpatient clinic visits, including patients’ survival status and disease recovery. Loss to follow-up was defined as the inability to contact the patient during the follow-up period. Definition of Recovery: “Recovery” was defined as a return to the patient’s pre-deterioration neurological baseline status, as assessed by the same neurologist using the Modified Young Scale (MYS) (12). Post-deterioration Management: Following neurological deterioration, the standard protocol involved immediate temporary suspension of DMPS, initiation of supportive therapy, and subsequent cautious reintroduction of chelation therapy at a reduced dosage once the patient had stabilized.

Clinical data were prospectively collected and independently assessed by two board-certified neurologists using standardized functional assessment scales at both admission and discharge time points. Based on changes in total scores, the patients were classified into deterioration group and non-deterioration group. The study employed the MYS to evaluate neurological function changes. The MYS has proven to be a valuable instrument in the clinical assessment of WD, effectively serving as a tool for monitoring disease progression and treatment response. This scale contains eight domains: language, oropharyngeal muscular dystonia, appendicular muscular dystonia, ataxia, tremors, chorea-like movements, gait status, and higher cortical functions. Each domain consists of two items, with a five-point scoring system for each item based on the severity of symptoms, ranging from 0 (mild) to 4 (severe). The total score was derived by summing the scores of all items. Treatment efficacy was assessed using changes in the total score of MYS compared to baseline, with an increase of more than 2 points indicating neurological deterioration (13). In the present study, an increase in total score of no more than 4 points was classified as mild deterioration, while an increase exceeding 4 points was classified as severe deterioration.

Both groups of patients had completed diagnostic evaluation and subsequently received standardized therapeutic management for a period exceeding 2 weeks, with each treatment cycle consisting of continuous copper chelation therapy for 5 days followed by a 2-day drug cessation period to mitigate adverse reactions (7). During this period, zinc and calcium supplements were administered. All neurological WD patients strictly adhered to a low-copper diet. DMPS (No.: H31021514, each 2 mL contains 0.125 g, Shanghai Hefeng Pharmaceutical Co., Ltd., Shanghai) was initiated intravenously at a dose of 5–10 mg·kg⁻¹·d⁻¹, gradually increased to 15–20 mg·kg⁻¹·d⁻¹ within 1 week, with administration once daily (14), this dosage was maintained throughout the treatment period.

Based on the quantification standards for Magnetic Resonance Imaging (MRI) abnormal signals established by Sinha et al., abnormal signals in WD were classified into high and low signals on T2-weighted images. The semi-quantitative evaluation of T2 sequence MRI findings can reflect and assess the pathological stages and severity of brain involvement in WD patients to a certain extent (15, 16). Using a 3.0 T MRI system, imaging specialists scored the regions of interest based on the extent of high signal (graded 0–3) and signal intensity (scaled 0–3) in WD patients. The sum of these two scores yielded brain MRI score, with higher scores indicating more severe damage (17).

SPSS 26.0 (SPSSInc., Chicago, Illinois, United States) was used for data analysis. All results were presented as the mean ± standard deviation, as percentage, or as the median [P25, P75]. Differences between groups for continuous variables and categorical data were assessed using the t-test, Mann–Whitney U test, and Chi-square test, respectively. Univariate analyses were performed to identify candidate variables related to DMPS-induced neurological deterioration in WD patients (p < 0.05). Subsequently, multivariate logistic regression analysis was conducted to quantify the independent effects of significant predictors. Odds ratios (OR) and 95% confidence interval (CI) were calculated, and the results were considered statistically significant at p < 0.05. A forest plot was generated using GraphPad Prism 9.0 (GraphPad Software, Inc., San Diego, California, United States) to assess the differences among the parameters. Simultaneously, a subgroup analysis based on age characteristics was conducted for all WD patients to assess the credibility and accuracy of the study results. And we performed a 6-month follow-up on the deterioration group to assess the recovery rate after deterioration. Additionally, we employed multivariable logistic regression to develop a composite diagnostic model integrating key biomarkers, subsequently validating its discriminative capacity through receiver operating characteristic (ROC) curve analysis. The predictive accuracy was quantified by calculating the area under the curve (AUC) with corresponding 95% CI, alongside determination of optimal cutoff value maximizing the Youden index (J = sensitivity + specificity − 1). Diagnostic performance strata were defined as follows: AUC > 0.90 (excellent discrimination), 0.70–0.90 (moderate clinical utility), 0.50–0.70 (limited predictive value), and <0.50 (no better than chance prediction).

As shown in Table 1, a total of 68 neurological WD patients with DMPS-induced neurological deterioration were included in the present study, accounting for 24.5% of the study population. Among the patients, 91.2% (62/68) exhibited mild deterioration, while 8.8% (6/68) experienced severe deterioration. Aged 10–52 years (mean, 26.38 ± 9.02 years), the 68 patients included 70.6% (48/68) males. Controls (n = 209) were WD patients without neurological deterioration, aged 11–52 years (mean, 28.51 ± 7.97 years), 45.9% (96/209) of whom were male. Both groups exhibited consistent biomarker profiles, characterized by positive K-F ring and serum CER levels below 200 mg/L. Moreover, the two groups demonstrated comparable characteristics with respect to age, ALT, AST, BUN, Scr, and ALB (p > 0.05).

However, the deterioration group exhibited a higher proportion of male (48/20 vs. 96/113, p < 0.001), as well as elevated levels in weight (mean: 62.63 vs. 59.79, p = 0.049), duration of illness (mean: 5.97 vs. 4.26, p = 0.002), brain MRI scores (mean: 5.00 vs. 3.94, p < 0.001), 24-h urinary copper (mean: 794.91 vs. 720.46, p = 0.044), lactate (mean: 0.66 vs. 0.61, p = 0.032), and HCY (mean: 20.85 vs. 17.73, p < 0.001). Additionally, the common neurological deterioration symptoms observed in patients with neurological WD included dysarthria (77.9%, 53/68), dysphagia (70.6%, 48/68), postural abnormalities (47.1%, 32/68), and limb tremors (44.1%, 30/68), choreic involuntary movements (30.9%, 21/68), ataxia (29.4%, 20/68), and psychiatric disorders (2.9%, 2/68).

In this study, we conducted follow-up assessments for WD patients with neurological deterioration over a period of 6 months. At 3 months, the recovery rate in the deterioration group was 76.5% (52/68). By 6 months, this rate increased to 89.7% (61/68). The four most frequent symptoms of improvement were as follows: tremor of the hands and feet, abnormal limb posture, gait abnormalities, and psychiatric disorders. Notably, there were no reported deaths by the end of the follow-up period.

Univariate analysis identified 7 parameters (including sex, weight, duration of illness, brain MRI score, 24-h urinary copper, lactate, and HCY) that were significantly associated with neurological deterioration (p < 0.05). These parameters were included in multivariate logistic regression model. Multivariate logistic regression analysis indicated that sex (OR, 0.41; 95% CI, 0.18–0.94; p = 0.035), brain MRI score (OR, 2.89; 95% CI, 1.99–4.21; p < 0.001), and HCY (OR, 1.45; 95% CI, 1.27–1.65; p < 0.001) were associated with neurological deterioration (Table 2; Figure 1).

Table 3 presented the baseline characteristics of WD patients in this subgroup. In the subgroup of patients aged <35 years, the deterioration group had a significantly higher male proportion, brain MRI score, and HCY level than the non-deterioration group (p < 0.05). For patients aged ≥35 years, brain MRI score and HCY level still showed significant differences between the two groups (p < 0.05).

The ROC curves (Figure 2) for sex, brain MRI score, HCY, and combined predictive indicators (CPI) showed the AUC values of 0.377, 0.778, 0.758, and 0.862, respectively (Table 4). The result indicated that CPI had moderate clinical utility. In the ROC curve, the closer a point is to (0, 1), the better the model’s discriminatory ability. The predictive value of CPI for diagnosing DMPS-induced neurological deterioration in WD patients was superior to that of other individual indicators.

This study has several limitations. First, the retrospective design may introduce bias, and the single-center nature of the research could limit the generalizability of the findings to a broader population. Furthermore, while the sample size is adequate for preliminary analysis, it may not fully capture the spectrum of neurological manifestations in WD patients receiving DMPS treatment across different environmental factors influencing disease expression. The 6-month follow-up period, while aligned with standard early assessment windows for WD, may limit detection of delayed neurological events such as late-onset paradoxical deterioration or therapeutic lag effect. Future research should aim for multi-center, prospective studies with larger cohorts and extended follow-up durations to validate these findings. Additionally, exploring the potential mechanisms of neurological deterioration during chelation therapy and the long-term impact of DMPS treatment on neurological outcomes in WD patients is essential.