Internal Medicine IV, Department of Gastroenterology, University Hospital Heidelberg, Heidelberg, Germany.
Department of Neurology, Rare Disease Reference Centre "Wilson's Disease and Other Copper-Related Rare Diseases", Rothschild Foundation Hospital, Paris, France.
J Hepatol. 2023 Aug;79(2):321-328. doi: 10.1016/j.jhep.2023.04.007. Epub 2023 Apr 26.
BACKGROUND & AIMS: Prevention of neurological worsening (NW) under therapy is an unmet need in the management of Wilson disease (WD). In this study, we aimed to characterize the occurrence, associated outcomes and potential reversibility of NW in WD.
From a total cohort of 457 patients with WD, 128 patients with WD and neurological features at any time point (all Caucasian, 63 females, median age at diagnosis 22 years) were identified by chart review at University Hospital Heidelberg and grouped according to initial presentation. The timing and occurrence of NW was assessed following a structured clinical examination during clinical visits.
Early NW (within the first 3 months of therapy) was observed in 30 out of 115 (26.1%) patients with neurological or mixed presentation and never in patients with a purely hepatic or asymptomatic presentation (0%). Late NW (after >12 months) was seen in a further 23 (20%) with neurological or mixed presentation and in 13 out of 294 (4.4%) patients with a hepatic or asymptomatic presentation. The median time from start of treatment to late NW was 20 months. Only three patients experienced NW between 3 and 12 months. NW was observed with D-penicillamine, trientine and zinc therapy and was reversible in 15/30 (50%) with early NW and in 29/36 (81%) with late NW.
In this study, we identified two peaks in NW: an early (≤3 months) treatment-associated peak and a late (>12 months of treatment) adherence-associated peak. Early paradoxical NW was attributed to treatment initiation and pre-existing neurological damage, and was not observed in those with a hepatic or asymptomatic presentation. Late NW is likely to be associated with non-adherence.
In patients with Wilson disease, defined as an excess accumulation of copper which can damage the liver, brain and other vital organs, neurological worsening can occur despite chelation therapy. The study identifies different patterns of 'early' (<3 months) vs. 'late' (>12 months) neurological worsening in relation to initiation of chelation therapy and establishes possible causes and the potential for reversibility. These data should be useful for counseling patients and for guiding the optimal management of chelation therapy.
在威尔逊病（WD）的治疗中，预防神经恶化（NW）是一个未满足的需求。本研究旨在描述 WD 中 NW 的发生、相关结局和潜在可逆性。
通过海德堡大学医院的病历回顾，从总共 457 例 WD 患者中确定了 128 例任何时间点均有神经症状的 WD 患者（均为白人，63 例女性，诊断时的中位年龄为 22 岁），并根据初始表现进行分组。在临床就诊期间进行结构化临床检查，评估 NW 的发生时间和发生情况。
30 例（26.1%）神经或混合表现的患者在治疗的前 3 个月内出现早期 NW，而无神经或混合表现的患者从未出现过（0%）。在进一步的 23 例（20%）神经或混合表现和 13 例（4.4%）肝脏或无症状表现的患者中出现晚期 NW。从开始治疗到晚期 NW 的中位时间为 20 个月。仅有 3 例患者在 3 至 12 个月之间出现 NW。NW 发生在用 D-青霉胺、曲恩汀和锌治疗的患者中，在 15/30（50%）早期 NW 和 29/36（81%）晚期 NW 患者中是可逆的。
在这项研究中，我们发现 NW 有两个高峰：早期（≤3 个月）与治疗相关的高峰和晚期（治疗>12 个月）与依从性相关的高峰。早期的矛盾 NW 归因于治疗开始和先前存在的神经损伤，在肝脏或无症状表现的患者中未观察到。晚期 NW 可能与不依从有关。
在 WD 患者中，铜的过度积累会损害肝脏、大脑和其他重要器官，尽管进行螯合治疗，仍可能发生神经恶化。该研究确定了与螯合治疗开始相关的“早期”（<3 个月）与“晚期”（>12 个月）神经恶化的不同模式，并确定了可能的原因和可逆性。这些数据对于患者咨询和指导螯合治疗的最佳管理将非常有用。
