Abstract

Background & aims: Prevention of neurologic worsening (NW) under therapy is an unmet need in the management of Wilson disease (WD). This study was aimed at characterizing occurrence, outcome and potential reversibility of NW in WD.

Methods: 128 WD patients with neurologic features at any time point (all Caucasian, 63 females, median age at diagnosis 22 years) were identified by chart review at University Hospital Heidelberg of 457 WD patients in total and grouped according to initial presentation. The timing and occurrence of NW was assessed following a structured clinical examination during clinical visits.

Results: Early NW (within the first 3 months of therapy) was observed in 30 out of 115 (26.1%) patients with neurologic or mixed presentation and never in patients purely hepatic or asymptomatic presentation (0%). Late NW (after >12 months) was seen in further 23 (20%) with neurological or mixed presentation and in 13 out of 294 (4.4%) patients with hepatic or asymptomatic presentation. The median time from start of treatment to late NW was 20 months. Only 3 patients had 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%) of late NW.

Conclusions: This single center study postulates to distinguish early (≤3 months) treatment associated from late NW (>12 months of treatment). Early paradoxical NW was attributed to treatment initiation and preexisting neurological damages, but was not observed in hepatic patients. Late NW is likely to be associated with non-adherence Despite limitations, this study defines the timing of NW, delivers important data for future studies and prevents inappropriate dose changes.

Impact and implications: In patients with Wilson disease, defined as an excess accumulation of copper which can damage the liver, brain and other vital organs, neurologic worsening can occur despite chelation therapy. The study identifies different patterns of 'early' (<3 months) vs. 'late' (>12 months) neurologic worsening in relation to initiation of chelation therapy and establishes possible causes and potential for reversibility. These data should be useful for counseling patients and optimal management of chelation therapy.