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

Abstract

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.

D-Penicillamine-Induced Myasthenia Gravis—A Probable Complication of Wilson’s Disease Treatment—A Case Report and Systematic Review of the Literature

“…Discussing our case report, it is also worth mentioning, that despite the favorable clinical outcome in WD-treated patients, the neurological deterioration of clinical symptoms (or de novo neurological symptoms) may occur in up to 11.5% of WD patients [ 7 ]. In case of early deterioration (up to 6 months since WD treatment introduction), it is usually related to the type of anti-copper treatment (especially DPA ADR’s) or to the natural course of the disease (usually advanced at diagnosis in such cases) [ 2 , 3 , 7 ].…”

“…Discussing our case report, it is also worth mentioning, that despite the favorable clinical outcome in WD-treated patients, the neurological deterioration of clinical symptoms (or de novo neurological symptoms) may occur in up to 11.5% of WD patients [ 7 ]. In case of early deterioration (up to 6 months since WD treatment introduction), it is usually related to the type of anti-copper treatment (especially DPA ADR’s) or to the natural course of the disease (usually advanced at diagnosis in such cases) [ 2 , 3 , 7 ]. “Late” WD neurological deteriorations, diagnosed after 6 months of WD treatment, are usually caused by non-compliance with anti-copper treatment reported mostly by patients’ relations and confirmed by copper metabolism (mainly increased daily urinary copper excretion > 500 µg/24 h with chronic use of chelators or > 100 µg/24 h on zinc salts) [ 7 ].…”

“…In general, if detected early and treated correctly, the prognosis is good: almost 85% of patients improve or their symptoms and diagnostic test results stabilize [ 6 ]. However, some patients’ neurological deterioration (early or late) may occur [ 7 ], as well as WD overtreatment or adverse drug reactions (ADR’s)—associated with anti-copper treatment leading to neurological symptoms aggravation [ 8 ].…”

“…WD overtreatment?) [ 7 , 8 ]. As there is little data in the literature about DPA-induced MG, we aimed to present a case of a patient with WD who developed DPA-induced MG and whose symptoms completely subsided after DPA cessation, with an additional systematic review of DPA-induced MG in WD.…”

Copper Deficiency as a Serious Complication of Anti‐Copper Treatment in Wilson's Disease

“…3 Such clinical worsening may prompt intensification of anti-copper treatment, which will further aggravate the neurological symptoms caused by copper deficiency. 4 Similarly, anemia and neutropenia due to copper deficiency may suggest progressive liver damage or hypersplenism, leading to unnecessary treatments, including splenectomy, which can worsen these hematological complications. 1 Therefore, clinicians must be aware that copper deficiency may worsen both the neurological and hepatic symptoms of WD.…”