Correspondence: Wilson’s Disease with Overlapping Neurological Syndromes-The Importance of Brain Neuroimaging in Differential Diagnosis

Dear Editor,

We read with great interest the article by Saibaba et al.,[1] describing a patient with late-onset Wilson’s disease (WD) presenting with clinical features mimicking or overlapping progressive supranuclear palsy (PSP), and we would like to share our comments.

WD is a metabolic disorder characterized by pathological copper accumulation in multiple organs, predominantly the liver and the brain, leading to hepatic and neuropsychiatric manifestations. Importantly, WD can be successfully treated with anti-copper therapy. Apart from the Kayser–Fleischer (K–F) ring, none of the clinical manifestations of WD are disease-specific. Hepatic symptoms such as fatigue, jaundice, bleeding tendency, or ascites may occur in various liver disorders. Neurological manifestations reflecting basal ganglia and cerebellar involvement—including tremor, dystonia, ataxia, parkinsonism, gait and postural instability, dysarthria, dysphagia—are observed in a wide spectrum of neurological diseases.[2] Psychiatric manifestations, including mood disorders, psychosis, and behavioral changes, are common in WD but are likewise nonspecific.[2] Similar clinical pictures may arise not only from other neurological or hepatic disorders but also from the coexistence of multiple diseases in the same patient.[2,3,4,5] This possibility should always be considered in the differential diagnosis of WD, particularly in patients whose clinical course is atypical or who fail to respond adequately to anti-copper treatment, as illustrated by the case reported by Saibaba et al.[1]

As WD typically manifests in children, adolescents, or young adults, diagnostic difficulties arise especially in patients with late-onset neurological symptoms. In a large retrospective European study, Ferenci et al. analyzed 1,223 patients with WD and identified 46 individuals (3.8%) with disease onset after the age of 40.[6] Among these patients, 31 (2.5%) presented initially with neurological symptoms, with a mean age at onset of 44.5 years. The authors discussed potential explanations for diagnostic difficulties in this subgroup, including a slower progression of clinical symptoms, reduced diagnostic accuracy of the Leipzig score in adults (the possibility of false-negative or false-positive results of diagnostic tests such as brain magnetic resonance imaging (MRI), ophthalmological examination, or copper metabolism parameters), the nonspecific nature of neurological manifestations, which often resemble more common neurodegenerative disorders (the mean diagnostic delay in neurologic WD has been reported to be approximately three years). Both the case presented by Saibaba et al.[1] and the observations reported by Ferenci et al.[6] emphasize that WD should always be considered in the differential diagnosis of extrapyramidal syndromes, regardless of patient age. In such cases, a comprehensive diagnostic approach is essential and should include assessment of copper metabolism, slit-lamp examination for K–F ring, brain MRI, and genetic testing, in accordance with the Leipzig diagnostic criteria.

A second important issue raised by the report of Saibaba et al. concerns the interpretation of brain MRI findings in WD.[7,8,9] Although the authors present MRI images demonstrating midbrain and cerebellar atrophy suggestive of PSP, no information is provided regarding signal abnormalities on T2- or T2*-weighted sequences in the basal ganglia, midbrain, or pons, which are characteristic of WD. In the neurological form of WD, such MRI abnormalities—reflecting edema, demyelination, necrosis, or iron accumulation—are reported in nearly all patients. Although brain atrophy is often present in WD and correlates with the severity of neurological symptoms and copper toxicity, it is rarely the sole imaging abnormality.[7,8,9] Importantly, typical MRI changes constitute an integral component of the Leipzig diagnostic score.[2]

Finally, neurological outcome is a key element in distinguishing WD from WD coexisting with neurodegenerative disorders such as PSP. Approximately 85% of patients with WD show clinical improvement or stabilization under appropriate pharmacological therapy.[1] Anti-copper treatment—lifelong except in cases requiring liver transplantation—includes copper chelators (D-penicillamine or trientine) or agents reducing intestinal copper absorption (zinc salts).[2] Hepatic manifestations usually improve within 2–6 months of treatment, whereas neurological improvement may require considerably more time, often 3–5 years. Nevertheless, neurological deterioration during treatment occurs in up to 15% of patients and represents a clinical challenge.[2] Based on our center’s experience, we have proposed diagnostic algorithms for patients with WD and neurological deterioration during anti-copper therapy. Evaluation should always include analysis of the potential effects of concomitant medications (particularly antipsychotics), assessment of treatment adherence through monitoring of copper metabolism, consideration of copper deficiency due to overtreatment (which may manifest as anemia, leukopenia, posterior column myelopathy, or sensory axonal neuropathy), and adverse reactions to copper chelators (such as drug-induced myasthenia gravis or lupus erythematosus) should be taken into account. Importantly, progression of neurological symptoms despite adequate anti-copper treatment and appropriate copper metabolism control should always prompt re-evaluation of the WD diagnosis and thorough investigation for coexisting neurological disorders.

We have previously reported cases illustrating diagnostic complexity, including a patient with multiple sclerosis (MS) coexisting with WD presenting with predominant cerebellar ataxia and a patient with MS in whom interferon beta therapy resulted in elevated liver enzymes, leading to the diagnosis of WD during differential evaluation.[4] Additional reports describe the coexistence of WD with other neurological disorders, including spinocerebellar ataxia type 3 and Duchenne muscular dystrophy.[3,4,5] One case involved a three-year-old boy diagnosed with WD due to abnormal liver enzymes and treated with D-penicillamine, who subsequently developed progressive neurological symptoms; Duchenne muscular dystrophy was later diagnosed based on clinical findings, electromyography, and genetic testing.[5]

These observations underscore that, although WD is a rare disorder, coexistence with other neurological diseases is possible and may influence clinical presentation, disease course, and response to treatment. In patients receiving anti-copper therapy, clinical improvement or at least stabilization is generally expected. Therefore, neurological deterioration or refractoriness to treatment should always prompt reassessment of the diagnosis, evaluation of treatment adequacy, and systematic consideration of coexisting neurological disorders.[2]

Conflicts of interest

There are no conflicts of interest.

Funding Statement

Nil.