Isolated neurological symptoms of Wilson’s disease manifesting as focal epileptic seizures without hepatic involvement: Insights from a case report

Abstract

Patients with Wilson’s disease, an autosomal recessive disorder caused by ATP7B mutations, present with hepatic and neurological symptoms, including tremors, chorea, personality changes, and rare manifestations such as neuropathy, autonomic dysfunction, headache, and epilepsy. This report describes the case of a 14-year-old man born to consanguineous parents who presented with focal seizures and oromandibular dystonia. A neurological exam revealed left upper limb hypotonia. An electroencephalogram showed right hemisphere epileptiform activity, and magnetic resonance imaging indicated bilateral basal ganglia hyperintensities. An ophthalmological exam revealed an incomplete Kayser–Fleischer ring. Laboratory tests confirmed Wilson’s disease with low serum ceruloplasmin (3 mg/dL) and elevated urinary copper excretion (1226 mcg/24 h) levels. Treatment included penicillamine (250 mg/day) and zinc (50 mg bi-daily), along with clonazepam for seizures. Routine follow-ups were recommended. This case highlights the importance of recognizing neurological presentations in patients with Wilson’s disease for timely diagnosis and management.

Introduction

Wilson’s disease (WD), also referred to as hepatolenticular degeneration, is a rare autosomal recessive disorder caused by mutations in the copper-transporting gene ATP7B. ¹ Its prevalence is approximately 1.7 cases per 100,000 individuals. ² WD is characterized by impaired copper excretion into the bile, resulting in excessive copper accumulation in the liver, kidneys, cornea, and brain. Clinical manifestations of WD include a range of hepatic and neurological dysfunctions; however, neurological symptoms are often overlooked in children, with over 15% of pediatric patients affected with WD. ³ Diagnosis of WD requires the fulfillment of two of the three criteria: serum ceruloplasmin <20 mg/dL, urinary copper excretion levels >100 mcg/24 h, and the presence of Kayser–Fleischer ring (K–F ring). Magnetic resonance imaging (MRI) is crucial for suspected neurological involvement. ⁴ This study reports a rare case of WD presenting with neurological symptoms without hepatic involvement, which was notable due to its onset during the second decade of life and the presence of focal epileptic seizures. The objective of this research was to contribute to the growing efforts in understanding this rare disease, increase awareness, and advance knowledge regarding its etiology.

Case presentation

Chief complaints

A 14-year-old man, born to consanguineous parents, presented to the emergency department with seizures involving 2 min of repetitive jerking in the left facial muscles and hand, maintaining consciousness throughout. The seizure was resolved with levetiracetam; postepisode, he was conscious and oriented but anxious and fearful.

Personal and medical history

There was no history of measles or convulsions during early childhood; however, the patient has had recurrent seizures in the last week. The patient’s family history was unremarkable for seizures or neurological diseases, except for two brothers diagnosed with adrenogenital syndrome. The patient experienced pre-episode symptoms of tingling and numbness on the left side of his face and hand, accompanied with postepisode anxiety and fear. His mother reported behavioral changes, agitation, declining academic performance, frequent drooling, and weight loss over the past 6 months.

Physical examinations

Physical examination revealed normal vital signs, with no evidence of pallor, icterus, or significant lymphadenopathy. A neurological evaluation showed an isolated reduction in muscle tone in the left upper limb, with normal muscle power (5/5) in all limbs. Facial examination revealed oromandibular dystonia, identified as an extrapyramidal symptom, along with hypersalivation. Other systemic examinations did not indicate any abnormalities.

Electroencephalogram (EEG) and laboratory examinations

An interictal EEG revealed focal epileptiform activity localized to the right hemisphere (Figure 1). Routine investigations, including complete blood count (CBC), creatinine, and electrolytes, were within normal limits.

Figure 1.

Interictal electroencephalogram (EEG) reveals focal epileptiform activity localized to the right hemisphere.

Imaging examinations and diagnosis of WD

Brain MRI without contrast showed bilateral symmetrical hyperintensities in the basal ganglia, brainstem, and cerebral cortex on fluid-attenuated inversion recovery (FLAIR) and T2-weighted sequences (Figure 2), suggestive of metabolic disorders. Liver ultrasound was normal. The ophthalmological examination using a slit lamp revealed an incomplete K–F ring. Liver function tests and enzymes were within normal limits; however, the serum ceruloplasmin level was low at 3 (normal range: 20–60) mg/dL, and the serum copper level was 26 (normal range: 60–160) mg/dL. The urinary copper excretion level was elevated at 1226 (normal range: 10–60) mcg/24 h. A diagnosis of WD was established. Although liver biopsy is the gold standard for copper quantification, it was not performed due to parental refusal.

Figure 2.

Noncontrast brain magnetic resonance imaging (MRI) images. (a) Axial diffusion MRI shows hyperintensity of the brainstem; (b) Coronal T2-weighted MRI demonstrates bilateral symmetrical hyperintensities in the basal ganglia and brainstem and (c) Axial fluid-attenuated inversion recovery (FLAIR) MRI shows bilateral symmetrical hyperintensities in the cerebral cortex.

Treatments

The therapeutic regimen included penicillamine (250 mg/day) and elemental zinc (50 mg bi-daily), supplemented with oral clonazepam for symptomatic therapy.

Outcome and follow-up

The patient was discharged from the hospital in stable condition and was asked to visit the clinic for periodic follow-ups and comprehensive guidelines on lifestyle modifications to minimize potential complications associated with WD. Recommendations included avoiding hepatotoxic substances, alcohol, and copper-laden foods (such as mushrooms, chocolate, nuts, dried fruits, liver, and shellfish). Long-term monitoring involved regular evaluations of urinary copper excretion, CBC, free copper levels, and liver and renal function every 4–8 weeks. One month postdischarge, the patient suffered a seizure, which was successfully managed with levetiracetam. Following treatment, the patient underwent examination, revealing no significant symptom improvement, but a reduction in hypersalivation was noted. The patient was advised to continue regular follow-ups at the clinic.

Discussion

In 1912, Dr. Samuel Alexander Kinnier Wilson first described WD, which is clinically known as hepatolenticular degeneration. ¹ WD is an autosomal recessive disorder caused by mutations in the ATP7B gene on chromosome 13, which encodes a copper-transporting protein ATPase. ² Reduced or absent function of ATP7B protein decreases hepatocellular excretion of copper into bile, leading to hepatic copper accumulation and subsequent damage. Eventually, this excess copper is released into the bloodstream and deposited in various organs, including the brain, kidneys, and cornea.^1,5 Consequently, most patients with WD exhibit decreased blood levels of ceruloplasmin due to a short half-life of apoceruloplasmin. ¹ WD usually presents with liver dysfunction by the first decade of life, whereas neurological symptoms develop in the third and fourth decades of life. WD develops over a wide spectrum of ages, with cases reported from the age of 3 years to the 80s. ⁴ The patient in our case presented with neurological symptoms in the second decade of life, consistent with the findings of the study conducted by Kalra et al. at the All India Institute of Medical Sciences. ⁶ Indian studies have indicated that the disease manifests at an earlier age in children, possibly due to a higher average copper intake of 5.7–7.1 mg/day, compared with 0.34–1.1 mg/day reported in Western countries. The use of copper and copper alloy pots for cooking and storing water may be a significant contributing factor.^7,8 The oxidative stress and cellular damage in WD can lead to a range of clinical manifestations.

Symptoms are primarily associated with liver and basal ganglia involvement.^3,9 Liver-related signs and symptoms include jaundice, itching, abdominal discomfort, weakness, vomiting, and ascites. Neurologically, the disease presents with tremors, chorea, personality changes, depression, anxiety, headache, insomnia, seizures, hallucinations, ataxia, and mask-like facies. ⁹ Copper deposition primarily occurs in the basal ganglia, thalamus, cerebellum, and upper brainstem. ¹⁰ Apart from movement disorders, WD may manifest as rare neurological symptoms such as neuropathy, autonomic dysfunction, headache, and epilepsy. ¹¹ WD may initially present as epilepsy, which can occur several years prior to the onset of other neurological manifestations. The occurrence and relevance of epilepsy in patients with WD were first reported by Dening et al. in 1988. ¹² Among patients with neurologic WD, 14.5% experience seizures, especially those with cortical, subcortical, or cerebellar involvement on MRI. ¹³ Seizures can manifest in various forms, such as grand mal, focal, or absence types. ¹⁴ Seizure types in patients with WD are similar to those in the general population, although focal motor seizures are more common. Conditions with involuntary movements can mimic epilepsy, complicating seizure detection. ¹² Moreover, the clinical hallmark of WD is a K–F ring, presenting in the majority of patients with neurologic symptoms. ¹⁰ Additionally, stigmata of chronic liver disease, K–F ring on the cornea, skeletal involvement akin to premature osteoarthritis and arthropathy, hemolytic anemia, Fanconi syndrome-like symptoms, and urolithiasis may be observed in some patients. ³ Herein, the patient showed neurological manifestations, predominantly focal seizures for 2 min, involving the left hemiface and upper limb, with preserved consciousness. There was no clinical or biochemical evidence of hepatic involvement.

For the diagnosis of WD, comprehensive evaluations such as neuroimaging, electrophysiological methods, and Leipzig score calculation using clinical signs are essential, given the limited specificity of laboratory tests.^3,10 Serum ceruloplasmin levels, although not definitive for diagnosis, are recommended as the first-line diagnostic test for WD, as 10% of the affected individuals may have normal levels, and 20% of the carriers may show reduced levels.^1,3 Urinary copper analysis is a crucial diagnostic tool for WD, requiring careful collection to prevent contamination; a 24-h urinary copper excretion test serves as a reliable confirmatory test. Normal copper excretion levels range from 20 to 50 mcg/24 h, whereas patients with WD typically exhibit levels exceeding 100 mcg/24 h. ¹ However, liver biopsy remains the gold standard, with copper levels exceeding 250 μg/g dry liver tissue confirming the diagnosis of WD. Genetic testing may be employed to screen family members of individuals with WD, which is caused by mutations in the ATP7B gene. ² In the present case, the diagnosis of WD was established through clinical presentation, serum ceruloplasmin levels, 24-h urinary copper excretion, and MRI. MRI is highly sensitive for detecting WD abnormalities. In T1-weighted sequences, hypointensities in the basal ganglia are observed in two-thirds of patients, whereas T2-weighted sequences demonstrate hyperintensities in the basal ganglia, white matter, thalamus, or brainstem. The observed abnormalities arise from neuronal loss, gliosis, degeneration of fibers, and vacuolization, which are associated with the increased water content within the brain. On T2-weighted axial MRI sequences, the midbrain displays the typical “face of the giant panda,” whereas the tegmentum region of the pons reveals the “face of the miniature panda.”^15,16 In the present case, bilateral symmetrical hyperintensities in the basal ganglia, brainstem, and cerebral cortex were observed on FLAIR and T2-weighted MRI. Neuropsychiatric disorders that could be confused with WD are parkinsonian syndromes, pantothenate kinase deficiency associated with neurodegeneration (iron accumulation), neuroacanthocytosis syndrome, and Huntington’s disease, which may exhibit similar symptoms such as rigidity, dystonia, and movement disorders. ³

WD treatment has two main options: lifelong pharmacological therapy and liver transplantation for those presenting with end-stage liver disease. Pharmacological therapy utilizes chelating agents, with significant improvement noted in most patients within 18 months. Common chelation agents include penicillamine, trientine, tetrathiomolybdate, and zinc. ⁴ Trientine is recommended owing to its reduced side effects. ³ Moreover, D-penicillamine is the preferred treatment for WD; however, it may exacerbate neurological symptoms, prompting consideration of alternative therapies. ⁴ Oral zinc is administered to compete with copper absorption at metallic ion transporter sites. ³ For WD presenting with neurologic/neuropsychiatric symptoms, ammonium tetrathiomolybdate is considered the optimal treatment, but its availability is limited as it is still an experimental medication in most countries. ¹ In WD, epilepsy prognosis is primarily influenced by WD therapy rather than anticonvulsants. While performing conventional epilepsy management, managing WD requires the inclusion of penicillamine or trientine. While choosing antiepileptic medications for patients with WD, it is crucial to consider hepatotoxicity, leading to the recommendation against valproate use. ¹⁷ Liver transplantation (LT) is the definitive treatment for WD and is recommended for patients with fulminant hepatic failure or end-stage cirrhosis unresponsive to medical therapy. Although the impact of LT on the improvement of neurological function in patients with stable liver disease remains controversial, preliminary evidence suggests that it serves as a rescue therapy when chelation treatment fails. ¹⁸ Future curative treatments for WD may include genetic therapy and hepatocyte transplantation, in addition to the currently available LT. ¹ Muscle rigidity, spasticity, and parkinsonian symptoms can be managed with muscle relaxants such as baclofen, anticholinergics (such as trihexyphenidyl), gamma-aminobutyric acid antagonists, and levodopa. ³ The patient in the present case was treated with oral zinc (as zinc acetate) at low doses and D-penicillamine. However, all presymptomatic individuals should receive prophylactic treatment due to the observed 100% penetration of the disease. ¹

Patient education should focus on dietary modifications, including the avoidance of hepatotoxic substances, alcohol, and copper-rich foods. As copper-chelating therapies may take up to 6 months to achieve optimal efficacy, physiotherapy and occupational therapy are recommended for neurological manifestations. Long-term monitoring is crucial, with assessments of urinary copper excretion, CBC, free copper levels, and liver and renal function every 4–8 weeks. Lifelong chelation therapy is often required, and untreated cases can eventually progress to chronic liver disease or hepatocellular carcinoma. Genetic counseling is advised to prevent the risk of gene transmission. ³

Conclusion

This study highlights the importance of recognizing WD as a potential neurological cause, even without liver involvement. Clinicians should maintain a high index of suspicion in younger patients with unexplained neurological symptoms, such as dystonia or cognitive decline. Early diagnosis through serum ceruloplasmin and urinary copper tests can improve outcomes. Increased awareness and interdisciplinary collaboration are essential for effective management. Future research should refine diagnostic protocols and deepen the understanding of WD’s pathophysiology to enhance patient care.

List of abbreviations

Wilson’s disease (WD)

Kayser–Fleischer ring (K–F ring)

Magnetic resonance imaging (MRI)

Electroencephalogram (EEG)

Complete blood count (CBC)

Liver transplantation (LT)

Fluid-attenuated inversion recovery (FLAIR)