Beyond the basal ganglia: Rare cortical involvement in a case of Wilson’s disease

INTRODUCTION

Wilson’s disease (WD) is a rare, autosomal recessive disorder characterized by abnormal copper metabolism. Copper accumulation predominantly occurs in the basal ganglia and brainstem. Here, we present the case of a 16-year-old boy with severe generalized dystonia. Neuroimaging of the patient revealed cortical hyperintensities, which have rarely been reported in the literature. Clinicians and radiologists should be aware of rare neuroimaging findings like gyral diffusion restriction suggestive of cortical involvement in this disease to avoid delay in diagnosis and treatment.

CASE REPORT

A 16-year-old boy born to a non-consanguineous marriage, with normal behavioral and developmental milestones, was diagnosed with hepatic WD in 2019 following jaundice and was initially treated with zinc and penicillamine. In 2022, he began experiencing dysarthria and dysphagia, leading to medication adjustments, which temporarily improved his symptoms. However, he discontinued his treatment for 1.5 years. Six months before presentation, he experienced reappearance of swallowing difficulty and dysarthria with behavioral changes and psychiatric manifestations in the form of delusions and obsessive symptoms. His family history included WD in his cousin sister.

Examination revealed abnormal facial expressions, including grimacing or unnatural grin suggestive of risus sardonicus and a vacuous smile, along with bradykinesia, slow responses, drooling, and motor abnormalities such as rigidity in all limbs, neck and left hand posturing, left dystonic toe posture, exaggerated reflexes, and bilateral extensor plantar responses. Sensory and systemic examinations were normal except for splenomegaly related to portal hypertension secondary to hepatic cirrhosis. A slit-lamp exam confirmed bilateral Kayser-Fleischer rings, solidifying the diagnosis of WD. Laboratory results showed low serum ceruloplasmin (14 mg/dL, normal value 20–60 mg/dL) and copper levels (59.2 µg/dL, normal value 70–140 µg/dL), elevated 24-h urine copper (120 µg, normal value 10–30 µg), and other signs of anemia and thrombocytopenia. A fibrotouch liver scan indicated stiffness of 16.9 kPa, consistent with F3-4 stage liver cirrhosis.

Magnetic resonance imaging (MRI) revealed symmetrical T2/fluid-attenuated inversion recovery (FLAIR) hyperintensities in the bilateral caudate and lentiform nuclei, with T2/FLAIR hyperintensities in the cortical grey matter and deep subcortical white matter of the frontoparietal lobes. It also showed diffusion restriction in the bilateral frontoparietal gyrus with low signal on apparent diffusion coefficient (ADC) [Figure 1]. The patient was managed with zinc and penicillamine, resulting in symptomatic improvement. ATP7B gene testing could not be done due to financial constraints and refusal by the attendants.

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Figure 1:

(A-D) Magnetic resonance imaging (MRI) brain shows symmetrical T2 and fluid-attenuated inversion recovery hyperintensities in the bilateral caudate and putamen nuclei. Altered signal intensity is also observed in the cortical grey matter and subcortical white matter of the frontoparietal lobes, with confluent hyperintensities on T2-weighted images. In addition, diffusion restriction is noted in the bilateral frontoparietal gyrus indicating restricted water mobility. (E) Slit-lamp examination showing Kayser-Fleischer (KF) ring. (F) Pedigree chart illustrating four generations, with arrows marking the affected individuals: The patient (16 years old) and his sister (13 years old), affected with examination revealing KF ring.

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DISCUSSION

WD is a rare autosomal recessive disorder caused by mutations in the ATP7B gene, leading to abnormal copper metabolism. Neurological symptoms typically arise later than hepatic symptoms, which can occur when liver disease is misdiagnosed, asymptomatic, or untreated.^[1] Neurological symptoms occur from extrahepatic copper accumulation, affecting nervous tissue and causing damage due to mitochondrial stress, oxidative damage, and enzyme inhibition. The putamen is particularly affected, with damage, astrogliosis, and iron-laden macrophages. Symptoms include tremor, dystonia, parkinsonism, ataxia, and chorea, often accompanied by dysphagia and dysarthria.^[2] Brain MRI abnormalities are prevalent in most WD patients with neurological symptoms and can also be present in about 40–70% of hepatic cases and 20% of presymptomatic cases.^[3] Untreated WD typically shows symmetric hyperintensities in deep gray matter nuclei, most notably the putamen, caudate, and thalamus, along with brainstem and white matter involvement.^[4]

Our patient exhibited white matter abnormalities in the subcortical regions of the frontal, parietal, and temporal lobes, which is uncommon and infrequently reported. Literature review reveals variable involvement of cortical gray and white matter. Grover et al. (2006)^[5] described a case with extensive gray and white matter abnormalities on MRI. Sinha et al. (2006)^[6] reported cortical involvement in only 9% of patients in a large series of 100 cases, and Ranjan et al. (2015)^[7] found cortical signal abnormalities in 26.5% of the patients.

The diffusion-weighted images of our patients showed hyperintensity in bilateral frontal and parietal gyri with low ADC signal, indicating restricted water molecule mobility typically seen in cytotoxic edema (acute ischemia and infarct). Classical cytotoxic edema (e.g., from ischemia) was deemed unlikely based on clinical context/radiological appearance. This restricted diffusion likely reflects acute copper-induced neuronal/glial injury/inflammation. Similar findings are highlighted by Kalekar et al. in their recent study.^[8]

To the best of our knowledge, gyral diffusion restriction on MRI in a patient with WD is only reported in very few case reports that this unique finding expands the neuroimaging spectrum associated with the condition and may provide further insight into its neuropathological mechanisms. Such a discovery highlights the importance of advanced neuroimaging techniques in diagnosing and monitoring WD, particularly in cases where neurological involvement is prominent. Moreover, while the diagnosis in our case was based on conventional diffusion-weighted imaging and qualitative assessment of restricted diffusion, quantitative apparent diffusion coefficient (ADC) mapping, if performed, could further enhance diagnostic confidence by providing objective numerical thresholds. This may help differentiate WD-related cortical diffusion restriction from acute ischemic infarction, where ADC values typically show a more profound reduction in the hyperacute phase. Moreover, diffusion restriction has been used as a parameter for prognostication.^[9]

Our report emphasizes that WD can involve extensive gray and white matter lesions beyond the basal ganglia and brainstem. Therefore, neurologists and radiologists should evaluate suspected WD cases for widespread gray matter and potential white matter abnormalities in addition to basal ganglia lesions.

CONCLUSION

This case expands the neuroimaging spectrum of Wilson’s disease by demonstrating rare cortical and gyral diffusion restriction beyond the classical basal ganglia involvement. Recognition of such atypical cortical changes is crucial, as early diagnosis and prompt reinstitution of chelation therapy can lead to meaningful neurological improvement and prevent irreversible damage.