Rapid Progression and Atypical Imaging in Neurological Wilson’s Disease

Sir, Wilson’s disease (WD) is a genetic disorder resulting in abnormal copper accumulation, leading to a spectrum of hepatic and neurological presentations. Typically, the disease progresses gradually, with symptoms developing over the years, contributing to diagnostic delays. However, we report a case of fulminant neurological Wilson’s disease, where symptoms rapidly deteriorated within two months, and neuroimaging revealed extensive involvement, including cortical regions. This unusual and severe progression underscores the importance of early recognition and intervention in atypical cases of WD. An adolescent female began experiencing progressive difficulty in walking and abnormal lower limb posturing which was preceded by a bout of fever. Concurrently, she developed postural and kinetic tremor in her upper limbs. Over a month, her speech output declined markedly, culminating in mutism. Her condition rapidly worsened, rendering her bedridden and dependent for daily activities. She had no significant perinatal history, was born to non-consanguineous parents, followed immunization schedules, and met developmental milestones. She exhibited an akinetic rigid state with an expressionless face, hypometric horizontal saccades, and restricted vertical saccades. Rigidity was noted in all four limbs, with brisk deep tendon reflexes and bilateral ankle clonus. Routine investigations were normal except for elevated aminotransferases (AST 97 U/L, ALT 45 U/L). Viral markers, thyroid function, and antinuclear antibodies (ANA) were normal. Given the history of fever with rapidly progressing symptoms, a cerebrospinal fluid examination was performed, revealing 15 cells (80% neutrophils, 20% lymphocytes) and a protein level of 98 mg/dL. The neuroviral panel (including Japanese Encephalitis, Herpes, Enterovirus, and Varicella) and autoimmune encephalitis panel returned normal results, and Ziehl–Neelsen stain for acid-fast bacilli, Gram stain, and KOH stain were negative. An ultrasound showed coarsened liver echotexture, prompting further evaluation for Wilson’s disease. Serum copper (27 mcg/dL) and ceruloplasmin (6 mg/dL) levels were decreased, while 24-hour urinary copper was elevated (460 mcg/24 hours). The presence of Kayser–Fleischer rings and a Leipzig score of 6 confirmed the diagnosis. There was extensive involvement in her MRI brain with hyperintensities on T2-weighted and FLAIR images, in bilateral frontal lobes [Figure 1], basal ganglia, thalami, midbrain, pons, and cerebellar peduncles. The pontine section showed the face of a miniature panda sign, characterized by the hypointensity of the medial longitudinal fasciculus and central tegmental tract forming the eyes, hyperintensity of the aqueduct opening into the fourth ventricle forming the nose and mouth, and the superior cerebellar peduncle representing the panda’s cheeks [Figure 2]. There was evidence of a putaminal rim sign on T2-weighted images characterized by a hyperintense signal on T2-weighted images outlining the putamen [Figure 3] and evidence of linear hyperintensity on the posterior limb of the internal capsule [Figure 3]. Chelation therapy with D-penicillamine and physiotherapy was initiated, resulting in marked improvement in speech, tremors, and rigidity on follow-up.Figure 1: T2W (a) and FLAIR (b and c) images showing hyperintensities in bilateral frontal lobes (yellow arrow)Figure 2: T2W (a and b) and FLAIR (c) images showing midbrain (a and c) and pons (b). The hypointensity of the medial longitudinal fasciculus and central tegmental tract forming the eyes (white arrow), hyperintensity of the aqueduct opening into the fourth ventricle forming the nose and mouth (red arrow), depicting the “face of a miniature panda sign” on T2W images (b). There are T2 hyperintensities in the midbrain as seen in (a)Figure 3: T2W (a) and FLAIR (b) images showing hyperintensities in bilateral thalami and basal ganglia, thin rim of hyperintensity in the putamen (yellow arrow) depicting the “putaminal rim sign.” There is also hyperintensity noted in the posterior limb of the internal capsule (red arrow)The diagnosis of WD is frequently delayed due to the disease’s protean clinical features and its ability to mimic other neurological disorders. The median time from onset to diagnosis is roughly two years. In our patient, the symptoms progressed rapidly over 1–2 months, which is atypical for Wilson’s disease and rarely reported in the literature. Fulminant neurological deterioration, as observed in our patient, is uncommon and underscores the need for heightened clinical suspicion and prompt diagnostic evaluation in cases of rapid symptom progression. For instance, a case reported by Svetel et al.[1] in 2009 described a patient with a similar rapid neurological decline, emphasizing the unusual nature of such presentations. Angius et al.[2] described a patient with Wilson’s disease who presented at 11 years of age with neurological symptoms, experiencing rapid progression of neurological impairment over eight months. This aggressive presentation may be attributed to the swift accumulation of copper in the brain, leading to cytotoxic edema in the affected areas. This hypothesis is supported by extensive involvement on brain imaging. Imaging studies play a pivotal role in the diagnostic process, especially in neurological Wilson’s. The most common MRI finding in Wilson’s disease is hyperintensity in T2-weighted images of the putamen as seen in our patient. The commonest areas involved in Wilson’s after putamen include pons, thalamus, caudate nucleus, midbrain, and globus pallidus. The involvement of the posterior limb of the internal capsule, as seen in our case, has also been documented in the literature, though only in a limited number of case reports.[3] Lobar involvement like frontal, parietal, and temporal is rarely reported (3%); however, occipital lobes are spared. Sinha et al.[4] analyzed MRI findings in 100 patients with Wilson’s disease, examining their correlation with clinical features. They affirmed that cerebral cortex and white matter changes are uncommon, with the frontal lobe being most frequently affected. Their study concluded that MRI findings corresponded with clinical severity scores but showed no association with the duration of illness. Cerebellum and corpus callosum may also be affected in 2% of cases. Additionally, hyperintensity in the midbrain tegmentum, combined with the typically hypointense red nucleus (representing the eyes), normal signal intensity of the pars reticulata of the substantia nigra (forming the ears), and low signal intensity of the superior colliculus (representing the chin), can produce the “face of the giant panda” sign on axial images in FLAIR sequences. This in combination with “face of a miniature panda” is termed as the “double panda sign.”[5] Abnormal hyperintensity observed in the pons, with characteristic hypointensity in the center forming a star shape on T2-weighted axial images, creates the Trident/Mercedes sign. There may be diffuse cerebral, cerebellar, midbrain, and pontine atrophy.[3] The oddity in our patient was the extensive involvement, including the cortex and hyperintensities in the posterior limb of the internal capsule, indicating bilateral corticospinal tract involvement—rarely witnessed in Wilson’s disease. Trocello JM et al.[6] observed that extensive cortical–subcortical involvement in Wilson’s disease is uncommon but should be recognized as a potential cause of diffuse leukoencephalopathy with cystic evolution. Similarly, Perugu A et al. and Rezende FM et al. reported cases of cystic leukoencephalopathy associated with severe disease.[7,8] In Wilson’s disease, cerebrospinal fluid (CSF) typically shows normal or mildly elevated protein levels with no pleocytosis, but our patient had an unusual finding of neutrophilic CSF, which is atypical for Wilson’s disease. Given the plethora of pleomorphic presentations of Wilson’s disease, which often pose a diagnostic challenge, the disease typically follows a protracted course. Our case emphasizes the importance of recognizing fulminant neurological Wilson’s disease as a potential presentation, along with considering atypical neuroimaging features. Clinicians must stay alert to prompt symptom escalation to ensure timely diagnosis and intervention, even in atypical cases, thereby optimizing patient outcomes. Financial support and sponsorship Nil. Conflicts of interest There are no conflicts of interest.