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NEUROSAE 2018 ANNUAL MEETING EDITION (VOLUME 10, ISSUE 3)
QUESTION 28 OF 100
A 32-year-woman presents with a history of a progressive tremor for the past year. She reports that although the tremor is present at rest it is enhanced when she uses or holds up her hands and arms and now disrupts her ability to dress, write, or use utensils. She is increasingly anxious and depressed, and her husband notes she is more irritable and distracted, often crying over the “littlest” things. History reveals she was told she has a fatty liver in association with chronic elevation of transaminases. Examination reveals a postural more than resting bilateral low-amplitude tremor in the upper extremities and slowed saccades. The patient appears to stick out her tongue throughout the examination, and her husband confirms she constantly licks her lips. An MRI scan of the brain is shown. Which of the following studies should be ordered to confirm the diagnosis?
A. Liver ultrasound and potential biopsy
B. Continuous EEG monitoring
C. Viral hepatitis panel
D. Slit lamp ophthalmologic examination **
E. Ioflupane I-123 brain SPECT (DaTSCAN )
** = Your answer
Wilson disease (WD) is a rare autosomal recessive disorder of copper metabolism that results in copper accumulation and multiple-organ damage. Wilson disease is caused by mutations in the gene coding for a metal-transporting P-type ATPase (ATP7B). The gene is located on chromosome 13. The WD protein is a late endosome-associated membrane protein that binds copper in its large N-terminal domain and then translocates it to the endosomal lumen, ultimately delivering excess copper to biliary canaliculi for excretion. Copper absorbed by the intestinal cells is stored in the enterocytes (bound to metallothionein) in a non-toxic form. It is delivered into the circulation by the copper transporting protein ATP7A. Copper complexed to albumin reaches the liver. Impaired function of ATP7B (the WD protein) leads to decreased hepatocellular excretion of copper into bile with subsequent hepatocellular copper accumulation and injury. WD urinary copper excretion increases but this increase is unable to compensate for the defect in biliary copper excretion. When hepatic storage capacity is exceeded copper is released in the blood and is deposited in other organs such as the brain, cornea, kidney, and bones.
The initial presentation of WD is neurologic, hepatic, and psychiatric in approximately 40%, 40%, and 20% cases respectively. WD presents with liver disease more often in children and young adults than in older individuals. Any patient <50 years with unexplained liver disease should be screened for WD. Patients who present with neurologic disease generally do so in the second and third decades. Most patients with neurologic involvement have liver disease at the time of presentation, but they are not symptomatic as a result of their liver disease. The possibility of WD should be considered in any young patient with a movement disorder.
The most frequent presenting neurologic manifestation of WD is tremors. The tremor may be resting, postural, or kinetic. A proximal, slow, high amplitude upper extremity tremor is the classic finding. It may take on a coarse, “wing-beating” appearance. Psychiatric symptoms may predominate or antedate the neurologic symptoms. Psychiatric manifestations appear at some point in the course of the disease in most patients with neurologic WD. WD should be considered with unexplained psychiatric symptoms in young individuals, particularly if accompanied by neurologic or hepatic dysfunction. The most common psychiatric manifestations of WD include personality or behavior changes and mood disturbances, most commonly depression.
The laboratory hallmarks of WD include a low serum ceruloplasmin and an elevated urine 24-hour copper excretion. Hepatic copper is frequently elevated. These tests, along with genetic testing and MRI are the primary diagnostic modalities. There is no single ideal test.
Hepatic copper elevations also are seen in asymptomatic individuals with WD. The cirrhotic liver may have significant regional differences in hepatic copper distribution, and sampling error may be responsible for normal or borderline values of hepatic copper content. Contamination, particularly in block specimens, may result in falsely elevated hepatic copper values. Despite this limitation, it is perhaps the best available biochemical test. It is invasive and is not required in all cases. Its use should be reserved for situations in which simpler approaches have not provided a definitive diagnosis. Further, it generally is not required in patients with neurologic disease as other tests can provide the diagnosis.
Brain abnormalities are seen on MRI scans in nearly all patients with neurologic WD. T2-weighted sequences show increased T2 signal in the caudate, putamen, thalamus, midbrain (including substantia nigra pars compacta), periaqueductal gray, pontine tegmentum, medulla, vermis, and dentate nuclei. Putaminal lesions with a bilateral, symmetric, concentric-laminar T2 hyperintensity are a characteristic finding. Also reported is increased T2 signal involving the subcortical white matter and cortex.
Copper accumulation in the Descemet’s membrane in the limbic area of the cornea (Kayser-Fleischer or K-F ring) is frequently seen patients of WD, particularly in those who have neurologic manifestations. WD may not have the K-F rings. K-F rings are generally bilateral; unilateral formation has been reported. The ring is not pathognomonic of WD and may be rarely seen in other cases of cholestatic liver disease. The K-F ring can disappear with therapy.
In this untreated case with supportive clinical, historical, and radiographic signs and symptoms, a slit lamp ophthalmologic examination is likely to be positive for K-F rings given the patient’s neurologic and psychiatric symptoms. However, genetic testing is confirmatory.
* Kumar N. Overview of the interface of neurology and medicine: an update. Neurologic Complications of Medical Disease C13 AAN Annual Meeting 2017.