1. Neurological Manifestations of Wilson’s Disease Aleksandar Videnovic, MD, MSc Assistant Professor of Neurology Feinberg School of Medicine Northwestern University Chicago, IL

2. Samuel Alexnader Kinnier-Wilson 1912 - neurological disorder with progressive lenticular degeneration of the brain and cirrhosis of the liver

3. Epidemiology 17 per million carrier frequency 1 in 122

4. Clinical manifestations Peak incidence – around 17 years Rare after age 35, but present Hepatic, neurologic and psychiatric manifestations

5. Neurologic manifestations Onset of neurological symptoms – about 15-21 yrs of age Initial presenting symptoms in 18-68% of diagnosed WD patients One or combination of several neurologic symptoms / signs Most common - a movement disorder Lorinz et al. 2009; Brewer 2005

6. MOVEMENT DISORDERS - definition - Neurological syndromes in which there is an excess of movements or a paucity of movements, unrelated to weakness or spasticity

7. Excess of movements - Hyperkinesias - chorea dystonia myoclonus tics tremors akathisia ataxia athetosis ballism hyperekplexia moving toes / fingers myokymia myorhythmia restless legs stereotypy

8. Paucity of movements - Hypokinesias - pakinsonism apraxia cataplexy catatonia hypothyroid slowness stiff-muscles

9. Abnormal movements - anatomy -

10. Cerebral Cortex Striatum D2 D1 GPe SNc STN Thalamus GPi/SNr PPN Brainstem Spinal Cord GLU GABA GLU GABA DA GLU GABA excitatory inhibitory GABA BASAL GANGLIA CIRCUITRY

11. Dystonia A neurological syndrome characterized by involuntary, patterned, sustained, or repetitive muscle contractions of opposing muscles, causing twisting movements and abnormal postures In 11-65% of neurologic WD 1-3 Focal, segmental, multifocal, generalized 1 Machado et al. 2006; 2 Oder et al. 1991; 3 Taly et al. 2007

13. Tremor In 22-55% of neurologic WD 1,2 Can occur at rest, with posture or action “wing-beating” tremor May be confused with essential tremor 1 Walshe et al. 1992; 2 Slotanzadeh et al. 2007

15. Parkinsonism Tremor Slowness (bradykinesia) Stiffness (rigidity) Unsteady gait In 19-62% of neurologic WD 1 1 Taly et al. 2007

16. Parkinsonism Resting tremor

17. Parkinsonism Bradykinesia

18. Chorea involuntary, irregular, purposeless, non-rhythmic, abrupt, rapid, un- sustained movements that seem to flow from one body part to another In 6-16% of neurologic WD 1-3 Mainly in young-onset disease Rarely isolated, usually together with other involuntary movements 1 Machado et al. 2006; 2 Oder et al. 1991; 3 Taly et al. 2007

20. Dysarthria Probably the most common neurologic manifestation In 85-97% of neurologic WD 1 Mixed type dysarthria 1 Machado et al. 2006

21. Cognition Cognitive impairment may be saddle Most commonly: –Impulsivity –Impaired social judgment –Apathy –Decreased attention –Executive dysfunction –Emotional lability

22. Kayser – Fleischer (KF) Rings seen in nearly 100% of neurologic WS 1 Lorinz et al. 2009

23. Natural history of neurologic WD Mean age of onset -15-21 yeas of age Variable clinical course Fluctuations are common Tremor-predominant disease may have somewhat slower course relative to dystonic forms Younger patients – dystonia and chorea Older patients - tremor

24. Differential diagnosis of neurologic WD Essential tremor Young-onset Parkinson’s disease Dystonia Huntington disease Benign familial chorea

25. Brain imaging in neurologic WD

26. Treatment Penicillamine Neurologic worsening Significant side effects Trientine Neurologic worsening Zinc acetate Tetrathiomolybdate Liver transplantation Symptomatic treatment of movement disorders