1. Approach to diagnosis and treatment of dystonia Terence D. Sanger University of Southern California Dept. Biomedical Engineering, Child Neurology, Biokinesiology

2. Types of Dystonia Hypertonic (stiff) Hyperkinetic (too much movement)

3. Hypertonia: Resistance to passive movement Spasticity: velocity-dependent, asymmetric and/or a catch Dystonia: sustained or intermittent muscle contractions cause twisting and repetitive movements or abnormal postures Spasticity: velocity-dependent, asymmetric and/or a catch Dystonia: sustained or intermittent muscle contractions cause twisting and repetitive movements or abnormal postures

4. Reflexes in Spasticity PhasicPhasicTonicTonic Characterized by catch: Sudden ONSET determined by position and velocity; not proportional.

5. Van Doornik and Sanger, 2009 Tonic stretch reflexes maintain fixed dystonic postures.

6. Dystonia is defined as a movement disorder in which involuntary sustained or intermittent muscle contractions cause twisting and repetitive movements, abnormal postures, or both. Chorea is a random-appearing sequence of movements or movement fragments with continuously variable timing, duration, direction, and anatomic location. Athetosis is a continuous flowing or writhing movements that prevent maintenance of a stable posture. Hyperkinetic disorders: Excess involuntary movement Hyperkinetic disorders: Excess involuntary movement

7. Hyperkinetic Dystonia

8. Where does dystonia come from? We are not really sure Best guess is often basal ganglia

9. How the Basal Ganglia Work Motor command in the cortex...... is amplified in basal ganglia......and sent back to the cortex. Dopamine controls whether the signal is increased or decreased. Over time, dopamine “teaches” the basal ganglia which signals to increase and which to decrease.

10. What goes wrong? Too little dopamine, or injury to basal ganglia, and the output may be too much or too little. Too little output -> Parkinsons Too much output -> Dystonia Involuntary and continual activation of a region of cortex.

11. Where’s the lesion? Rigidity: brain Dystonia: brain Spasticity: brain-to-cord Secondary effects Mechanical: muscle-tendon, joint Disuse or neglect Rigidity: brain Dystonia: brain Spasticity: brain-to-cord Secondary effects Mechanical: muscle-tendon, joint Disuse or neglect

12. Long pulse trains to cortex trigger stable multijoint postures Graziano, Taylor, Moore 2002

13. What causes dystonia? Inserted postures in dystonia...... are caused by involuntary stimulation of motor cortex...... by the basal ganglia (or anything else).

14. Approach to Treatment Etiology-specific: treatment of underlying disease Anatomy-specific: treat sensory, basal ganglia, frontal, or cerebellar origin Nonspecific: reduce stretch reflexes

15. Approach to Treatment Etiology-specific: treatment of underlying disease For AHC: Flunarizine, or treat underlying genetic disorder.

16. Approach to Treatment Anatomy-specific: treat sensory, basal ganglia, frontal, or cerebellar origin Levodopa, Trihexyphenidyl, Deep- Brain Stimulation

17. Medicines for Dystonia Artane: takes months to work; may affect attention; works in many types of dystonia Sinemet: works quickly; naturally-occurring neurotransmitter; only works if dopamine deficit Clonazepam: works for hyperkinetic dystonia; can cause drowsiness and drooling Tetrabenazine: works only for chorea

18. Approach to Treatment Nonspecific: reduce stretch reflexes Baclofen, Intrathecal Baclofen, Benzodiazepines, Botulinum Toxin

19. Medicines for stretch reflexes Baclofen: primarily for spasticity; may help dystonia at high doses; may cause trunk and neck weakness Botox: localized to targeted muscles; effect lasts 3 months; requires repeated injections Tizanidine: probably no better than baclofen Dantrolene: causes permanent changes to muscle

20. Treatment Often need a combination of treatments. Botulinum toxin if only a small number of muscles are the problem. Trihexyphenidyl (Artane) and Levodopa (Sinemet) affect the whole body.

21. Deep-brain stimulation Wire in basal ganglia blocks abnormal activity and reduces excessive stimulation of the motor cortex. Pacemaker is in the chest. Can be programmed externally. Batteries last 2-5 years.

22. Taskforce on childhood motor disorders Multi-disciplinary Funded by NIH Consensus definitions and measurement technology

24. ConclusionConclusion Treatments for dystonia target multiple places in the chain from the disease to the symptoms. Need more research to find new treatments that are less invasive. Need to understand the details of dystonia in AHC short-term rescue treatment prevention of progression Treatments for dystonia target multiple places in the chain from the disease to the symptoms. Need more research to find new treatments that are less invasive. Need to understand the details of dystonia in AHC short-term rescue treatment prevention of progression