1. Movement Disorders Update Colleen Peach, RN, MSN, FNP Movement Disorders Clinic Emory University School of Medicine

2. Movement Disorders • Clinically, divided into 2 categories • Poverty of movement (Akinesia) • Associated with an increase in muscle tone • Excessive abnormal involuntary movements (Dyskinesia) • Classified as tremor, chorea, ballism, dystonia, athetosis, myoclonus, and tic

3. Dystonia Tourette’s Syndrome Restless Leg Syndrome Huntington’s Disease Essential Tremor Parkinson’s Disease Movement Disorders

4. Dystonia • Characterized by sustained muscle contractions that frequently cause twisting or repetitive movements and abnormal, sometimes painful, postures or positions • May affect any part of the body

5. Dystonia (cont.) • Primary Dystonia • may be due to DYT1 mutation • Secondary Dystonia • Most common cause is neuroleptic administration • Dystonia assoc. with parkinsonism • Psychogenic causes

7. Dystonia (cont.) • Treatment • Medications • Klonopin • Baclofen • Levodopa • Botulinum toxin injections (Botox) • Surgery • Deep Brain Stimulator

8. Dystonia (cont.) • Diagnostic Challenge: Frequent Misdiagnoses • Blepharospasm • Dry eye syndrome or tics • Cervical dystonia • Stiff neck, arthritis, subluxation of the cervical vertebrae, posterior fossa tumors • Writer’s cramp • Carpal tunnel, strain, “tennis elbow”

9. Dystonia (cont.) • Frequent Misdiagnoses (cont.) • Laryngeal dystonia • Sore throat, laryngitis, vocal abuse • Oromandibular dystonia • TMD (temporomandibular joint disorder) • All dystonia • Psychogenic, stress, nervousness

10. Tourette’s Syndrome • Characterized by sudden, involuntary, repetitive muscle movements (motor tics) and vocalizations (verbal tics) such as repeated eye blinking, facial twitching, head jerking, grunting, snorting, barking, sniffing, echolalia, palilalia, coprolalia, etc.

11. Tourette’s Syndrome (cont.) • Motor Spectrum – Tics • Behavior Spectrum • Obsessive Compulsive Disorder • Attention Deficit Hyperactivity Disorder • Other behaviors such as aggressiveness, immaturity, anxiety and depression

12. Tics • Repetitive, irregular stereotypic movements or vocalizations that can be mimicked by the observer and often can be willfully held in check by the patient, usually at the expense of mounting inner tension which is then relieved when the tic is expressed • Resemble myoclonis when they are rapid and shocklike but can also be prolonged or complex motor acts

13. Tourette’s Syndrome (cont.) • Treatment • Tics: Orap, antipsychotics, Effexor, clonidine, Klonopin, Haldol • OCD: Klonopin, SSRI’s • ADHD: Stimulants, clonidine • Behavior Modification • Therapy/Counseling

14. Restless Leg Syndrome • Characterized by sensory and motor abnormalities such as the desire to move the legs in association with unusual or uncomfortable sensations; motor restlessness; symptoms are worse at rest and occur most frequently in the evening or early part of night

15. Restless Leg Syndrome (cont.) • Treatment • None may be needed • Medications • Dopamine agonists: Requip, Mirapex, Permax • Levodopa

16. Huntington’s Disease • Hereditary progressive neurodegenerative disorder • Characterized by emotional, behavioral, and psychiatric abnormalities • Loss of previously acquired intellectual or cognitive functioning • Motor disturbances

17. Huntington’s Disease (cont.) • Treatment • Motor symptoms (chorea) • Dopamine depleters • Dopamine blocking agents • Prefer atypicals – risk of drug induced PD • Psychiatric symptoms • SSRI’s • Antipsychotics

18. Huntington’s Disease (cont.) • Treatment • Safety Considerations • PT • OT • Nutrition support- encourage high protein/high fat diet • Support system for caregivers

19. Tremor • An involuntary movement of a body part resulting from alternate contractions of opposing muscles.

20. Essential Tremor • Characterized by a rhythmic “back and forth” or “to and fro” movement produced by involuntary contractions of the muscle • ET may be asymmetric at onset and have a kinetic component (action-postural tremor of the hands, arms, and head)

21. Essential Tremor (cont.) • Supportive Criteria for Diagnosis • History and Physical/Neuro Exam • Tremor assessment • Improvement with use of alcohol • Family history – but not definite

22. Essential Tremor (cont.) • Goals for treatment • Reduce tremor severity • Improve ability to function • Decrease social handicap

23. Essential Tremor (cont.) • Treatment (depending on severity, there may be no treatment) • Medications: • propanolol (Inderal) • primadone (Mysoline) • trihexphenidyl (Artane) • clonazepam (Klonopin) • diazepam (Valium) • alprazolam (Ativan)

24. Essential Tremor (cont.) • Treatment (cont.) • Botox injections • Surgical Interventions • Thalamotomy • Deep Brain Stimulation (DBS)

25. Parkinson’s Disease • Progressive, chronic, neurodegenerative disease • Slow, selective loss of substantia nigra dopaminergic neurons • Clinical features due to severe loss of striatal dopamine

26. Epidemiology of Parkinson’s Disease • ~ 1 million patients diagnosed in US • Approximately 60,000 new cases/year • Average age of onset is 60 years • 5% to 10% of PD patients have symptoms before age 40 (“young-onset PD”) • Prevalence in population >80 years old is 10% Lang AE et al. N Engl J Med. 1998;339(15):1044, 1049-50. Olanow CW et al. Neurology. 2001;56(suppl 5):S1.

27. Parkinson’s Disease (cont.) • Age is single most consistent risk factor • Onset is insidious • Male predominance 3/2 • Affects all ethnic and socioeconomic groups • James Parkinson first described “shaking palsy” in 1817

28. Pathophysiology • PD occurs when neurons in the substantia nigra die or become impaired • Substantia nigra is located in the midbrain. Dopamine pathways are also connected to the frontal and limbic (emotional) regions of the brain

29. Pathophysiology (cont.) • Dopamine is the chemical messenger responsible for transmitting signals between the substantia nigra and the “relay station” of the brain, the corpus striatum, to produce smooth, purposeful muscle activity • Loss of dopamine in the striatum leaves the patient unable to direct or control their movements in a normal matter

30. Classification of PD • Primary, Degenerative form • Idiopathic Parkinsonism • Secondary • Toxins • Drugs • Trauma, Vascular, and Post-Encephalitic

31. Classification (cont.) • Parkinson-Plus Syndromes • Multi-system atrophy (MSA) • Progressive Supranuclear Palsy (PSP) • Cortical-basal Ganglionic Degeneration (CBGD) • Dementia Syndromes • Alzheimer’s with PD symptoms • Lewy Body Disease

32. Potential Causes of PD • Genes • -synuclein • Parkin • UCH-L1 • Susceptibility genes • Environment • Pesticides • Rural living • Other (?) • Pathogenic Mechanisms • Protein aggregation • Mitochondrial dysfunction • Oxidative stress • Inflammation • Excitotoxicity Apoptosis (cell death) UCH-L1 = ubiquitin hydrolase L1. McNaught K St P et al. Ann Neurol. 2003;53(suppl 3):S73-S86; Olanow CW, Tatton WG. Annu Rev Neurosci. 1999;22:123-124; Steece-Collier K et al. Proc Natl Acad SciUSA. 2002;99:13972-13974.

33. Characteristic Motor Symptoms • Tremor • Bradykinesia/akinesia • Rigidity • Postural instability

34. PD Symptoms • Micrographia • Masked Facies/Hypomimia • Hypophonia • Decreased Arm Swing • Shuffling Gait • Truncal Flexion • Fatigue

35. PD Symptoms(cont.) • Dysphagia • Sialorrhea • Decreased Gastric Emptying • Dry Eyes • Seborrhea

36. Non-Motor Symptoms in PD • Mental Changes • Dementia • Depression • Sleep Disturbance • Fragmented Sleep • REM behavioral sleep disorder

37. Non-Motor Symptoms in PD • Dysautonomia • Constipation • Sexual dysfunction • Bladder dysfunction • Sweating • Orthostasis • Pain • Untreated patients • Shoulder and back pain • Treated patients • Off dystonia (foot pain)

38. Diagnosing PD • Requires at least 2 of the 4 cardinal features, without other neurologic deficits and a clear-cut response to L-dopa therapy • Almost all patients with idiopathic PD will improve with L-dopa therapy • Parkinson-Plus syndromes will not improve as dramatically

39. Diagnosing PD (cont.) • No abnormalities of routine x-rays, labs, EEG, or EKG • CT/MRI • PET scan • SPECT scan

40. Treating PD • When considering treatment, ask the patient….. • What symptoms bother you most? • How much do these symptoms interfere with daily function and lifestyle?

41. Management of PD Disease Progression

42. Medication Management • Mainstay of therapy is dopaminergic medication • Dopamine replacement • Activate dopamine receptors • Stimulation of dopamine release • Inhibit dopamine uptake

43. Medication Management (cont.) Anticholinergic Medications (Reduce relative excess acetylcholine) Trihexiphenidyl (Artane®) Benztropine (Cogentin ®) MAO Inhibitor, Other Selegiline (Eldepryl ®) Amantadine (Symmetrel®) Zydis Selegiline (Zelapar®) Rasagiline (Azilect®) Levodopa (L-dopa) ( Dopamine) Give with carbidopa (reduces nausea) Carbidopa/Levodopa (Sinemet ®) Dopamine Agonists (Mimic dopamine) Pergolide (Permax®) Pramipexole (Mirapex ®) Ropinerole (Requip®) Apomorphine (Apokyn ®) Rotigitine (Neupro patch ®) COMT-Inhibitors (Slow dopamine breakdown) Entacapone (Comtan®) Tolcapone (Tasmar ®)

44. Levodopa • Most effective drug for parkinsonian symptoms • First developed in the late 1960’s; rapidly became the drug of choice for PD • Large neutral amino acid; requires active transport across the gut-blood and blood-brain barriers • Side effects: nausea, postural hypotension, dyskinesias, motor fluctuations

45. Levodopa (cont.) • Motor fluctuations • Up to 50% of patients after 5 years of treatment • 70% of patients after 15 years of treatment • End-of-dose “wearing off” phenomenon • Unpredictable “on-off” fluctuations • Dyskinesias • Peak dose or diphasic • Neuropsychiatric disturbances • Hallucinations • Confusion Lang AE et al. N Engl J Med. 1998;339(16):1134-36.

46. Response to Levodopa and Progression of Parkinson’s Disease Moderate PD Advanced PD Early PD Dyskinesia Threshold Dyskinesia Threshold Dyskinesia Threshold Response Threshold Clinical Effect Clinical Effect Clinical Effect Clinical Effect Clinical Effect Response Threshold Response Threshold Levodopa 2 4 6 Levodopa Levodopa 2 4 6 2 4 6 Time (h) Time (h) Time (h) • Long duration motor response • Low incidence of dyskinesias • Shorter duration motor response • Increased incidence of dyskinesias • Short durationmotor response • “On” time consistently associated with dyskinesias Olanow CW, Agid Y. http://www.medscape.com/viewprogrm/1847-pnt.

47. Dopamine Agonists • Ergot-derived dopamine agonists-First generation: • pergolide (Permax ® ) • bromocriptine (Parlodel ® ) • Non–ergot-derived dopamine agonists-Second generation: • ropinirole HCl (Requip® ) • pramipexole (Mirapex ® ) • apokyn injection • rotigitine (Neupro patch ® ) Olanow CW et al. Neurology. 2001;56(suppl 5):S14.

48. MAO-B Inhibitors • Inhibit monoamine oxidase B enzyme, which breaks down dopamine following its action in synaptic cleft • Selegiline is an irreversible MAO-B inhibitor • DATATOP study • Provided slight symptomatic benefit • delayed the need to begin levodopa therapy by 9 months • Inconclusive evidence in humans that selegiline slows progression in PD Olanow CW et al. Neurology. 2001;56(suppl 5):S6-S7. Parkinson Study Group. Ann Neurol. 1996;39:37-38.

49. Rasagiline • An irreversible selective MAO-B inhibitor • Administered orally once per day • No amphetamine or amphetamine-like metabolites • FDA approved for the treatment of PD as both initial therapy and adjunctive therapy

50. Amantadine • Provides mild-to-moderate benefit • Neuropsychiatric adverse effects limit use in older patients or those with dementia • Other adverse events: • Anticholinergic – Livedo reticularis • Antidyskinetic effect: can reduce dyskinesia by about 45%, but benefit lasts less than 8 months Mendis T et al. Can J Neurol Sci. 1999;26:91. Lang AE et al. N Engl J Med. 1998;339(16):1134. Olanow CW et al. Neurology. 2001;56(suppl 5):S24-S25. Thomas, A et al. JNNP. 2004;75:141-143.