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Presentation on theme: "Disclosure You may only access and use this PowerPoint presentation for educational purposes. You may not post this presentation online or distribute it."— Presentation transcript:

1 Disclosure You may only access and use this PowerPoint presentation for educational purposes. You may not post this presentation online or distribute it without the permission of the author.

2 Movement Disorders D. A. Grimes, MD, FRCPC

3 Objectives Briefly discuss the basal ganglia connections and their relationship to motor pathways 4901 Compare and contrast clinical manifestations of hypokinetic and hyperkinetic movement disorders 4902 Describe the pathology and main neurotransmitter abnormality in Parkinson's disease 4903 Discuss the basic approaches to the treatment of Parkinson's disease 4904 Discuss other extrapyramidal diseases: essential tremor, tic disorders, Huntington’s disease, Wilson’s disease 4938 Recognize key movement disorder patterns: tic, chorea, athetosis, tremor, myoclonus, hemiballismus, dystonia, psychogenic Movement Disorders – Dr. Grimes

4 Terms basal ganglion: – caudate + putamen = striatum – globus pallidus = pallidum Interna Externa – subthalamic nucleus – substantia nigra “lentiform” nucleus – putamen and globus pallidus amygdala and claustrum

5 “Striatum”


7 Movement Disorders – Dr. Grimes

8 Caudate Putamen Globus pallidus Thalamus

9  Dopamine  Glutamate  GABA  Acetylcholine  Serotonin Neurotransmitters in the Basal Ganglia Movement Disorders – Dr. Grimes

10 Striatal Cell Types Medium spiny neurons – Express both D1 and D2 receptors – Massive arborization – Use GABA to transmit Giant aspiny – 1-3% – Cholinergic Medium aspiny – < 5% of striatal cells – GABA – Local inhibition?

11  It’s role is complex and has both excitatory and inhibitory components  Different sub receptors D1 (D1 and D3) and D2 (D2, D4, D5)  Very dense inputs into the striatum with upwards of 5,000 synapses per medium spiny neuron Dopamine Movement Disorders – Dr. Grimes

12  Cortex  excitatory  glutamate  Substantia nigra  inhibitory and excitatory  dopamine Main inputs into the Striatum Movement Disorders – Dr. Grimes

13 However are many more striatal neuron inputs

14 Flow of signals to control function Movement Disorders – Dr. Grimes Direct Indirect

15 Motor Cognitive Visual Affective striatum Globus Pallidus Thalamus striatum Thalamus striatum Thalamus Cortex Striatum BG Output Thalamus striatum Different loops for different functions Globus Pallidus Globus Pallidus Globus Pallidus

16 Movement Disorders – Dr. Grimes ]

17 cortex striatumGPe subthalamic nucleus Globus Pallidus interna thalamus SNc D2D1 Brake Foot on brake Go ahead

18 cortex striatumGPe subthalamic nucleus Gpi thalamus SNc D1D2 Basal ganglia model - dopamine deficiency More braking Pushing harder

19 “Focusing”

20 Does this explain Tremor? NO Theory: tremor is due to different oscillators – perhaps spinal or other mechanical mechanisms

21 Categorization of Movement Disorders Movement Disorders Pyramidal syndromes Basal ganglia disorders Spasticity HypokineticHyperkinetic slownessStiffness ChoreaDystoniaMyoclonusTicsTremor Cerebellar disorders Ataxia Stereotypy

22 Movement Disorders first classify “where” is lesion “what” is lesion

23 Phenomenology “Hypokinetic ” – akinetic rigid syndrome (parkinsonism) “Hyperkinetic” – tremor – chorea – athetosis – ballism – tics – dystonia – myoclonus – stereotypies

24 Tremor rhythmical oscillation of a body part from Latin tremere - "to tremble" types – rest – postural – kinetic intention

25 Essential Tremor 10X more common than Parkinson’s disease kinetic/postural vs rest tremor Bilateral (but often asymmetric) head and voice tremor history of tremor over many years positive family history rigidity, gait disorder, bradykinesia, and postural instability are ABSENT

26 Diagnostic red flags for Essential Tremor



29 Chorea irregular, unpredictable, brief, jerky, continuous movements which move randomly from one part of the body to another “flitting” some - brisk and abrupt some - slow and flowing - “choreoathetosis”

30 Huntington’s disease Autosomal dominant disease Trinucleotide repeat disease Begins in ~ age 40 yrs old Main clinical features – Chorea – Postural instability – Dementia – Psychiatric

31 Ballism wide amplitude flinging movements usually proximal limbs often one side (hemiballism)

32 Dystonia – New definition is a movement disorder characterized by sustained or intermittent muscle contractions causing abnormal, often repetitive, movements, postures, or both. Dystonic movements are typically patterned, twisting, and may be tremulous. Dystonia is often initiated or worsened by voluntary action and associated with overflow muscle activation. “sensory tricks” focal, segmental, hemi or generalized

33 Tics usually abrupt, transient, stereotypic, coordinated movements irregular “inner urge” suppressible simple or complex

34 Suppressibility tics >>> chorea > dystonia > tremor

35 Myoclonus sudden, brief, shock-like positive or negative usually arrhythmic and irregular spontaneous or stimulus sensitive (light, visual threat, touch, muscle stretch, noise)

36 Stereotypy non–goal-directed movement pattern is repeated continuously for a period of time in the same form and on multiple occasions typically distractible. “concept of looping of an invariant movement pattern for a period of time”

37 Keys to Classifying Hyperkinetic Movements rhythmical vs. arrhythmical paroxysmal vs. continual vs continuous speed suppressibility

38 Wilson’s Disease Genetic disorder of copper metabolism Copper deposition in the brain, liver, cornea, and other organs Presentations – Neurologic (50%) – Psychiatric – Liver dysfunction

39 Neurological manifestations pediatric disease (ie < 20 yrs old majority) tremor: – most common presenting feature – proximal « wing beating » dysarthria dystonia rigidity can be any movement disorder!!!!

40 Ophthalmic manifestations - Kayser-Fleischer ring

41 Diagnosis Serum ceruloplasmin (low) 24 h urinary copper (high) Hepatic copper levels (elevated) MRI (increased signal on T2-weighted imaging in basal ganglia, brain stem and thalamus) Slit lamp examination for KF rings

42 Parkinson’s disease Tremor – rest Rigidity Akinesia Postural Instability

43 Other common signs Low voice (hypophonia) Small handwriting (micrographia) Decreased facial expression (masked facies) Loss of smell (anosmia) REM sleep behavior disorder “frozen shoulder” Parkinson ’ s Disease

44 Leg tremor = Parkinson’s

45 Chin tremor = Parkinson’s

46 Head tremor = NOT Parkinson’s = Essential tremor or Dystonic head tremor

47 Symptoms of PD Depression Psychiatric Disturbance Autonomic Disturbance Cognitive Impairment Sleep Disturbance Tremor - rest Rigidity Akinesia Postural Instability

48 Parkinson’s disease ~100,000 individuals in Canada with Parkinson’s M>F affected Age-specific: – 1-3% of population age > 65 Clinical diagnostic accuracy – 65-90%

49 [Unit name – Lecture title – Prof name] Dopamine cells in substantia nigra Parkinson’s disease

50 Dauer/Przedorski Neuron Sept 2003

51 Lewy Bodies

52 Potential Cause of PD Deficient immunologic mechanisms Toxic exposure Genetic predisposition Aging Trauma Mitochondrial dysfunction Infections Gender

53 GENETIC PREDISPOSITION ENVIRONMENTAL TOXIN MITOCHONDRIAL FAILURE OXIDATIVE STRESS Excitotoxicity ( Ca 2+ ) Apoptosis Energy Crisis Protein Handling Dysfunction – Lewy body ? Neurotrophic Failure CELL DEATH INFLAMMATION

54 Parkinson’s disease Parkinsonism

55 Differential Diagnosis of a Parkinsonism Drugs – Always check carefully Progressive supranuclear palsy Multisystem atrophy - SND - OPCA - Shy-Drager syndrome - Motor neuron disease- parkinsonism Corticobasal degeneration syndrome Dementia syndromes - Alzheimer disease - Diffuse Lewy body disease Vascular

56 PD vs Normal Aging Parkinson’s disease often asymmetrical rest tremor Normal aging symmetrical rest tremor not a feature * caution - arthritis may mimic rigidity - paratonia may mimic rigidity

57 Canadian Guidelines on Parkinson’s Disease CJNS July 2012

58 Suspect Parkinson ’ s Rest tremor slowness/stiffness Gait disorders Early falls Poor response to levodopa Symmetry at onset Rapid progression Lack of tremor Prominent dysautonomia Referral to specialist Consider possibility of atypical parkinsonism No confirmatory tests available (Discuss option of brain donation) Predictors of more benign course Predictors of more rapid course Younger onset Rest tremor Older onset and rigidity/hypokinesia Postural instability/Freezing gait Dementia Associated comorbidities Male sex Poor levodopa response PROGNOSIS IDENTIFY DIAGNOSIS

59 Treatment options - Improving Symptoms anticholinergics (Artane, Cogentin) amantadine (Symmetrel) selegiline (Eldepryl, Deprenyl) rasagiline (Azilect) levodopa/carbidopa (Sinemet, Prolopa) dopamine agonists – bromocriptine (Parlodel) – not used – ropinirole (Requip) – pramipexole (Mirapex) – dopamine agonist patch, rotigotine(Neupro)

60 Levodopa Lewitt NEJM 2008

61 How do dopamine agonists work?

62 COMT and MAO-B Inhibitors Lewitt, NEJM 2008

63 Levodopa developed in the 1960’s still the “gold standard” for improving symptoms

64 How to use levodopa Three main formulations: – Levodopa-Carbidopa usually 100/25 – Sinemet CR – rarely used 100/25 or 200/50 – Prolopa - levodopa/benserazide -not used as much - Can't break - comes as 50/12.5,100/25, 200/50

65 How to start levocarb 100/25 tabs AMNOONSUPPER X3 – 7 days*1/2 X3 – 7 days1/2 X3 – 7 days11/2 X3 – 7 days111/2 X 1 month111 If you are concerned that may be a problem with tolerance (nausea, orthostatic hypotension or delirium) would titrate every 7 days Should be taken with food to minimize chance of nausea in early disease

66 What to expect Clinical effect - should be considerable – if no effect on BRADYKINESIA probably don't have PD Side effects: peripheral – nausea – orthostatic hypotension – Domperidone 10 mg – 1-2 tabs before (or with) levodopa central: somnolence, hallucinations, etc.

67 Symptoms less responsive to dopaminergic therapy Motor – postural instability, gait disorders, speech problems Mental changes – dementia, depression, anxiety, apathy Autonomic nervous system dysfunction – orthostatic hypotension, constipation, sexual dysfunction, urinary problems, sweating Sensory phenomenon – pain, dysesthesias Sleep disturbances – sleep fragmentation, sleep apnea, REM behavioral disorder

68 Treatment options - Slowing disease progression selegiline ? rasagiline? dopamine agonist? Coenzyme q10? Growth factors? NMDA antagonist? Nothing has been shown to clearly work

69 wearing off dyskinesias Symptom resistance psychiatric - hallucinations Problems with Levodopa

70 About 10 % of patients each year Stable Wearing Off Dyskinesias On-Off Fluctuations and Dyskinesias

71 Parkinson’s disease progression

72 My approach Give levodopa first if: – over 70 – prominent gait disturbance – severe trouble with ADL's, job, etc. Give other agent (usually dopamine agonist or rasagiline) first if: – under 60 – mild or tolerable symptoms In between (60-70, mild to mod sx) - ??? If start with other and not well, 'bail' out quickly!

73 Information on the web Parkinson Society Canada Parkinson Society Ottawa Movement Disorders Society National Parkinson Foundation, Inc. Parkinson's Disease Foundation Canadian Movement Disorders Group

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