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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
Dopamine Glutamate GABA Acetylcholine Serotonin Neurotransmitters in the Basal Ganglia Movement Disorders – Dr. Grimes
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?
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
Cortex excitatory glutamate Substantia nigra inhibitory and excitatory dopamine Main inputs into the Striatum Movement Disorders – Dr. Grimes
Tremor rhythmical oscillation of a body part from Latin tremere - "to tremble" types – rest – postural – kinetic intention
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
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”
Huntington’s disease Autosomal dominant disease Trinucleotide repeat disease Begins in ~ age 40 yrs old Main clinical features – Chorea – Postural instability – Dementia – Psychiatric
Ballism wide amplitude flinging movements usually proximal limbs often one side (hemiballism)
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
Tics usually abrupt, transient, stereotypic, coordinated movements irregular “inner urge” suppressible simple or complex
Myoclonus sudden, brief, shock-like positive or negative usually arrhythmic and irregular spontaneous or stimulus sensitive (light, visual threat, touch, muscle stretch, noise)
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”
Keys to Classifying Hyperkinetic Movements rhythmical vs. arrhythmical paroxysmal vs. continual vs continuous speed suppressibility
Wilson’s Disease Genetic disorder of copper metabolism Copper deposition in the brain, liver, cornea, and other organs Presentations – Neurologic (50%) – Psychiatric – Liver dysfunction
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!!!!
Ophthalmic manifestations - Kayser-Fleischer ring
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
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
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
Canadian Guidelines on Parkinson’s Disease CJNS July 2012
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
Levodopa developed in the 1960’s still the “gold standard” for improving symptoms
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
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
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.
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
Treatment options - Slowing disease progression selegiline ? rasagiline? dopamine agonist? Coenzyme q10? Growth factors? NMDA antagonist? Nothing has been shown to clearly work
wearing off dyskinesias Symptom resistance psychiatric - hallucinations Problems with Levodopa
About 10 % of patients each year Stable Wearing Off Dyskinesias On-Off Fluctuations and Dyskinesias
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!
Information on the web Parkinson Society Canada www.parkinson.cawww.parkinson.ca Parkinson Society Ottawa www.parkinsons.cawww.parkinsons.ca Movement Disorders Society www.wemove.orgwww.wemove.org National Parkinson Foundation, Inc. www.parkinson.orgwww.parkinson.org Parkinson's Disease Foundation www.pdf.orgwww.pdf.org Canadian Movement Disorders Group www.cmdg.org