Transcript Parkinson’s Disease – Past & Present William R. Rossing MD Neurology Associates, P.C. March 7, 2014

Parkinson’s Disease –
Past & Present
William R. Rossing MD
Neurology Associates, P.C.
March 7, 2014
Goals
Understand what Parkinson’s disease is.
Recognize the clinical signs of Parkinson’s
Disease and it’s diagnosis.
Appreciate past and present views of PD
Review old & new treatment strategies.
Parkinson’s Disease
PD is a neurodegenerative disorder caused by a
loss of dopaminergic neurons in the Substantia
Nigra, as well as, other areas of the brain.
5-10% are misdiagnosed
20% diagnosed reveal alternative diagnosis at
autopsy (MSA, PSP, cerebral vascular disease)
PD is a progressive disorder that eventually
results in significant morbidity/disability.
Epidemiology
Prevalence
General population: 329/100,000
Subsets 50-59 y/o: 1/1000
80-89 y/o: 31/1000
Incidence 11/100,000/yr
Cumulative lifetime risk 2.7%
Average age onset 62.5
Men/women affected equally
Famous Names in Neuroscience &
Medicine
PD History
1817 - James Parkinson
Essay on the Shaking
Palsy:
Described Rest tremor,
Bradykinesia, Postural
instability
Contents of the Essay:
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Clinical description by casual observation of 3
and examination of 3 men in England.
“Involuntary tremulous motion, with lessened muscular power,
in parts not in action and even when supported; with a
propensity to bend the trunk forward, and to pass from a
walking to a running pace: the senses and intellects being
uninjured.”
Added sleep disturbance and impairment of
speech and bodily function.
Called for further research of the condition.
PD History
Late 1800’s –
Jean Martin Charcot:
Coined “Parkinson’s
Disease”
Added rigidity, dysautonomia,
micrographia and tremor w/
writing.
Initial descriptions of
Parkinsonism
Richer Statue
Charcot’s Parkinsonism:
Progressive Supranuclear Palsy
Cortical Basal Degeneration
Progressive Supranuclear
Palsy vs. Corticobasal
Degeneration Patient presented by
A. Dutil as an atypical case of
Parkinson’s.
Why?
Asymmetrical Hemiplegic Features.
Extended Posture.
Suspected Dx: CBGD
Present day Understanding
Dx = Two of four Cardinal Signs:
T remor (resting / assymetrical)
R igidity (Charcot)
A kinesia/Bradykinesia
P ostural instability
5th Cardinal Sign: Response to Dopamine
Early PD Signs/Symptoms
Anosmia
Constipation
Reduced facial expression/eye blink
Soft speech
Unilateral tremor w/ reduced arm swing
Micrographia (small handwriting)
Bradyphrenia (slow thinking…not dementia)
Stooped posture
Other Systems
Cognitive/memory issues
Psychiatric-neuropsychological
Autonomic dysfunction
Sensory
Sleep-either too much or not enough
PD Time Line
Clinical Course Predictors:
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Older age of onset (over 57-78) &
Akinetic/Rigid Type (Westfall variant) 
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More rapid rate of motor progression.
Possibly less robust response to medications.
Tremor predominant presentation 
Possible slower progression and longer response to
therapies.
PD Tremor
Etiology / Pathophysiology:
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Dr. Parkinson –
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Charcot –
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No defined anatomical lesion.
Cause – cold exposure, trauma, emotional stress
Nevrose – Neurologic condition w/o organic lesion.
Cause – Environmental stress, cold , emotional stess.
Couper (1837) – Manganese toxicity produced
tremor, bent posture and hypophonia.
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Edouard Brissaud –
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Greenfield/Bosanquet –
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Postulates Midbrain involvement.
Discover the Lewy Body (1912).
Discredits the idea of “Nevrose”.
1960’s Dopamine deficiency and theraputic
response to L Dopa reported. Revolutionized
threatment of PD at that time.
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Loss of Balance between Dopamine and
Acetylcholine determined.
Neuropathology
Neuroanatomy
Basal Ganglia
Neuroanatomy
PET / DAT IMAGING
Neuropathology
DOPA NEURON
DEPLETION
LEWY BODY
Neuropathology
Oxidative stress, free radicals
Iron, Calcium, possibly dopamine
Probably environmental + genetic predisposition
Loss of Dopamine producing brain cells (80%)
Rare inherited forms associated with Parkin gene
Alphasynuclein
Current Thoughts & Theories
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Alpha synuclien –
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Protein found throughout the nervous system.
Increased prevalence in PD patients.
Primary protein of the Lewy Body.
This protein is deposited in peripheral nerves
possibly suggesting causes for early PD symptoms
of anosmia and dysautonomia.
Possible future Biomarker for early PD.
Heiko Braak MD Theory
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Autopsied Brains of PD patients showed Alpha
synuclein in large amounts in Medulla and
Pons in addition to Substantia Nigra.
Protein also found in guts of PD patients.
Hypothesis of ascending spread of the protein
from lower to upper brain stem and then to
cortex.
May support why early GI and autonomic
symptoms occur.
Ascending Hypothesis
Neurodegenerative D Dx
Progressive Supranuclear Palsy (PSP)
- EOM disorder, early falls, axial rigidity
Multiple System Atrophy (MSA)
- Shy-drager, Striatoniagral Degeneration,
- Olivopontocerebellar atrophy
- Dysautonomia, Symmetric/axial rigidity
Cortical-Basal Ganglionic Degeneration (CBGD)
- Apraxia (Alien Limb) ipsilateral to increased
tone
Other: Diffuse Lewy Body Disease, Spinocerebellar
Atrophy, Huntington’s (early onset), dystonias
Secondary Parkinsonism DDX
Drug induced - Neuroleptics/antiemetics
Vascular/multiple stroke
Normal pressure hydrocephalus (NPH)
Metabolic
Wilson’s disease, hypoparathyroidism,
hypothyroidism, hepatic failure
Pseudo/psychiatric - Depression
Infectious
Syphilis, Creutzfeld-Jacob Disease, Whipple’s
Traumatic – Pugilistic PD (Mohammed Ali)
Vascular PD
Dx Clinical Red Flags
Failure to respond to carbidopa/levodopa
Prominent or early:
Dementia
Dysautonomia
Falling
Bilaterally
Persistent unilaterality for more than 5 yrs
Prominent pyramidal or cerebellar signs
Severe vertical gaze palsy (especially downgaze)
Severe axial>appendicular rigidity
Roads To Early Treatments:
Mechanical Therapies:
Vibratory Helmet
Vibratory Chair
Early Therapies
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Charcot (Late 1800’s): Anticholinergics and
rye-based products. These may have related to
ergot based dopaminergic agonists.
Vib chair
Vibrating helmet
Early surgery
Charcot’s Presciption
Treatment
Art and Science
Tailor therapy to the patient’s need and desire
Incorporate pharmacotherapy, physical therapies
and safety / lifestyle recommendations
Surgical treatments gaining favor
Medicine
Motor - Targets
Goal
Restore Dopamine/Acetylcholine balance
Primary targets
Tremor, Bradykinesia, Rigidity
Secondary effects
Gait
Speech
Swallow
Restless Legs Syndrome
Pharmacotherapy Expectations
Parkinson’s subtypes
Tremor predominant - Best responder:
Akinetic/Gait dysfunction predominant Worst responder:
Theraputic window can reduce quickly over time if
autonomic involvement is prominent:
Treatment can exacerbate autonomic sx’s even at
low doses.
Pharmacotherapy
Most common
Carbidopa/Levodopa
Rasalagine
Selegaline
Entacapone
Carbidopa/levodopa/entacapone
Pramiprexole
Ropinirole
Rotigotine transdermal
PharmacotherapyOthers
Anticholinergics
Benztropine
Amantadine
Trihexphenidyl
COMT (catecholamine-O-methyltransferase)inhibitor
tolcapone - hepatitis, entacapone
Bromocriptine , pergolide
Selegeline - MAO inhibitor, ? Delayed disease
progression
Carbidopa/levodopa
50-75% will develop complications in 5-7 yrs
Dyskinesias
Motor fluctuations
Protein Sensitive
Start 2-3 x’s/day – Low dose Rx when able
One hour prior to or after meals
IR preferred:
CR preparation with only approx. 1 hr longer halflife and more erratic absorption
Carbidopa/levodopa side-effects
Motor fluctuations
Hypotension
Nausea
Hallucinations
Agonists
Dopamine “look-alikes” – Not Protein Bound
Pramipexole (Mirapex)
Ropinirol (Requip)
Rotigotine (Neupro) - Patch
Agonist side-effects
Cognitive-behavioral
Hallucination
Confusion
Agitation
Sleep attacks
Hypotension
Compulsive-addictive behavior history
Physical Therapy
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LSVT – Big/Loud Therapy
Yoga
Tai Chi
Walking / Wellness
Swimming / Water Therapies
Future Therapy
Attempt to mimic natural steady state
L Dopa pumps
Small intestine Dopa gel infusion
Inhaled or transdermal medication delivery
Stem cell / Tissue Transplants
Surgical Advances: DBS
Additional Considerations
Home Safety
Rugs, bathroom, swallowing
Drug Safety
Proper dosing, light-headedness
Sleep
Melatonin
Exercise
“Use it or lose it.”
DBS – “Cutting Edge PD
Management”
Henk Klopper MD
Avera Neurosurgery