PARKINSON*S DISEASE

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Transcript PARKINSON*S DISEASE

PARKINSON’S DISEASE
Dr. M. Sofi MD; FRCP (London);
FRCPEdin; FRCSEdin
James Parkinson
Born
Died
Cause of death
Nationality
Ethnicity
Occupation
Known for
Spouse(s)
11 April 1755
Shoreditch, London, England
21 December 1824 (aged 69)
Langthorne, North Yorkshire,
England
Stroke
British
White British
Surgeon
First description of Parkinson's
disease
Mary Dale
James Parkinson
Four
generations of family were
surgeon-apothecaries in London
He was initially medical
apprentice with his father
Became medical student at
London Hospital (1776)
Awarded diploma of the company
of surgeons (1784)
Founding member MedicoChirurgical Society (1812)
Founding member of Huntarian
Society (1819)
Gold Medalist of Royal College of
Surgeons (1822)
Classification of Parkinson Syndromes
in a Community
Idiopathic PD ~ 85% of all PS cases
 Neuroleptic-induced parkinsonism (DIP) 7% - 9%
 MSA (SDS, SND, OPCD) ~ 2.5%
 PSP ~ 1.5%
 Vascular parkinson syndrome ~ 3%
 PS due to MPTP, CO, Mn, recurrent head trauma is
extremely rare
 No new cases of postencephalitic parkinsonism since
l960s

Descriptive Epidemiology of Parkinson
Syndrome
• Incidence
– 5-24/ 105 worldwide (USA: 20.5/105)
– Incidence of PS/PD rising slowly with aging
population
• Prevalence
– 57-371/105 worldwide (USA/Canada 300/105)
– 35%-42% of cases undiagnosed at any time
• Onset
– mean PS 61.6 years; PD 62.4 years
– rare before age 30; 4-10% cases before age 40
Pathology of Parkinson’s Disease
A
B
C
a)
b)
c)
d)
Normal substantia nigra
Severe depigmentation due to loss of nigral neurons in PD.
Loss of pigmented neurons in the PD brain
Lewy body
D
Main Biochemical Abnormality
• Marked striatal DA depletion
•
•
•
•
–“Striatal dopamine deficiency syndrome”
At death, DA loss > 90%
<50% DA loss is asymptomatic
~70% DA loss for symptom manifestations
Severity of DA loss best correlates with
bradykinesia in PD
Normal Basal Ganglia Functional
Anatomy
Normal
Cortex
Cingulate
Sensory
Motor
Prefrontal
Insular
+
GPe
D2
-
D1
+
Premotor
Prefrontal
+
+
Thalamus
VA/VL
+ = excitatory
SNc
STN
-
+
Striatum
Suppl. Motor
Premotor
+
+
+
+
SNr GPi
-
- = inhibitory
-
Brainstem
SC
Functional Anatomy of Parkinson’s Disease
Parkinson’s Disease
Cortex
Cingulate
Sensory
Motor
Prefrontal
Insular
+
GPe
+
Striatum
D2
-
D1
+
Premotor
Prefrontal
+
+
Thalamus
VA/VL
-+ = excitatory
SNc
STN
--
Suppl. Motor
Premotor
+
++
++
++
- = inhibitory
SNr GPi
-
--
Brainstem
SC
Parkinson’s Disease Risk Factors
• Definite: Old age
• Highly likely: MZ co-twin with early-onset
PD
• Probable: Positive family history
• Possible: Herbicides, pesticides, heavy
metals, proximity to industry, rural
residence, well water, repeated head
trauma, etc.
• Possible protective effect: Smoking
Cause of PD
• Unknown in most cases;
not accelerated aging
• Genes
– AD inheritance very
rare; mutation
unknown
– mutation of Alpha
synuclein gene
(chromosome 4q)
identified in one large
Italian (Contursi) and
5 Greek autosomal
dominant families
– mutation of parkin
gene in autosomalrecessive juvenile
parkinsonism
• Environment
– Majority of cases
believed caused by
environmental factor
(s) but none identified
so far
• Genes plus
environment?
Environmental Toxin Model: MPTP
• Reproduces all the major motor features of
PD
MAO-B
MPTP
MPP+
(In astrocytes)
• Dopaminergic neuron mitochondria
• Inhibits NADH--CoQ1 (Complex I) of
mitochondrial respiratory chain
• ATP production falls
• Cell death
Schematic representation
of the mechanisms
involved in toxicity of 1methyl-4-phenyl-1,2,3,6tetrahydropyridine
(MPTP). BBB, blood—
brain barrier;MPDP+, 1methyl-4-phenyl-2,3dihydropyridinium; MPTP
1-methyl-4-phenyl-1,2,3,6tetrahydropyridine; MPP+,
its four-electron oxidation
product 1-methyl-4phenylpyridinium; MAO,
monoamine oxidase.
Early Signs and Symptoms
• Cardinal
Characteristics
–Resting tremor
–Bradykinesia
–Rigidity
–Postural
instability
• Other
–Micrographia
–Masked face
–Slowing of ADLs
–Stooped,
shuffling gait
–Decreased arm
swing when
walking
Additional Signs and Symptoms
• Difficulty arising from a chair
• Difficulty turning in bed
• Hypophonic speech
• Sialorrhea
• Loss of the sense of smell
• Foot dystonia
Criteria for Diagnosis
• At least two of three: resting
tremor, bradykinesia, rigidity
• Absence of a secondary cause—
drugs, metabolic, etc.
• Definitive diagnosis can only be
made by autopsy
Clues Suggesting Atypical Parkinsonism
• Early onset of, or rapidly progressing,
dementia
• Rapidly progressive course
• Supranuclear gaze palsy
• Upper motor neuron signs
• Cerebellar signs—dysmetria, ataxia
• Urinary incontinence
• Early symptomatic postural
hypotension
Neurodegenerative disorders with
Parkinsonism (I)
• Progressive supranuclear palsy
– Supranuclear downgaze palsy, square
wave jerks
– Upright posture/frequent falls
– Pseudobulbar emotionality
– Furrowed brow/stare
• Corticobasal degeneration
– Unilateral, coarse tremor
– Limb apraxia/limb dystonia/alien limb
Neurodegenerative disorders
with Parkinsonism (II)
• Multiple system atrophy
–Shy-Drager syndrome
• Autonomic insufficiency—
orthostasis, impotence
–Striatonigral degeneration
• Tremor less prominent
–Olivopontocerebellar atrophy
• Cerebellar signs
Neurodegenerative Disorders
with Parkinsonism (III)
• Diffuse Lewy body disease
–Early onset of dementia
–Delusions and hallucinations
–Agitation
• Alzheimer’s disease
–Dementia is the primary clinical
syndrome
–Rest tremor is rare
Differential Diagnosis of PD:
Secondary Parkinsonism
•
•
•
•
Drug-induced
Toxin-induced
Metabolic
Structural lesions (vascular
parkinsonism, etc.)
• Normal pressure Hydrocephalus
• Infections
Toxin-induced Parkinsonism
• MPTP
• Carbon monoxide
• Manganese
• Cyanide
Vascular Parkinsonism
• Abrupt onset, usually unilateral
• Step-wise or no progression
• Other signs—hemiparesis,
aphasia, hyperreflexia
• Infarcts on neuroimaging helpful
in confirming diagnosis
Hydrocephalus-induced
Parkinsonism (NPH)
• Can be communicating or obstructive
• Normal pressure hydrocephalus—
idiopathic
• Clinical triad:
–parkinsonism/gait disorder
–urinary/fecal incontinence
–dementia
Treatment Options
• Preventive treatment
– No definitive treatment available
• Symptomatic treatment
– Pharmacological
– Surgical
• Non-motor management
• Restorative—experimental only
– Transplantation
– Neurotrophic factors
Drug Classes in PD
• Dopaminergic agents
–Levodopa
–Dopamine agonists
• COMT inhibitors
• MAO-B inhibitors
• Anticholinergics
• Amantadine
Sites of Action of PD Drugs
Substantia Nigra
selegiline
Amantadine*
levodopa
GABA
DA
BBB
carbidopa
benserazide
tolcapone
entacapone
Dopamine agonists
bromocriptine
pergolide
pramipexole
ropinirole
ACh
Striatum
baclofen
trihexiphenidyl
Anticholinergics
• Dopaminergic depletion cholinergic
overactivity
• Initially used in the 1950s
• Effective mainly for tremor and rigidity
• Common agents (Start low, go slow):
– Trihexyphenidyl: 2-15 mg/day
– Benztropine: 1-8 mg/day
• Side effects:
– Dry mouth, sedation, delirium, confusion,
hallucinations, constipation, urinary
retention
Levodopa
• Most effective drug for parkinsonian symptoms
• First developed in the late 1960s; rapidly became the
drug of choice for PD
• Large neutral amino acid; requires active transport
across the gut-blood and blood-brain barriers
• Rapid peripheral decarboxylation to dopamine
without a decarboxylase inhibitor (DCIs: carbidopa,
benserazide)
• Side effects: nausea, postural hypotension,
dyskinesias, motor fluctuations
Selegiline
• Irreversible MAO-B inhibitor
• Clinically active by inhibiting dopamine
metabolism in brain
• May be neuroprotective
• Dosage: 5 mg at breakfast and lunch
• Side effects: insomnia, hallucinations, nausea
(rarely), OH
• Potential interactions with tricyclic and SSRI
antidepressants
Levodopa/Carbidopa Formulations
Onset
Duration
Immediate Release
10/100, 25/100, 25/250
20-40 min
2-4 hr
Controlled Release
25/100, 50/200
30-60 min
3-6 hr
“Liquid levodopa”
(dissolved tablets)
10-20 min
0.5-1 hr
DAs: Common Adverse Effects
•
•
•
•
•
•
•
•
Nausea, vomiting
Dizziness, postural hypotension
Headache
Dizziness
Drowsiness & somnolence
Dyskinesias
Confusion, hallucinations, paranoia
Erythromelalgia; pulmonary & retroperitoneal
fibrosis; pleural effusion & pleural thickening;
Raynaud’s phenomena. May be more common with
ergotoline DAs
Levodopa-Induced Dyskinesias
• Manifestation of excessive dopaminergic
stimulation
• Typically late effect, and with higher doses
• Narrowing of therapeutic window
• Rare in LD-naive patients on DA monotherapy
• Most common is “peak dose” dyskinesia
– disappears with dose reduction
• Choreiform, ballistic and dystonic movements
• Most patients prefer some dyskinesias over the
alternative of akinesia and rigidity
COMT Inhibitors
• Newest class of antiparkinsonian drugs: tolcapone,
entacapone
• MOA similar to dopa decarboxylase inhibitors
• Potentiate LD: prevent peripheral degradation by
inhibiting catechol O-methyl transferase
• Reduces LD dose necessary for a given clinical effect
• Helpful for both early and fluctuating Parkinson’s
disease
• May be particularly useful for patients with “brittle”
PD, who fluctuate between off and on states frequently
throughout the day
Entacapone
• Dosage: 200 mg w/each levodopa
dose
• Parkinson’s Study Group 1997:
Increased on time by 5%, more in pts
w/least on time
• Rinne et al., 1998: Increased on time
by ~10%; decreased levodopa
• Diarrhea, dopaminergic SEs
Dopamine Receptor Subtypes
• D1, D2 subcortical
• D3, D4, D5 cortical
• Differentiated biochemically &
pharmacologically into two
families:
–D1 family: D1, D5
–D2 family: D2, D3, D4
DAs: Receptor Effects
D1
D2
D3
D4
D5
Ergot
Bromocriptine ++
++
+
+
Cabergoline
0
+++
?
?
?
Lisuride
+
++
?
?
?
Pergolide
+
+++
+++
+
+
++
++++
++
0
Non-Ergot
Pramipexole
0
Ropinirole
0
Neurology 1998; 50(suppl 3)
Off-period Dystonia
• Appears when LD level is low,
especially early AM
• w/ or w/o parkinsonism
• Dose adjustments, add-ons:
–more frequent LD dosing to avoid
low plasma levels
–add DA, COMT inhibitor, MAO-B
inhibitor
Apomorphine
• D1/D2 agonist
• Parenteral delivery (s/c., i/v., sublingual, intranasal,
rectal)
• Rapid “off” period rescue
– 2-5 mg s.c.; pen injection systems
• Treatment of unpredictable, frequent motor
fluctuations
– continuous s/c. infusion via mini-pump
• SE: nausea, vomiting, hypotension
– trimethobenzamide 250 mg TDS.
– domperidone 20 mg TDS; not available in U.S.
Managing Early Complications:
Altered Mental States
• Confusion, sedation, dizziness,
hallucinations, delusions
• Reduce or eliminate CNS-active drugs of
lesser priority
– anticholinergics
– sedatives
– amantadine
– muscle relaxants
– hypnotics
– urinary spasmodics
• Reduce dosage of DA, COMT inhibitor, or LD
Initial Therapy: What is the Chief Complaint?
Predominant Symptom
Clinical Options
No functional impairment
Delay therapy
Mild symptoms
Amantadine, selegiline
Discrete symptoms
Tremor—anticholinergic
Depression—
antidepressant
Anxiety—anxiolytic
Functionally disabling
symptoms
Levodopa, dopamine
agonist, COMT inhibitor
Managing Early Complications:
Wearing Off/Mild Dyskinesia
• For pts on DA monotherapy:
–elevate dosage of agonist
–add LD, w/ or w/o COMT inhibitor
• For pts on LD:
–add DA, COMT inhibitor, or MAO
inhibitor
–reduce LD dosage
–use combination of immediate and CR
Late Complications
• Motor
– response fluctuations, dyskinesias,
dystonia, freezing, falls
• Behavioral/neuropsychological
– depression, sleep disorders, psychosis
• Autonomic
– orthostatic hypotension; hyperhidrosis,
constipation, impotence, urinary
incontinence or retention
Peak Dose Dyskinesia or Dystonia
•
•
•
•
Chorea more common than dystonia
May be worse on more affected side
May not be as disabling as akinesia/rigidity
Dose adjustments, add-ons:
– reduce LD dose, increase dose frequency
– convert to LD-CR
– reduce LD, add DA, COMT inhibitor, or
MAO-B inhibitor
Wearing Off
• Regular and predictable decline in
response 2-4 hours after LD dose
• Most common motor fluctuation
• Dose adjustments, add-ons:
–change to LD-CR, or increase LD
frequency
–reduce LD, add DA or COMT
inhibitor
On-off Response
• Sudden and unpredictable off
periods unrelated to dosing
schedule
• One of the hardest features to
manage
• Dose adjustments, add-ons:
–reduce LD, add DA
Other Motor Complications
• Diphasic dyskinesia
– dyskinesia at beginning and end of dose
– Dose adjustments, add-ons: add DA
• Drug failure
– late afternoon, probably related to poor
gastric emptying or absorption
– liquid preparations; increase gastric
motility; decrease dietary protein
– apomorphine rescue
Freezing and Falls
• Freezing
–motoric block; at initiation of gait,
turning, narrow spaces
–use auditory, visual, proprioceptive
cues
• Falls
–physical therapy evaluation
–cane, scooter, wheelchair may be
necessary
Cognitive Assessment
• Memory difficulties: 11-29% of PD patients
– Benign forgetfulness
– Delirium
– Alzheimer’s disease
– Other dementias
• Evaluation
– Brain imaging
– Lumbar puncture
– EEG
– Blood work for thyroid profile, vitamin B12,
serology, chemistry panel
Orthostatic Hypotension
• Light-headedness, dizziness, fatigue,
shoulder or neck pain, blood pressure
drops when standing
• Taper anti-hypertensive agents
• Taper non-PD drugs
• Increase salt intake
• Compression stockings
• Fludrocortisone (0.1-0.4 mg/d)
• Midodrine (2.5 - 20 mg/d)
Surgical Treatments for Parkinson’s Disease
• Ablative
–thalamotomy
–pallidotomy
• Electrical stimulation
–VIM thalamus, globus pallidus
internus, sub-thalamic nucleus
• Transplant
–autologous adrenal, human fetal,
xenotransplants, genetically
engineered transplants
Improvements with Pallidotomy
• Specific Features:
–Dyskinesia
–Wearing off dystonia
–Tremor
–Rigidity
–Bradykinesia
–Gait
70-90 %
70-90 %
25-60 %
25-50 %
25-50 %
25-50 %
Deep Brain Stimulation (DBS)
• High frequency, pulsatile, bipolar
electrical stimulation
• Stereotactically placed into target
nucleus
• Can be activated and deactivated with an
external magnet
• Exact physiology unknown, but higher
frequencies mimic cellular ablation, not
stimulation
Cell Transplants
• Autologous adrenal transplants
–No efficacy
• Allogenic human fetal transplants
–Initial encouraging clinical results
• Xenogenic fetal transplant (porcine and
bovine)
–Preliminary results pending
• Genetically engineered cells
–Research ongoing
• Efficacy
– Encouraging
preliminary results in
young (<60) PD pts
– Patients greater than
50 years did not
improve
– PET studies
consistent with cell
functioning
– Autopsies (2) show
cell survival
• Problems
– 4-10 embryos < 10
weeks gestation
needed
– Immunosuppression
requirements
unknown
– Numerous technical
problems
– Potential for
dyskinesias, even
without any
PD medications