Transcript Parkinson`s Disease Definition

Parkinson’s Disease
Definition
Most prevalent type of parkinsonian presentation
Clinical motor syndrome caused by lesions in the
basal ganglia, predominantly in the substantia
nigra
Appearance of clinical symptoms associated with
a reduction in the number of dopaminergic
neurons in the substantia nigra by 60-70%
Manifests as deficits in motor behavior,
Accompanied by a complex set of non-motor
symptoms
Prevalence Rate and Incidence
of PD
Incidence of PD by age and gender2
200
Incidence per 100,000
Male
160
120
80
Female
40
0
0-29
30-39
40-49
50-59
60-69
Age (years)
70-79
80+
Pathology in PD
Normal brain
PD brain
Pathophysiology of PD:
Degeneration of the Nigrostriatal
Pathway
Signs and Symptoms of PD
Motor signs and symptoms
Unilateral resting tremor
Rigidity
Bradykinesia
Later postural instability
Nonmotor signs and symptoms
Cognitive decline/dementia
REM Sleep behavioral disorder (RBD)
Sensory symptoms
Autonomic dysfunction
Mood disorders
Sleep disturbance
Parkinson’s disease or Idiopathic P. D.
Parkinsonism / Parkinsonian syndrome.
Drug induced Parkinsonism.
Post encephalitic parkinsonism.
Vascular pseudo Parkinsonism.
Lower body parkinsonism.
Terminology in P. D.
● Parkinson’s disease or Idiopathic P. D.
● Parkinsonism / Parkinsonian syndrome.
● Drug induced Parkinsonism.
● Post encephalitic parkinsonism.
● Vascular pseudo Parkinsonism.
● Lower body parkinsonism.
Terminology in P. D.
● Parkinsonism plus syndrome.
– PSP
– MSA
– CBD
Diagnostic Criteria and
Symptoms of PD
UK Parkinson’s Disease Society Brain Bank Clinical
Diagnostic Criteria
Step 1: Diagnosis of parkinsonian syndrome
Bradykinesia (slowness of initiation of voluntary movement with
progressive reduction in speed and amplitude of repetitive actions)
And at least one of the following:
Muscular rigidity
Resting tremor
Postural instability not caused by primary visual, vestibular,
cerebellar, or proprioceptive dysfunction
Step 2: Exclude other disorders
Diagnostic Criteria and
Symptoms of PD (cont’d)
UK Parkinson’s Disease Society Brain Bank Clinical Diagnostic Criteria
Step 3: Supportive Prospective Positive Criteria for PD (three
or more required for diagnosis of definite PD)
Unilateral onset
Rest tremor present
Progressive disorder
Persistent asymmetry mostly affecting side of onset
Excellent response (70–100%) to levodopa
Severe levodopa-induced chorea
Levodopa response for 5 years or more
Clinical course of 10 years or more
Hoehn and Yahr Stages of PD
Stage I: unilateral symptoms of disease
Stage II: bilateral symptoms of disease
Stage III: all of above, plus postural instability
Stage IV: all of above, plus patient need assistance
Stage V: patient cannot function independently
Prognosis
First 5 years are the “honeymoon period”, and
patients generally do well
Between 5 and 10 years, most patients experience
medication-related difficulty
By 10 years, many develop poor balance
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How to diagnose PD.
What is the D/D of PD
How to treat PD ( Medical treatment.)
When to refer pts to secondary care.
Tricks of the trade in managing special problems
related to PD.
● What services are available in our area for PD
patients.
● Nice guidelines on PD and results of our audit.
Brain Bank Criteria
● Step 1
● Diagnosis of parkinsonian syndrome
● Step2
● Exclusion criteria for IPD
● Step3
● Supportive criteria for IPD
4 stage clinical management scale
● Diagnosis
● Maintenance therapy
● Complex
● Palliative care
Step1- Diagnosis of parkinsonian
Syndrome.
● Bradykinesia +at least one of the following
● Muscular rigidity
● 4 –6 Hz resting tremor
● Postural instability
Brady / Hypokinesia
● Hypokinesia –poverty of movement
● Loss of facial expression, arm swing,
gesture etc.
● Bradykinesia -Slowness of movement
● ‘Decay’ – finger/ heel tap
Rigidity
● Resistance to passive movement
– Reinforcement – ‘froment’s manoeuvre’
● Constant [ c. f. ‘clasp-knife’]
– ‘Lead pipe’
– ‘cogwheel’
● Gagenhalten
Tremor
● Involuntary rhythmical alternating
movement
● Begins unilaterally – upper limb
● 4 – 6 hertz, ‘pill rolling’
● First symptom in 75%
● - 20 % never develop it
● Postural tremor can also occur
Postural instability.
● Last cardinal feature to appear
● Limited diagnostic specificity in the elderly.
● Pull test
● Early falls – ‘red flag’
Step 2 – exclusion criteria
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History of repeated strokes.
History of repeated head injury.
History of definite encephalitis.
Cerebellar signs.
Early severe autonomic involvement
Supranuclear gaze palsy
Neuroleptic drugs
Negative response to large doses of levodopa
Step3- positive supportive criteria
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[>3 for ‘definite’ PD ]
Unilateral onset.
Rest tremor
Progressive
Persistent asymmetry
Excellent levodopa response
Severe levodopa induced chorea
Levodopa response>=5years
Clinical course>=10 years
Is the diagnosis correct?
● Diagnosis of P. D. can be very difficult.
● There is no diagnostic test.
● Diagnosis is made clinically.
● DAT scan of limited value.
● Error rate is high. 25 % in the hands of
neurologist. Upto 50 % in the community.
● F.U. and review of diagnosis is important.
scanner
Dopamine Transporter Imaging agent
•Parkinson’s disease
•Progressive Supranuclear
Palsy
•Multiple System Atrophy
Abnormal
•Essential Tremor
•Neuroleptic-induced
Parkinsonism
•Vascular disease
Normal
Differential diagnosis of parkinsonian
syndrome
● Idiopathic Parkinson’s disease
● Drug induced – phenothiazines
● Multiple cerebral infarct state.
● Trauma – pugilistic encephalopathy
● Toxin induced- MPTP, CO, Mn, Cu,
● Parkinson’s plus syndromes
Essential tremor
● Most common diagnostic error.
● 10 times more common than PD.
● Postural or action tremor.
● Titubation.
● Family history.
● B – Blockers help.
Drug induced parkinsonism.
● Causes
– Predictable
Neuroleptic drugs (both typical and atypical)
Hidden neuroleptics- metoclopromide,
prochlorperazine
Combination with antidepressants( fluphenazine )
Calcium antagonist
--Idiosyncratic
Lithium, sodium valproate, amiodarone
mainly tremor but parkinsonism reported.
Medications**/chemicals—
neuroleptics (typicals more than the atypicals),
SSRI (selective serotonin reuptake inhibitors),
metoclopromide/maxeran,
Reserpine,
MPTP,
in Methcathinone (ephedrone) users – high
plasma Manganese levels (NEJM Mar 6, 2008)
CO, cyanide, organic solvents, carbon disulfide
Structural Causes—
Strokes
Tumors
Chronic subdurals
NPH (Normal Pressure Hydrocephalus)
Lewy Body spectrum of Diseases (DLB=Dementia
LB)-----early onset visual (or other) hallucinations
---fluctuating cognitive abilities
---sleep disorders
---neuroleptic sensitivity, even to atypicals
PSP (progressive supranuclear palsy)—or Steeles
Richardson Olszewski Syndrome
---gaze abnormalities
---postural instability, early unexplained falls
---bulbar features—dysphonia, dysarthria, dysphagia
---rapidly progressive---median 6 yrs
CBD (cortico basal degeneration)-----Asymmetric parkinsonism
---postural instability
---ideomotor apraxia
---aphasia
---alien limb phenomenon
---impaired cortical sensations
Multi System Atrophy-- (alpha-synuclein + glial cytoplasmic
inclusions, autonomic dysfunction, pyramidal signs)
Shy Drager Syndrome,
Olivopontocerebellar atrophy,
Striatonigral degeneration
Other Neurodegenerative Disorders—
Alzheimer’s Disease, later stages**
Huntington’s Disease (rigid form)
Frontotemporal Dementia with Parkinsonism, Chromosome-17 linked (FTDP-17)
Spinocerebellar ataxias
Infections--encephalitis
HIV/AIDS
Neurosyphilis
Toxoplasmosis
CJD (Creuzfeld Jakob)--prion disease
Progressive multifocal leukoencephalopathy
Essential Tremor-----action tremor (not rest tremor)
---more rapid (greater than 3-6 Hz)
---usually hands, but can also affect legs, head/chin, voice, trunk
---can present with falls if legs and trunk involved
Multiple infarct state
● Synonymous with leucoariosis,
Binswanger’s encephalopathy
● Related to hypertension and other risk
factors
● Common misdiagnosis.
● Poor prognosis
● Aspirin and dipyridamole retard may be
effective and safe
Vascular parkinsonism
● PM studies 2-3 %incidence of ‘pure’
vascular causes
-no lewy bodies or nigral degeneration
Acute or abrupt onset
basal ganglia infarct
Insidious progression
Diffuse sub cortical white matter ischaemia.
Metabolic causes-Hypothyroidism
Hypoparathyroidism
Alcohol withdrawl (pseudoparkinsonism)
Chronic liver failure
Wilson’s disease
Medical treatment of P. D.
Only 18 drugs for PD in BNF 2008
14 Dopaminergic
4 Anticholinergic.
Drugs to avoid 1
● Antiemetics
– Metoclopromide (Maxalon)
– Prochlorperazine (Stemetil)
● The only recommended antiemetics are
– Domperidone
– 5ht3 antagonists eg. Ondensetron.
Drugs to avoid 2
● Antipychotics
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Chlorpromazine
Sulpride
Haloperidol
Thioridazine.
● Newer antipsychotic can be used with
caution
When to start treatment ?
● Controversial
● Is the diagnosis certain.
● Age of patient.
● Effect on ADL.
● Patient Choice.
Drugs in PD
● Levodopa preparations.
● Dopamine receptor agonists.
● Monoamine oxidase-B inhibitors.
● Catechol-o-methyltransferase inhibitors.
● Anticholinergics.
● Amantadine
Levodopa
● Used since the 1960’s
● Remains the ‘gold standard’
● Always used with dopa decarboxylase
inhibitor.( either carbidopa or benserazide.)
● Side effects are common.
Levo dopa preparations.
● Madopar or co beneldopa—Levodopa with
benserazide
● Sinemet or co careldopa—Levodopa with
carbidopa
Levodopa formulations
● Effervescent or dispersible eg. Madopar
dispersible.
● Conventional release.eg. Madopar
● Controlled release.eg. Madopar CR or
Sinemet CR
● Duodopa– As a gel.
Levodopa preparations
● Dispersible preparations—Use for morning
kick start or for on off fluctuations. Also in
patients with swallowing difficulties.
● CR preparations– unpredictable absorption.
Use now mostly at night for nocturnal
symptoms like difficulty turning in bed or AM
dystonias
Side effects of levodopa
● Very common
● Nausea, vomiting
● Excessive drowsiness
● Insomnia
● End of dose fluctuations.
● Nocturnal immobility.
● Motor fluctuations and dyskinesias.
Dopamine agonists
● First available since 1970’s
● Six DA’s available for oral use.
● Apomorphine administered parenteraly
● Act directly on post synaptic receptors.
● Two types
– Ergot derived.
– Non ergot derived.
Rotigotine
● DA
● Mono therapy or adjunct.
● Patches.
Side effects of DA’s
● Similar to levodopa
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Nausea.
Vomiting.
Postural hypotension.
Confusion.
Hallucinations.
Somnolence.
Side effects of ERGOT DA’s
● Fibrotic reactions.
● Pulmonary, retroperitoneal and pericardial
fibrosis.
● Cardiac valvulopathy.
● In most cases non ergot DA’s preferred.
● CXR, PFT’s, ESR,and S. creatinine before
starting treatment.
Unusual side effects of DA’s
● Complex group of impulse control disorders
– Pathological gambling.
– Hypersexuality.
– Compulsive eating or shopping.
. Repetitive perseverative behavior.
-- Punding
--Excessive hobbyism.
Unusual side effects of DA’s 2
● ‘Dopamine dysregulation syndrome’
– Compulsive use of increasing doses of
levodopa
● ‘hedonistic homeostatic dysregulation
syndrome’.
● 14% prevalence of ICD.
● Eight fold increase in those taking DA’s
● Young pts. are particularly prone.
SOOS
● Excessive day time sleepiness and soos
can occur with levodopa preparations and
with DA’s
● Warn patients about driving.
Amantidine
● Antiviral properties.
● Weak DA
● Only for moderate to severe dyskinesia.
● Glutamate antagonist.
● 100 mg. BD or TDS
COMT inhibitors
● Entacapone
● Talcapone
● In combination with levo dopa
– ( STALEVO)
Stalevo
● Combination of Levodopa, carbidopa and
Entacapone.
● 50 mg./12.5 mg./200 mg.
● 100 mg./25mg./200mg.
● 150 mg./37.5mg./200 mg.
● 200 mg./50 mg./ 200 mg.
MAO -B inhibitors
● Selegiline
– 10 mg. Od or 5 mg. Bd
– 2.5 mg in elderly.
– Zelapar( oral lyophilisate ) 1.25 mg. Before
breakfast. Place on tongue and allow to
dissolve
– Neuroprotective??
● Rasagiline
– 1 mg.
Expensive.
Antimuscarinic drugs.
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Benzatropine, Procyclidine,Orphenadrine
Limited use.
Cognitive impairment in elderly.
Useful in drug induced Parkinsonism.
can be used for excessive salivation.
Apomorphine
● Potent dopamine agonist.
● Significant cost (10,000 £ PA for cont.
infusion.) offset by keeping pts. Out of NH’s
● Only parenteral use.
– Subcutaneous (rescue ) injections.
– SC continuous infusion.
DO NOT MISS P. D. MEDICATION
● Akinetic Rigid Syndrome.
● Malignant neuroleptic syndrome.
● ‘GET IT IN TIME’
DBS System
P. D. and Driving
● Booklet from PDS.
● Diagnosis of P. D. does not necessarily
disqualify people from driving
● Dopamine agonists– Drowsiness
– SOOS
Stages of P. D.
● Diagnostic phase
● Maintenance phase.
● Complex phase.
● Palliative phase.
Parkinson’s disease
“Essential Tremor”
Multiple System Atrophy (MSA)
Progressive Supranuclear Palsy (PSP)
Dementia with Lewy Bodies (DLB)
Cortical Basal Syndrome (CBS)
Unclear Diagnosis
IS ALL PARKINSON’S DISEASE THE
SAME?
Diagnosis agreed
Yet clinical course different
- some patients progress more rapidly
- some patients have very slow progression
- some patients respond very well to
medication
- some patients have severe side effects
What is the difference?
What can we except in the near
future?
● Neuroprotective agents. – Problems in trial
designs.
● Continuous dopaminergic stimulation.
Rotigotine patch,once daily formulations of
pramipexol and Ropinirole.
● Neurorestoration- Stem cell implants, Nerve
growth factors
Take home messages
● Diagnosis of PD is clinical and can be difficult.
● Every patient should be referred to secondary
care to confirm the diagnosis and initiate
treatment
● Treatment should only be started if there is
functional impairment
● Levodopa is the gold standard but DA cause
much less diskinesia
● Follow up should be life long