Transcript DIAGNOSIS & TREATMENT OF PARKINSON’S DISEASE

DIAGNOSIS & TREATMENT
OF PARKINSON’S DISEASE
May 7, 2008
Sadhana Prasad
Symposium on Changes and
Challenges in Geriatric Care
Disclosures
• Work with various pharmaceutical
companies intermittently
• Honorarium will be donated
OBJECTIVES
1. Illustrate medications and
conditions that may mimic PD
2. Describe the early symptoms of Parkinson’s
Disease (PD)
3. Discuss initiating and stopping medications
Parkinson’s Disease
Characterized by: (Slow,Stiff,Shaky)
• Bradykinesia *
• Rigidity *
• Rest tremor--3-6Hz pill-rolling (absent 1/3)
• Postural instability
Parkinson’s Disease (PD)
• First description 1817
Parkinson, James An Essay on the Shaking Palsy, Sherwood, Neely, and Jones,
London
• Progressive neurodegenerative disease
• Affects ages 40 onwards, mean age at
diagnosis 70.5
• Complex disorder with motor, non-motor,
neuropsychiatric features
Disease vs Syndrome
• Disease = a morbid process having
characteristic symptoms; pathology,
etiology, and prognosis may be known
• Syndrome = a set of symptoms occurring
together; different etiologies but similar
presentation
Parkinson’s Syndromes
Metabolic causes-• Hypothyroidism
• Hypoparathyroidism
• Alcohol withdrawl (pseudoparkinsonism)
• Chronic liver failure
• Wilson’s disease
P. Syndromes
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
P. Syndromes
Structural Causes—
• Strokes
• Tumors
• Chronic subdurals
• NPH (Normal Pressure Hydrocephalus)
P.Syndromes
Lewy Body spectrum of Diseases
(DLB=Dementia with LB)-----early onset visual (or other) hallucinations
---fluctuating cognitive abilities
---sleep disorders
---neuroleptic sensitivity, even to atypicals
P. Syndromes
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.
P. Syndromes
CBD (cortico basal degeneration)-----Asymmetric parkinsonism
---postural instability
---ideomotor apraxia
---aphasia
---alien limb phenomenon
---impaired cortical sensations
P. Syndromes
Multi System Atrophy-- (alpha-synuclein +
glial cytoplasmic inclusions, autonomic
dysfunction, pyramidal signs)
• Shy Drager Syndrome,
• Olivopontocerebellar atrophy,
• Striatonigral degeneration
P. Syndromes
Other Neurodegenerative Disorders—
• Alzheimer’s Disease, later stages**
• Huntington’s Disease (rigid form)
• Frontotemporal Dementia with
Parkinsonism, Chromosome-17 linked
(FTDP-17)
• Spinocerebellar ataxias
P. Syndromes
Infections--• encephalitis
• HIV/AIDS
• Neurosyphilis
• Toxoplasmosis
• CJD (Creuzfeld Jakob)--prion disease
• Progressive multifocal
leukoencephalopathy
P. Syndrome
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
P. Disease
??DIAGNOSIS??
P. Dis -- Diagnosis
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A clinical diagnosis
Cardinal features: Bradykinesia, rigidity
Trial of sinemet (Levodopa/carbidopa)
Confirmatory test: neuropathologic
(autopsy)
P. Disease-Diagnosis
• 1/3 will not respond to levodopa therapy
• 1/5 with P. Syndrome will respond to
levodopa
---Follow- up with time needed to clarify
diagnosis
P. Disease---Diagnosis
Minimum therapeutic dose:
---300mg levodopa per day in divided doses
---can be lower in biologically old old
---vast majority will need 400-600mg
levodopa daily to achieve significant
benefit
P. Disease- Diagnosis
Consider alternative diagnosis if:
• Early falls (postural instability)
• Poor response to levodopa
• Dysautonomia (urinary retention/atonic
bladder, incontinence, orthostatic
hypotension, impotence)
• No rest tremor (in 1/3)
P. Disease-Diagnosis
Alternative Diagnosis cont’d…
• Cerebellar signs
• Positive Babinski
• Apraxia
• Gaze abnormailities
• Dementia concurrently with Parkinsonism
• Strokes
P. Disease
INVESTIGATIONS:
• TSH
• Calcium, albumin
• CT head
OBJECTIVES
1. Illustrate medications and conditions that may
mimic PD
2. Describe the early
symptoms of Parkinson’s
Disease (PD)
3. Discuss initiating and stopping medications
PD- CASE
• Mr AB, married, active farmer, stressed
care-giver
• Drove his wife to the clinic, wife to see me
re agitated dementia
• One son also attended
• Mr AB –stressed care-giver, on paxil
(SSRI)
PD- case
Mr. AB--- stressed caregiver
• Slightly flexed posture
• Slightly bradykinetic
• Slightly diminished facial expression
• No difficulty turning, getting in/out of
armless chair
PD-case
“I don’t have Parkinson’s Disease!!”
PD- case
Mr. AB--• 1 month later, referred re ? PD??
• CT head, TSH, Ca normal
• Slowing down x 1 yr, hypophonia, denied
trouble turning in bed but took 5 tries in
clinic, trouble getting out of soft chair,
stopped taking baths x 3 years, mild rest
tremor R hand, trouble doing up buttons
and laces
IADL
Instrumental Activities of Daily Living
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S
H
A
F
T
shopping
housework
accounting
food preparation
transportation
ADL
Activities of Daily Living
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D
E
A
T
H
dressing
eating
ambulation
toiletting
hygiene
PD- case 1
PD-case 1
clock
PD –Case 1
Diagnosis:
Parkinson’s disease ---Hoehn & Yahr’s**
stage 2
Hoehn and Yahr scale
• 1. Unilateral involvement only, usually with minimal or
no functional disability
• 2. Bilateral or midline involvement without impairment of
balance
• 3. Bilateral disease; mild to moderate disability with
impaired postural reflexes; physically independent
• 4. Severely disabling disease; still able to walk or stand
unassisted
• 5. Confinement to bed or wheelchair unless aided
Hoehn, MM, Yahr, MD. Parkinsonism: onset, progression and mortality. Neurology 1967;
17:427.
PD- case 1
• MTO notified, “not to cancel license”
• Paxil *
• Sinemet regular 100/25 mg ½ tid, increase
by ½ weekly till 1 tid
• Calcium and vitamin D3
• 2 months later, smiling, clock better,
moving better, still flexed, no falls
PD-case 1
clock
PD—other issues
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Depression
Dementia
Driving
Falls
Neuropsychiatric features
“slowing down of thought processes” (the
clock in Mr AB)
• Constipation
PD-Treatment
????
OBJECTIVES
1. Illustrate medications and conditions that
may mimic PD
2. Describe the early symptoms of
Parkinson’s Disease (PD)
3. Discuss initiating and
stopping medications
PD--Treatment
• Geared towards mobility—levodopa, dopamine
agonists, MAO B inhibitors
• Rest tremor, cosmetic—anticholinergics (may
worsen cognition)
• Postural imbalance—no pharmacological
treatment; exercise, gait aids, prevent fractures
(Ca, Vit D3, +/- bisphosphonates)
• Dyskinesias-- ?amantadine (no clear evidence)
Almeida,QJ, Recent Patents on CNS Drug Discovery, 2008:3, 5--54
PD--Which pharmaceutical?
In Elderly-• Levodopa/ carbidopa (sinemet) – regular
vs CR (controlled release)
or
Levodopa/ benserazide (prolopa) – regular
vs HBS
• COMT- inhibitor– entacapone (comtan)
PD- medications
Levodopa
• Well-established, for bradykinesia and
rigidity
• SE: nausea, orthostatic hypotension
• Combined with peripheral decarboxylase
inhibitor (carbidopa, benserazide) to
prevent conversion to dopamine in the
periphery before it crosses blood brain
barrier
PD- medications
Levodopa (l-dopa)
-- l-dopa / carbidopa = sinemet reg. or CR
-- l-dopa / benserazide = prolopa, medopar or
medopar HBS
• Competes with amino acids from protein for GI
absorption
• Regular-- before meals, quick in quick out, T1/2
= 90 min
• CR--- With meals,Controlled Release, slow in
slow out, need 30% more to achieve same effect
as reg. dose, erratic absorption in elderly
PD-medications
L-dopa cont’d
• SE- Nausea (Rx Domperidone)
-Hallucinations (Rx lower dose, atypical
n
neuroleptics)
-somnolence, confusion, agitation
-motor fluctuations- after sev yrs of Rx
PD- medications
L-dopa cont’d
• Motor fluctuations (in 50%, after 5-10yrs)
-wearing-off– Rx COMT – inhibitor*, ?CR
-dyskinesias –(??Rx amantadine??)
-dystonias
-variety of complex fluctuations in motor
function
PD- medications
L-dopa cont’d
• Discontinuation—
- gradually –over weeks,
- to prevent malignant neuroleptic like
syndrome or akinetic crisis
PD-medications
L-dopa cont’d
• Dopaminergic dysregulation syndrome (DDS)—
tolerance to mood elevating effects
- Compulsive use of dopaminergic drugs
- Early onset males
- Cyclical mood disorder
- Impulse control disorder (hypersexuality,
pathologic gambling)
Giovannoni, G, Hedonistic homeostatic dysregulation…J. Neurol Neurosurg Psychiatry
2000; 68:243
PD- medications
COMT – inhibitor
-Catechol-O-Methyl Transferase Inhibitor
-((eg Tolcapone (Tasmar)---off market due to
fulminant hepatitis causing 3 deaths))
-eg Entacapone (Comtan)
-for wearing-off at end-of-dose of L-dopa
-dose 200mg-1600mg, divided, daily, with L-dopa
-SE-diarrhea in 5%, due to increased
dopaminergic stimulation from L-dopa
availability
PD-medications
Dopamine Agonists: adjunct Rx to L-dopa.
-Ergotamines—bromocriptine, ((pergolide)),
((cabergoline))
SE-same as L-dopa, uncommon Raynaud’s,
erythromelalgia, retroperitoneal/pulmonary
fibrosis
-Non-Ergot—pramipexole, ropinirole, ((transdermal
rotigotine))
SE—same as L-dopa, Sudden somnolence –
caution with driving
PD-medications
MAO-B inhibitors--adjunct Rx to L-dopa
-eg selegiline (eldepryl), rasagiline
-somewhat helpful in young, early in disease
-neuroprotective properties in animal models
only
Arch Neurology. 2002; 59:1937
PD-medications
Anticholinergics—adjunct Rx to L-dopa, best
avoided in elderly
-acetylcholine (ACh) and dopamine in balance in
basal ganglia
-decrease Ach to balance decrease in L-dopa
-eg trihexyphenidyl (artane), benztropine
(cogentin), orphenadrine, procyclidine
(kemadrin)
-SE-confusion, hallucinations, dry mouth, blurred
vision, constipation, nausea, u. retention,
glaucoma
PD-medications
Amantadine-adjunct to L-dopa, best
avoided in elderly
-for dyskinesias
-Antiviral agent—mechanism unknown
-NMDA-receptor antagonist propertiesinterferes with excessive glutamate
-SE-livedo reticularis, ankle edema,
hallucinations
PD- Medications
When do you stop the medications?
--ALWAYS taper gradually over days to
weeks to avoid NM-like syndrome
--unable to take meds (dysphagia)
--significant, intolerable SE impairing QOL
--end-stage--- “infection comes as a friend”
OBJECTIVES
1. Illustrate medications and conditions that
may mimic PD
2. Describe the early symptoms of
Parkinson’s Disease (PD)
3. Discuss initiating and stopping
medications