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Treatment of parkinson’s disease
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DIAGNOSIS & TREATMENT OF PARKINSON’S DISEASE
May 7, 2008Sadhana Prasad
Symposium on Changes and Challenges in Geriatric Care Brought to you by
Disclosures
• Work with various pharmaceutical companies intermittently
• Honorarium will be donated
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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
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Parkinson’s Disease
Characterized by: (Slow,Stiff,Shaky)
• Bradykinesia *
• Rigidity *
• Rest tremor--3-6Hz pill-rolling (absent 1/3)
• Postural instability
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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
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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
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Parkinson’s Syndromes
Metabolic causes--
• Hypothyroidism
• Hypoparathyroidism
• Alcohol withdrawl (pseudoparkinsonism)
• Chronic liver failure
• Wilson’s disease
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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
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P. Syndromes
Structural Causes—
• Strokes
• Tumors
• Chronic subdurals
• NPH (Normal Pressure Hydrocephalus)
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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
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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.
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P. Syndromes
CBD (cortico basal degeneration)---
---Asymmetric parkinsonism
---postural instability
---ideomotor apraxia
---aphasia
---alien limb phenomenon
---impaired cortical sensationsBrought to you by
P. Syndromes
Multi System Atrophy-- (alpha-synuclein + glial cytoplasmic inclusions, autonomic dysfunction, pyramidal signs)
• Shy Drager Syndrome,
• Olivopontocerebellar atrophy,
• Striatonigral degeneration
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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
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P. Syndromes
Infections---• encephalitis• HIV/AIDS• Neurosyphilis• Toxoplasmosis• CJD (Creuzfeld Jakob)--prion disease• Progressive multifocal
leukoencephalopathyBrought to you by
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
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P. Disease
??DIAGNOSIS??
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P. Dis -- Diagnosis
• A clinical diagnosis
• Cardinal features: Bradykinesia, rigidity
• Trial of sinemet (Levodopa/carbidopa)
• Confirmatory test: neuropathologic (autopsy)
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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
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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
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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)
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P. Disease-Diagnosis
Alternative Diagnosis cont’d…
• Cerebellar signs
• Positive Babinski
• Apraxia
• Gaze abnormailities
• Dementia concurrently with Parkinsonism
• StrokesBrought to you by
P. Disease
INVESTIGATIONS:
• TSH
• Calcium, albumin
• CT head
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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
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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)
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PD- case
Mr. AB--- stressed caregiver
• Slightly flexed posture
• Slightly bradykinetic
• Slightly diminished facial expression
• No difficulty turning, getting in/out of armless chair
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PD-case
“I don’t have Parkinson’s Disease!!”
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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
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IADLInstrumental Activities of Daily Living
• S shopping
• H housework
• A accounting
• F food preparation
• T transportation
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ADLActivities of Daily Living
• D dressing
• E eating
• A ambulation
• T toiletting
• H hygiene
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PD- case 1
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PD-case 1
clock
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PD –Case 1
Diagnosis:
Parkinson’s disease ---Hoehn & Yahr’s** stage 2
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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 aidedHoehn, MM, Yahr, MD. Parkinsonism: onset, progression and mortality. Neurology 1967;
17:427. Brought to you by
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 fallsBrought to you by
PD-case 1
clock
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PD—other issues
• Depression• Dementia• Driving• Falls• Neuropsychiatric features• “slowing down of thought processes” (the
clock in Mr AB)• Constipation
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PD-Treatment
????
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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
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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
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PD--Which pharmaceutical?
In Elderly--
• Levodopa/ carbidopa (sinemet) – regular vs CR (controlled release)
or
Levodopa/ benserazide (prolopa) – regular vs HBS
• COMT- inhibitor– entacapone (comtan)Brought to you by
PD- medications
LevodopaLevodopa• 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
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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
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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
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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
functionBrought to you by
PD- medications
L-dopa cont’d
• Discontinuation—
- gradually –over weeks,
- to prevent malignant neuroleptic like syndrome or akinetic crisis
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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 Brought to you by
PD- medications
COMT – inhibitorCOMT – 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
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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
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PD-medications
MAO-B inhibitors-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
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PD-medications
AnticholinergicsAnticholinergics—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
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PD-medications
Amantadine-adjunct to L-dopa, best avoided in elderly
-for dyskinesias
-Antiviral agent—mechanism unknown
-NMDA-receptor antagonist properties-interferes with excessive glutamate
-SE-livedo reticularis, ankle edema, hallucinations
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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”
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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
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