treatment of parkinson’s disease

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

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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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