DIAGNOSIS & TREATMENT OF PARKINSON’S DISEASE

May 7, 2008Sadhana 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

• 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

IADLInstrumental Activities of Daily Living

• S shopping

• H housework

• A accounting

• F food preparation

• T transportation

ADLActivities of Daily Living

• D dressing

• E eating

• A ambulation

• T toiletting

• H 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 aidedHoehn, 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

• 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

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

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 – 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

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-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

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

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

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