Optimizing the Treatment of Parkinson's Disease: Patient-specific - - PDF document

Optimizing the Treatment of Parkinson's Disease: Patient-specific Considerations 1

Optim izing the Treatm ent of Parkinson's Disease

Patient-specific Considerations

Pravin Khem ani, MD Associate Professor, Movement Disorders Department of Neurology and Neurotherapeutics University of Texas Southwestern Dallas, TX

Outline

• Epidemiology of Parkinson’s Disease (PD)
• Pathology
• Making the diagnosis of PD
• Clinical features of PD
• Motor features
• Non-motor features
• Pre-motor features
• Natural history of PD
• Treatment of PD
• Non-pharmacologic treatment
• Dopaminergic treatment
• Motor fluctuations
• Treatment of selected non-motor features
• f PD
• Indicators for the need to refer to a

specialist

• Surgical and niche treatments for PD

London, 1 8 1 7 Pathology

Braak’s Hypothesis

Spread of Synucleinopathy

Braak et al. Neurobiol Aging 2003;24:197-211.

Epidem iology of PD

Dorsey et al. Neurology 2007;68:384-386. Van Den Eeden et al. Am J Epidemiol 2003;157:1015-1022.

Direct and indirect costs associated with PD exceed $20 billion annually in United States

Optimizing the Treatment of Parkinson's Disease: Patient-specific Considerations 2

Making the Diagnosis of PD

• PD remains a clinical diagnosis based on recognition of the three cardinal

signs

• Rest tremor
• Bradykinesia
• Limb rigidity
• DaTscan is a diagnostic tool which can indicate if nigral dopaminergic

degeneration is present or not, but it is not specific for PD, and patients should receive a neurologic consultation before considering DaTscan

• DaTscan is generally recommended when suspicion exists for neuroleptic

induced or psychogenic parkinsonism or when an atypical tremor is present

DaTscan

Normal PD

Motor Features of PD

• 70% of patients
• “Pill-rolling” tremor in hands
• Can involve lips, chin, jaw, legs

Resting tremor1,2

• 80% to 90% of patients
• Most disabling symptom of PD

Bradykinesia1,3,4

• >90% of patients
• “Cogwheel” (fluctuating) or “lead pipe” (continuous)

Rigidity1,4

• Indicative of advanced-stage PD
• Frequent cause of falls

Postural instability1

• 1. Jankovic. J Neurol Neurosurg Psychiatry. 2008;79:368-376. 2. Bhidayasiri. Postgrad Med J. 2005;81:756-762.
• 3. Berardelli et al. Brain. 2001;124(pt 111):2131-2146. 4. Weintraub et al. Am J Manag Care. 2008;14(2 suppl):S40-S48.

Associated Motor Features

• Stooped posture
• Small handwriting
• Decreased arm swing
• Cramping
• Difficulty swallowing
• Changes in facial expression
• Shuffling

Non-m otor Features of PD

• Depression in up to 40% of patients
• Anxiety in ~30% of patients

Psychiatric disorders1

• Mild cognitive impairment
• Dementia in 15% to 40% of patients

Cognitive disorders1,2

• >70% of patients
• REM sleep behavior disorder

Sleep abnormalities1,3

• Constipation
• Orthostatic hypotension

Autonomic dysfunction1,3

• Olfactory dysfunction

Sensory3

• Fatigue and weight loss

Miscellaneous1,2

• 1. Thanvi et al. Postgrad Med J. 2003;79:561-565. 2. Fahn and Sulzer. NeuroRx. 2004;1:139-154.
• 3. Jankovic. J Neurol Neurosurg Psychiatry. 2008;79:368-376.

Pre-m otor Features

• Constipation, anosmia, REM sleep behavior disorder, depression
• Presence of alpha-synuclein in colonic mucosa is controversial

Shannon, KM et al. Mov Disord 2012;27:716-719. Antunes et al. Mov Disord 2016;31:1567-1570.

Control Control PD PD

Optimizing the Treatment of Parkinson's Disease: Patient-specific Considerations 3

Natural History of PD Progression of Motor Sym ptom s

5 4 3 2 1

Symptoms

• n one

side of the body only Bilateral symptoms; no balance impairment Impaired postural reflexes; physically independent Severe disability, yet still able to walk or stand unassisted Wheelchair bound or bedridden

Increasing disability; decreasing independence Hoehn and Yahr Staging

Treatm ent of PD Non-pharm acologic Treatm ent

• Education: it is essential that the patient understands the natural

history of the disease and treatment options

• Emotional and social support: depression and needs for care

must be addressed early on

• Exercise is critical and may slow the progression of the disease
• Tai Chi, boxing, cycling, aerobic exercise, resistance training are all

helpful

• In animal studies, the mechanism of exercise-induced benefit appears

to be the elaboration of brain growth hormones

• Nutrition: weight loss is common and should be addressed

Chaves da Silva et al. J Neurol Sci. 2016;363:5-15.

Non-dopam ineric Drug Treatm ent for PD

• Anticholinergics
• Benztropine and trihexyphenidyl are most commonly used
• Most effective in ameliorating rigidity and tremor; little or no effect on bradykinesia
• Serious side effects such as visual blurring, urinary hesitancy, and memory

impairment are common, especially in elderly patients

• Amantadine
• Exerts anticholinergic effects, NMDA antagonism, and inhibits dopamine reuptake
• Produces a mild to moderate antiparkinsonian effect
• Side effects include ankle edema and livido reticularis, and when combined with

levodopa, hallucinations are common

• The best-studied drug for inhibiting levodopa-induced dyskinesia

Dopam inergic Treatm ent of PD

• Direct or indirect stimulation of striatal dopamine receptors is the primary

pharmacologic treatment for PD

• Categories of dopaminergic treatment
• Levodopa
• Dopamine agonists
• Monoamine oxidase inhibitors
• C-O-Methyl transferase (COMT) inhibitors
• While very effective for the major motor features of PD, some clinical

symptoms do not respond well including balance impairment and non- motor PD features

Optimizing the Treatment of Parkinson's Disease: Patient-specific Considerations 4

Levodopa

• By far the most clinically effective drug for the symptoms of

Parkinson’s disease, introduced in 1975 as carbidopa/levodopa

• Helpful in alleviating all of the three cardinal symptoms

(tremor, rigidity, bradykinesia)

• When started early in the disease it can produce a

dramatic and smooth clinical response lasting years

• Uptake and conversion to dopamine allows storage and

release in a physiologic fashion

I m pact of Levodopa on Mortality

Hoehn MM. Adv Neurol. 1986;45:457-461.

Levodopa Dose Response

Fahn S et al. N Engl J Med. 2004;351:2498-2508.

Levodopa Adverse Effects

Fahn S et al. N Engl J Med. 2004;351:2498-2508.

Levodopa’s Lim itation is Short Half-life

• Short half-life of levodopa leads

to pulsatile stimulation of DA receptors which alters BG signaling resulting in dyskinesia

Levodopa Recom m endations

• As levodopa is the most effective drug for PD, it should be

used in almost all patients at some point in the disease

• Always use the lowest dose of levodopa that is sufficient to

control PD symptoms

• To minimize the risk of nausea, avoid 10/100 preparation;

generally one needs a 1:4 ratio of carbidopa to levodopa

• Always give levodopa a minimum of 3 times daily to reduce

plasma levodopa fluctuations

• Consider treatment with carbidopa/levodopa extended

release due to longer half-life

Optimizing the Treatment of Parkinson's Disease: Patient-specific Considerations 5

Dopam ine Agonists

• Symptomatic efficacy is moderate (second in power to

levodopa)

• Because of their long half-lives, these drugs produce more

physiologic receptor stimulation and have been shown to delay the onset of dyskinesia

• Slow upward dose titration is the key to achieving adequate

doses for full efficacy; side effects may prevent optimal dosing

• When used in addition to levodopa in fluctuators, they result in

a 2-3 hour reduction in off time per day

Available Dopam ine Agonists

Ropinirole Pramipexole Ropinirole XL Pramipexole ER Rotigotine Apomorphine Class Non-ergot Non-ergot Non-ergot Non-ergot Non-ergot Non-ergot Half-life 8-12 hours 6 hours 24 hours 24 hours Continuous 1 hour Delivery Oral Oral Oral Oral Patch Injection Dosing 0.25 - 8 mg TID 0.125 – 1.5 mg TID 2-24 mg

• nce daily

0.375 - 4.5 mg

• nce daily

2-8 mg daily 2-6 mg SC PRN

Agonist Side Effects

• Sedation
• Sleep attacks
• GI side effects (nausea and vomiting)
• Orthostatic hypotension
• Leg edema
• Compulsive behaviors (impulse control disorders)

I m pulse Control Disorders

17.1 6.4 3.5 4.4 7.2 5.6 6.9 2.3 1.6 1.7 2.9 1.7 5 10 15 20 Any ICD Problem/pathologic gambling Pathologic gambling

• nly

Compulsive sexual behavior Compulsive buying Binge-eating disorder Dopamine Agonist (n=2040) No Dopamine Agonist (n=1050)

Weintraub et al. Arch Neurol. 2010;67:589-595. ‡

ICD Type Current ICD, %

COMT I nhibitors

• By blocking peripheral degradation of levodopa, these drugs potentiate the effect of

levodopa and lengthen its half-life

• Entacapone and tolcapone are available, but tolcapone almost never used due to

idiosyncratic liver toxicity

MAO-B I nhibitors

• Work by blocking breakdown of dopamine inside the brain

thus enhancing the effect of both endogenous and exogenous dopamine

• Rasagiline, selegiline and safinamide currently available
• Rasagiline and selegiline produce symptomatic effects in

monotherapy and when used with levodopa

• Safinamide has anti-glutaminergic properties and reduces

dyskinesia in animal models, but this finding was not confirmed in humans

Shapira et al. JAMA Neurol. 2017;74:216-224.

Optimizing the Treatment of Parkinson's Disease: Patient-specific Considerations 6

Motor Fluctuations

• Almost universal in advanced Parkinson’s disease
• 40% of patients on levodopa for 4-6 years
• 70% of patients on levodopa for >9 years
• The chief cause of motor disability in this disorder
• Common manifestations: “wearing-off” effect, “skipped-

dose” or “no-on” effect, “on-off” phenomenon

• Related to variations in levodopa absorption,

distribution and metabolism

Ahlskog, Muenter. Mov Disord. 2001;16:448-458.

Motor Fluctuations I llustrated Managem ent of Motor Fluctuations

• The wearing-off effect is best managed by more frequent,

but not overlapping, levodopa dosing

• The “skipped-dose” effect is due to administration of

subthreshold amounts of levodopa; the size of the dose should be raised until 80% of doses actually kick in

• The “on-off” effect is caused by dietary protein or too

frequent administration of small levodopa doses

• Adjunctive drug therapy with MAO-B inhibitors, COMT

inhibitors, amantadine, or dopamine agonists may be helpful

Carbidopa/ Levodopa Extended Release

C/L extended-release product information

Healthy volunteers, C/L extended release, 2 caps of 245 mg

Managem ent of Non-m otor Features of PD Orthostatic Hypotension

• Orthostatism is common in PD due to degeneration of the

post-ganglionic autonomic nerves resulting in reduced release of norepinephrine

• Non-pharmacologic measures include liberalizing dietary

salt and sleeping with the head of the bed elevated

• Pharmacologic therapy consists of
• Fludrocortisone
• Midodrine (agonist of norepinephrine receptors)
• Droxidopa (pro-drug of norepinephrine)

Optimizing the Treatment of Parkinson's Disease: Patient-specific Considerations 7

Hallucinations and Delusions

• Positive psychotic features are common in advanced PD,

particularly when dementia is also present

• Typical neuroleptics and most “atypical” antipsychotics must be

avoided due to the risk of worsening PD motor symptoms

• Quetiapine and clozapine are atypical antipsychotics which at

usual doses do NOT worsen PD and which may be effective for psychosis

• Pimavanserin is a new antipsychotic specifically indicated for PD

psychosis with no anti-dopaminergic activity that works by reducing serotonergic tone

Pim avanserin

• A serotonin inverse agonist
• Dosed as 17 mg two tablets
• nce daily
• Full effect may take 6 weeks

to fully wash in

• Common side effects are

nausea and peripheral edema

Pim avanserin Efficacy

Pimavanserin product information

Placebo Pimavanserin

W hen to Refer to a Specialist

• Management of early PD is straightforward and consists of
• Recommendation for regular exercise
• Annual dermatologic examinations
• Treatment with levodopa/carbidopa, preferably long-acting forms given a

minimum of three times daily

• General neurology referral is appropriate early in the course of PD to

ensure dopaminergic drugs of differing classes have been considered

• As PD advances, motor complications and non-motor features develop

which may require movement disorders specialist involvement

• Consider referring patients to a movement disorder specialist for

clinical trial participation

Surgical and Niche Treatm ents

• f PD

Surgery for PD

• Originally developed in the 1960s, surgery is now offered to

patients with established levodopa-responsive PD for whom drug treatment is no longer adequate

• Most commonly employed technique is deep brain stimulation of

the subthalamic nucleus (STN) or globus pallidus (GPi)

• Most often, these procedures are performed bilaterally to achieve

best results

• Patients undergoing STN stimulation usually need to reduce oral

dopaminergic medication postoperatively, while GPi stimulation may not require drug dose reduction

Optimizing the Treatment of Parkinson's Disease: Patient-specific Considerations 8

Surgical Selection Criteria

• Advanced PD having failed reasonable medical management
• Persistent favorable response to levodopa (just marred by

dyskinesia or motor fluctuations)

• Good gait and balance in the on state
• Normal or essentially normal cognition (dementia is exclusionary)
• Depression (if any) is well controlled by medication
• Adequate support system and ongoing accessibility to a

specialized center for device programming

Motor Block Phenom ena

• Motor blocks are sudden, often unpredictable inhibitions of

voluntary movement

• Most commonly, these affect gait and result in sudden “freezing”
• Freezing is most frequent when the patient enters doorways or

enclosed spaces

• Can occur with peak, trough or mid-range brain levodopa levels
• Off-state freezing of gait (FOG) is most common and treatable by

reducing off states

• On-State FOG is highly resistant to drug treatment

Visual Cueing

• Several studies have pointed
• ut that a variety of visual

and auditory cues may help

• vercome FOG
• The mechanism of action of

these devices is unknown

Sum m ary

• Parkinson’s disease is a common neurodegenerative disease of the

elderly that will be increasingly common as the population ages

• The disease is complex because of its myriad clinical features which

include both motor and non-motor symptoms

• Dopaminergic treatment with levodopa is the mainstay of treatment
• f the motor aspects of the disease
• Practitioners should be alert to the worsening of symptoms that

result from disease progression which necessitates drug dosage adjustment

• Referral to a movement disorders neurology specialist is

recommended when complex features arise or to consider clinical trial participation