Management of Parkinson s Disease in Primary Care Dr June Tan National University Hospital System (NUHS) Division of Neurology Senior Consultant
Topics: Diagnosing PD Choice of medication in the de novo pt Treatment of motor fluctuation Non-motor complications
Approach to diagnosis of PD: Confirm the presence of parkinsonism Detect atypical features that suggest an alternative diagnosis to PD
Approach to diagnosis of PD: Confirm the presence of parkinsonism Detect atypical features that suggest an alternative diagnosis to PD
Parkinsonism Parkinsonism refers to the presence of rest tremors leadpipe rigidity bradykinesia These are the 3 cardinal features of PD
The motor features in early PD are often asymmetric at disease-onset respond well to levodopa Note: these features are not specific to PD if considered separately.
Approach to diagnosis of PD: Confirm the presence of parkinsonism Detect atypical features that suggest an alternative diagnosis to PD
Exclusion of alternative diagnoses Conditions which may mimic PD include: atypical parkinsonian syndromes (MSA, PSP, DLB, CBD, AD) drug-or toxin-induced parkinsonism cerebrovascular disease encephalitis hydrocephalus recurrent head trauma
Exclusion of alternative diagnoses Young-onset parkinsonism may be due to Huntington s disease Westphal variant Wilson s disease Dopa-responsive dystonia The tremors in PD may be misdiagnosed as Essential tremors Enhanced physiological tremors Dystonic tremors
Red Flags in PD Early frequent falls Early dementia Early hallucinations Early bulbar symptoms Early impaired EOM Early dysautonomia Early means within 1 year of onset Rapid deterioration Symmetrical motor signs Poor/no response to L-dopa Pyramidal signs Cerebellar dysfxn Apraxia, cortical signs
Investigations No gold standard investigation to diagnose PD Instead, clinical criteria are used to increase diagnostic accuracy In patients with typical features of PD in the correct age group, no further investigations are required for diagnosis. However, patients with young-onset parkinsonism, and patients with unusual or atypical features require further investigations to exclude alternative diagnoses.
Choice of medication in de novo patients
Which one is best for my patient?
In PD, decision on when to treat and what to use is highly individualized. Why? Choice of therapy depends on: Regional availability of drug Patient factors: e.g functional age, pre-morbid status, stage of disease, co-morbidities, expectations, financial means, etc Physician s familiarity with PD meds Understanding of disease progression & aim of treatment
Aim of treatment Cure? No evidence Slow disease progression? Putative evidence for ropinirole, pramipexole and rasagiline Symptomatic treatment? Yes, motor symptoms respond well in early stages. Improves quality of life
Aim of treatment Cure? No evidence Slow disease progression? Putative evidence for ropinirole, pramipexole and rasagiline Symptomatic treatment? Yes, motor symptoms respond well in early stages. Improves quality of life
MOTOR FLUCTUATIONS and how they influence our choice of medication
Levodopa s history, potency and eventual fall from grace Levodopa-induced motor fluctuations in PD Inevitable, occurs at rate of 10% per year of L-dopa treatment Causes significant deterioration in QOL L-dopa induced dyskinesia is the commonest cause of choreoathetosis seen in clinical practice
Early PD, no motor fluctuation Dyskinesia threshold time L-dopa
Dyskinesia threshold Early morning foot dystonia Wearing OFF nocturnal akinesia time
More robust and rapid but shorter ON, peak dose dyskinesia, deep OFF Dyskinesia threshold time
Dose failure Sudden OFF Dyskinesia threshold time
Peak-dose dyskinesia Dyskinesia threshold Biphasic dyskinesia time
Problems caused by dyskinesia Hypercatabolic state Axial imbalance Impaired limb function Impaired ability to fall asleep Social embarassment
Try and delay the onset of motor fluctuations for as long as possible
Natural course without medication Diagnosis preclinical motor symptoms + dementia + non-motor symptoms onset 6-7 3 6 2
Natural course without medication Diagnosis preclinical motor symptoms + dementia + non-motor symptoms onset 6-7 3 6 2
Natural course without medication Diagnosis preclinical motor symptoms + dementia + non-motor symptoms onset 6-7 3 6 2
Pulsatile dopaminergic stimulation Continuous dopaminergic stimulation (CDS) delays onset of motor fluctuation
Commonly available drugs for early PD L-dopa (Madopar, Sinemet) Dopamine agonists (eg Ropinirole, Pramipexole, Piribedil, Bromocriptine) MAOBI (eg Selegiline) Anticholinergics (eg Benzhexol) NMDA antagonists (eg Amantadine)
Dopamine agonists (eg Ropinirole, Pramipexole, Piribedil, Bromocriptine) Longer T1/2 Directly stimulates dopamine receptors, bypasses neuronal storage issues Gives a more stable drug level Delays onset of motor complications Ropinirole & pramipexole have putative neuroprotective effects
Dopamine agonists Limitations: Less potent than L-dopa General side effects: nausea, sleepiness, ankle edema, giddiness. Neuropsychiatirc manifestations: Confusion and psychosis - esp in elderly Impulse Control Disorders Punding Ergot-derived DAs (e.g. bromocriptine, carbegoline, lisuride, pergolide) may cause fibrosis Non-ergot DAs are relatively costly.
MAOBI (eg Selegiline, Rasagiline) Inhibits breakdown of L-dopa, so more can be used by the brain Used as monotherapy in mild cases or add-on in motor fluctuations Selegiline Mild motor benefit 5mg twice a day, last dose before 5pm Limitations: Drug interactions with TCAs, SSRIs, dextromethorphan serotonin reaction Similar to cheese reaction with tyramine-rich food (Bovril, aged cheese, alcohol) MAOBIs may worsen psychosis
Amantadine Anti-viral agent NMDA antagonist Use as single agent in mild cases or add-on to L-dopa Mild motor benefit Anti-dyskinetic properties but benefit often lasts < 1 year Limitations: Side effects psychiatric, skin rashes Cost issues Caution in renal disease
Anticholinergics (e.g benzhexol) Use as monotherapy in mild disease or add-on to L-dopa Mild motor benefit Not well tolerated by elderly pts Hallucinations, psychosis Dry mouth and eyes Constipation Contraindicated in patients with urinary retention, glaucoma
Pt s functional age Pt s expectations Pt s existing medical conditions Need to treat? Yes Not yet What to use? Regular review Stage of PD Pt s financial means Availability of drugs
General principles: Engage the patient in deciding which drugs to use and when to start Start low, go slow Single agent Monitor for side-effects Monitor for disease progression and need for dose adjustment
General principles: 2 ends of the spectrum: Mild motor symptoms in elderly frail patient with multiple medical conditions or dementia not to treat or start cautiously with L-dopa
General principles: 2 ends of the spectrum: Good physical and mental status (regardless of age) - delay use of L-dopa as long as possible start with DA or MAOBI, add on L-dopa only when needed - young patients can better tolerate benzhexol and amantadine
Management of motor fluctuations
Motor response WEARING OFF Time L-dopa/DDI WEARING OFF add DA or long-acting MAOBI L-dopa/DDI + DA or long-acting MAOBI
Motor response WEARING OFF add COMTI Time L-dopa/DDI + COMTI WEARING OFF last resort: use frequent L-dopa Frequent doses of L-dopa/DDI erratic response, may be better than nothing
Motor response Night-time OFF, early morning dystonia Time L-dopa/DDI Motor response L-dopa/DDI L-dopa/DDI + L-dopa HBS or COMTI Time Or L-dopa/DDI doses through the night - erratic
Motor response REFRACTORY OFF Time L-dopa/DDI s/c apomorphine or liquid L-dopa
Motor response Absorption failure Time L-dopa/DDI lunch dinner Motor response Adjust meal times, smaller protein portions Time lunch dinner
Motor response Peak-dose dyskinesia Time Motor response L-dopa/DDI Time L-dopa dose, + DA or COMTI or MAOBI
Motor response Biphasic dyskinesia Sleep Time L-dopa/DDI Motor response Sleep Time s/c apomorphine or liquid L-dopa L-dopa/DDI L-dopa/DDI L-dopa/DDI
NON-MOTOR SYMPTOMS
Non-motor manifestations of PD Autonomic, neuropsychiatric, olfactory and sensory Common and prominent in later stages of PD Relatively resistant to, and may be worsened by PD meds Cause significant disability Often neglected in PD management. Remember to screen your pts for non-motor symptoms
Natural course without medication Diagnosis preclinical motor symptoms + dementia + non-motor symptoms onset 6-7 3 6 2 Postural hypotension Dysphonia Dysphagia Constipation Urinary incontinence Pain syndromes Depression Hallucination Gait difficulties: Axial instability Freezing Start hesitancy Listing Shuffling Propulsion
Non-motor symptoms Some worsened by anti-pd meds May need to decrease or stop these meds at the expense of motor benefit Symptomatic meds can alleviate some non-motor problems But does not cure it and may add to side effects in elderly Physio, occupational, speech therapists play very important role at this stage Physical therapy is an effective and often safer choice compared to adding on more and more meds Decreasing anti-pd meds dose