First described in 1817 by Dr. James Parkinson as a “shaking palsy,” Lewy-body dementia is a chronic, progressive neurodegenerative disease characterized by both motor and non-motor features. The disease has a significant clinical burden through its progressive degenerative effects on mobility and muscle control. These motor symptoms are attributed in Parkinson Disease (PD) to loss of striatal dopaminergic neurons, although the presence of non-motor symptoms supports the pathophysiology of a neuronal loss in non-dopaminergic areas also. Parkinsonism is a symptom complex referring to the motor features of resting tremor, bradykinesia, and muscular rigidity. PD is therefore the most common cause of this syndrome of parkinsonism, although there are other, secondary causes; including drug-induced and rarer degenerative disorders that can mimic PD.
One of the most common neurologic disorders, affecting 1% of people over 60 years, Parkinson Disease causes progressive disability that can be slowed, but not halted, by treatment. The pathological hallmarks of PD are loss of dopaminergic neurons in the substantia nigra pars compacta (SNpc) and accumulation of misfolded alpha-synuclein in intra-cytoplasmic inclusions called Lewy bodies (LBs). But it is not clear how these cause neurodegeneration. At diagnosis, a substantial proportion of dopaminergic neurons in the SNpc has already been lost and neurodegeneration spread to other central nervous system (CNS) regions.
The majority of cases of PD probably are not associated with a specific genetic abnormality. Instead, it is likely that the risk of PD is, in part, determined by a combination of polygenic susceptibility factors. Environmental influences may also contribute to PD risk, although the relationship between the development of the disease and factors such as smoking, caffeine, and pesticide exposure, remain poorly understood.
Clinical Timeline of PD: shows typical symptoms and their development once some 70% of nigral cells have been lost. Disease progression parallels the progressive cell loss. Rate of progression and mix of symptoms vary greatly between patients.
Onset of motor signs include the following:
- Typically asymmetric
- The most common initial finding is a resting tremor in an upper extremity
- Over time, patients experience progressive bradykinesia, rigidity, and gait difficulty
- Axial posture becomes progressively flexed and stride shortens
- Postural instability (balance impairment) is a late phenomenon
Non-motor symptoms are common in early Parkinson disease. Recognition of the combination of non-motor and motor symptoms can promote early diagnosis and thus early intervention, often resulting in better quality of life.
| Non-motor Symptoms of Parkinson’s Disease |
| Autonomic Dysfunction a |
| • Constipation (parasympathetic nervous system cholinergic) • Orthostatic hypotension (sympathetic nervous system noradrenergic) • Sexual dysfunction (parasympathetic nervous system cholinergic) • Sweating (sympathetic nervous system cholinergic) • Urinary retention (parasympathetic nervous system cholinergic) |
| Neuropsychiatric Symptoms |
| • Anxiety • Cognitive impairment (mild) • Dementia • Depression (e.g., dysphoria, suicidal ideation, apathy) • Impulse-control disorders (e.g., preoccupations, hypersexuality, compulsive shopping, binge eating)b • Panic disorder • Psychosis (e.g., hallucinations, delusions) |
| Sensory Symptoms |
| • Olfactory dysfunction (hyposmia) • Paresthesias • Pain |
| Sleep Disturbance c |
| • Daytime somnolence • Insomnia • Rapid eye movement disorder • Restless legs syndrome • Sleep attacks • Sleep apnoea |
| Other |
| • Fatigue • Sialorrhea • Weight loss |
| a. Depends on components of nervous system that are affected. b. Usually associated with use of dopamine agonists. c. Complex aetiology; linked to neurodegenerative process, motor features, and drug therapy |
Alerts to a reduced quality of life and higher risk of developing cognitive decline in PD include the “DASH” symptoms of Depression, Anxiety, Sleep disturbance, Hallucinations and psychosis, all amenable to medical and non-medical therapy. While people with PD do lose their ability to derive pleasure from activities, they are generally less troubled by sadness, low mood, and guilt, than they are by a disturbance in concentration, and feelings of apathy and fatigue. Generalised anxiety is common, including symptoms of worry, nervousness, stress, tension, and often panic attack. Sleep disturbance is very common and variable in form, both night and daytime sleep disturbances reduce quality of life and are linked to higher rates of cognitive decline in PD. The common sleep disturbances in PD are:
- Insomnia
- Rapid-eye-movement-sleep behaviour disorder
- Excessive daytime sleepiness
Frequency of visual hallucinations and psychosis—commonly manifesting in paranoid behaviour or delusions—dramatically rises in advanced PD. Psychotic symptoms have an insidious onset over months and years, with the common progression of hallucinations and psychosis in PD following a sure sequence of: vivid dreams; misperceptions; benign hallucinations; and then paranoid psychosis. Memory is also affected, with impaired gist memory found in advanced-stage, but not in early stage, patients with PD.
Course of Parkinson Disease
Course of PD from prodromal phase to clinical phase, including levodopa-related complications. PIGD: postural-instability-gait-disorder; RBD: rapid-eye-movement sleep behaviour disorder.
No laboratory biomarkers exist for the condition, and findings on routine MR imaging (MRI) and CT scans are unremarkable. Parkinson disease is a clinical diagnosis, MRI used only to exclude other causes.
Such clinical diagnosis requires the presence of 2 of 3 cardinal signs:
- Resting tremor
- Rigidity
- Bradykinesia
Symptomatic Therapy
The decision to initiate symptomatic medical therapy in patients with PD is determined by the degree to which the patient is functionally impaired. The timing of this decision varies greatly among patients but is influenced by a number of factors:
- effect of disease on the dominant hand
- degree to which disease interferes with work, activities of daily living, social and leisure function
- presence of significant bradykinesia or gait disturbance
- patient values and preferences regarding use of medication
The major drugs available for the treatment of PD motor symptoms are:
- Levodopa
- Dopamine agonists
- Monoamine oxidase (MAO) B inhibitors
- Anticholinergic agents
- Amantadine
- Catechol-O-methyl transferase (COMT) inhibitors
Symptomatic drug therapy usually provides good control of motor signs of Parkinson disease for 4 to 6 years:
- Levodopa/carbidopa remains gold standard of symptomatic treatment
- Monoamine oxidase (MAO)–B inhibitors can be considered for initial treatment of early disease
- Other dopamine agonists e.g., ropinirole, pramipexole: consider as monotherapy in early disease or as adjunctive therapy in moderate to advanced disease
- Anticholinergic agents (e.g., trihexyphenidyl, benztropine) are second-line drugs for tremor only
Treatment for non-motor symptoms:
- Sildenafil citrate (Viagra) for erectile dysfunction
- Polyethylene glycol for constipation
- Modafinil for excessive daytime somnolence
- Methylphenidate for fatigue (caution: potential for abuse and addiction)
Deep brain stimulation
- Surgical procedure of choice for Parkinson Disease
- Does not involve destruction of brain tissue
- Reversible
- Can be adjusted as the disease progresses or adverse events occur
- Bilateral procedures can be performed without a significant increase in adverse events
Commonly used and recommended medications for the treatment of motor symptoms of Parkinson disease
| Mechanism of Action | Side Effects | Typical Dose | Level of Evidence | |
| Levodopa with carbidopa or benserazide* Sinemet, Levocarb, Prolopa | Metabolism to dopamine | Nausea, Vomiting, constipation, psychosis, hallucina1ions, hypotension, and dyskinesias | 300-1200 mg (higher if tolerated)/day (Divided tid, qid, q3h, q2h) | A |
| Dopamine Agonists – Ropinirole, Pramipexole, Rotigotine patch | Directly stimulate dopamine receptors | As above, plus leg edema. reward-seeking behaviour, daytime sleepiness and sudden- onset sleep. Skin reae1ions may occur with the rotigotine patch | Ropinirole: 3-24 mg/day (tid) Pramipexole: 1.5- 4.5 mg/ day (tid) Rotigotine: 4-8 mg/24h (patch) | A |
| Catechol-O-methyltransferase (COMT) inhibitors – Entacapone | Blocks peripheral COMT activity (reduce metabolism of levodopa) | Related to increase levodopa delivery: diarrhea, urine discoloration | 200 mg tab, up to 8 times/day (Given with each dose of levodopa) | A |
| Monoamine Oxidase (MAO) inhibitors – Selegiline, Rasagiline | Blocks MAO-B to reduce metabolism of dopamine (central and peripheral) | Nausea, hypotension, confusion, and hallucinations | Rasagiline: 0.5 to 1 mg/day (od) Selegiline: 5 to 10 mg/day (bid), early in the day | A |
| Amantadine | Blocks NMDA and acetylcholine receptors | Confusion, hallucinations, Leg edema, rash (livedo reticularis) | 100 mg od t0 100 mg tid | C |
| Anticholinergics e.g. Trihexyphenidyl | Blocks acetylcholine receptors | Dry eyes and mouth, urinary retention, confusion. worsening of glaucoma | Trihexiphenadyl: 1 to 6 mg/day (tid) | U |
Rizek P, Kumar N, Jog MS. An update on the diagnosis and treatment of Parkinson disease. CMAJ 2016. DOI:10.1503/cmaj.151179. Copyright © 2016 Joule Inc. or its licensors
A pragmatic “on/off” terminology arose to describe the relative proportion of the day in which patients show a good response to treatment; in particular to effects on overall functioning from motor symptoms:
• Off = Stiff, cannot move well
• On = Good mobility (near to normal) without involuntary movements
Swallowing restrictions
The leading cause of death in Parkinson Disease is aspiration pneumonia due to swallowing disorders. Elements of dysphagia occur early in PD and, because the disease is progressive, their nature and severity change over time. The patient living with PD should have speech pathologist assessment of their function of swallowing early and regularly.
Most patients with PD can go without anti-Parkinson medications for a brief period (< 24 hours) when oral intake is temporarily restricted (e.g., perioperative or periprocedural), or when seriously ill, while parkinsonian symptoms in patients who become critically ill are typically overshadowed by the burden of other medical problems, and anti-Parkinson medications may not provide any clear benefit. However, sudden withdrawal or dose reduction of anti-Parkinson medications can rarely precipitate a parkinsonism-hyperpyrexia syndrome.
Metabolic pathway of dopamine synthesis and clearance. Dopamine is synthesized from phenylalanine or tyrosine via sequential reactions catalyzed mainly by phenylalanine hydroxylase (PH), tyrosine hydroxylase (TH), and DOPA decarboxylase. It can also be synthesized from tyramine in a minor pathway by CYP2D6. Dopamine is effectively degraded into the main inactive metabolites 3,4-dihydroxyphenylacetic acid (DOPAC) and homovanillic acid (HVA) via a series of reactions mediated predominantly by monoamine oxidase (MAO), catechol-O-methyl transferase (COMT), aldehyde dehydrogenase (ALDH), and alcohol dehydrogenase (ADH).
Either levodopa or a dopamine agonist can be used initially for PD patients who require symptomatic therapy. Commonly therapy is initiated with a dopamine agonist in younger patients and with levodopa in older patients (> 65 years). However, there are exceptions to these general rules. Levodopa is the drug of choice for symptoms, particularly those related to bradykinesia that seriously impede patient lifestyle. While individualising therapy for PD patients is crucial, always aim for the lowest effective dose of dopaminergics, singly or in combination.
Levodopa
Levodopa (L-dopa) is the most effective drug for the symptomatic treatment of idiopathic or Lewy body PD. It is particularly effective for the management of bradykinetic symptoms and should be introduced when these become intrusive or troublesome or uncontrolled by other drugs. Tremor and rigidity also respond to levodopa therapy, but postural instability is less likely to do so. Levodopa is combined with a peripheral decarboxylase inhibitor (either carbidopa or benserazide) to block its conversion to dopamine in the systemic circulation and liver (before it crosses the blood-brain barrier) in order to reduce nausea, vomiting, and orthostatic hypotension. An immediate-release oral dissolution formulation of carbidopa-levodopa (Parcopa) is available and can be taken without water for convenience although the pharmacokinetics are little changed.
| Levodopa/carbidopa (Sinemet™) | |
| Sinemet™ M | Levodopa 100 mg/carbidopa 10 mg |
| Sinemet™ t 100/25 | Levodopa 100 mg/carbidopa 25 mg |
| Sinemet™ | Levodopa 250 mg/carbidopa 25 mg |
| Sinemet™ CR# | Levodopa 200 mg/carbidopa 50 mg controlled release |
| Levodopa/benserazide (Madopar™) | |
| Madopar™ Q | Levodopa 50mg/benserazide 12.5 mg |
| Madopar™ M | Levodopa 100mg/benserazide 25 mg |
| Madopar™ | Levodopa 200mg/benserazide 50 mg |
| Madopar™ HBS# | Levodopa 100 mg/benserazide 25 mg controlled release |
| Levodopa/carbidopa/entacapone (Stalevo™) | |
| Stalevo 50™ 75 mg | Levodopa 50 mg + carbidopa 12.5 mg + entacapone 200 mg |
| Stalevo 100™ 125 mg | Levodopa 100 mg + carbidopa 25 mg + entacapone 200 mg |
| Stalevo 150™ 200 mg | Levodopa 150 mg + carbidopa 37.5 mg + entacapone 200 mg |
| # Slow release levodopa |
Dopamine agonists
With the exception of pergolide and cabergoline, the synthetic dopamine agonists are a useful group of agents that directly stimulate dopamine receptors and used either as monotherapy in early PD or in combination with other antiparkinsonian drugs for treatment of more advanced disease. They are ineffective in patients who show no response to levodopa. They possibly delay the need to initiate levodopa therapy and the subsequent appearance of levodopa dyskinesia and motor fluctuations, but at the risk of slightly less efficacy and increased adverse effects. Dopamine agonists (DAs) currently approved by the United States Food and Drug Administration (USFDA) include bromocriptine, pramipexole, ropinirole, rotigotine, and injectable apomorphine. (Pergolide has been withdrawn because of an association with cardiac valvular abnormalities.) Apomorphine and lisuride (Europe) are additional DAs that can be administered parenterally for “rescue therapy” in patients experiencing sudden akinetic episodes. Injectable apomorphine has been approved by the USFDA for the motor fluctuations in PD. Apomorphine infusion pumps may also be useful. Unlike carbidopa-levodopa (Sinemet), these drugs are direct agonists that do not require metabolic conversion, do not compete with amino acids for transport across the gut or into the brain, and do not depend upon neuronal uptake and release. An additional advantage over immediate-release forms of levodopa is the longer duration of action of most of these agents. Dopamine agonist therapy is, however, associated with an increased risk of impulse control disorders including pathologic gambling, compulsive sexual behaviour, or compulsive buying.
Initiating Medication
Initiating levodopa
Start with 50 – 100 mg tds of levodopa, taken with meals to avoid nausea, and uptitrate at weekly intervals until functional improvement or symptom relief is achieved. Patients with mild or early PD may respond to single doses of the drug but a four or even five times a day dose regimen often proves necessary. It is the rare patient whose dose of levodopa will remain stable at length.
Maintenance levodopa
Follow patients regularly. Patients with more advanced disease and especially those with motor fluctuations can take their levodopa on an empty stomach with little risk of major nausea but with improved efficacy because of reduced competition from other amino acids for gastrointestinal absorption.
Clinical Course & Medication Requirements
Initially, the patient may do well on a daily dose of dopamine agonist. Eventually, the patient will require the introduction of levodopa in larger and more frequent doses to maintain motor function and treat other symptoms. The so-called honeymoon period ends when the motor fluctuations and dyskinesias of advanced PD start to impact on the patient’s life. The total daily dose may even need to be cut when dyskinesias cause disability, at the cost of increasing the chance of significant ‘off’ symptoms.
Typical changes in medication over the clinical course of the disease.
Strategies:
• GI absorption: take drugs away from food, treat constipation
• Avoid troughs: long acting DA agonist, COMT/MAO inhibitor, shorter LD dosing interval
• Avoid peaks: as above, plus smaller more frequent LD doses
Atypical Parkinsonism
A neurodegenerative disorder characterized by autonomic failure and parkinsonism and/or cerebellar signs is Multiple System Atrophy (MSA). Motor signs of MSA include an akinetic-rigid parkinsonism but, in contradistinction to that of PD, a symmetric distribution and minimal or no response to levodopa; pyramidal signs (extensor plantar responses and hyperreflexia), cerebellar signs (dysarthria, dysmetria, nystagmus, ataxia) and oculomotor dysfunction (impaired smooth pursuit movements, dysmetric saccades, suppression of the vestibuloocular reflex) can occur. Classic resting tremor is rare, patients can rather show a jerky poly-mini-myoclonus. Neck (antero- or latero-collis) or orofacial dystonia can occur, especially in response to levodopa administration. Dysautonomic features are common from early stages of the disease; they include urogenital, cardiovascular (orthostatic hypotension and its manifestations such as syncope and postural dizziness), respiratory (stridor, sleep-related breathing disorders, respiratory insufficiency) gastrointestinal, and sudomotor symptoms. Dementia can occur in later stages of the disease. Pathologically, MSA is a synucleinopathy; the neurodegeneration more often affects the striatonigral and/or olivopontocerebellar systems.
Different variants of a progressive supranuclear palsy (PSP) are recognized. The classic phenotype is Richardson (Steele-Richardson-Olszewski) syndrome. Richardson syndrome usually presents with axial akinetic-rigid parkinsonism and minimal or no response to levodopa, postural abnormalities of head and trunk hyperextension / retrocollis (cf. camptocormia in PD), broad-based gait abnormalities with freezing, postural instability and falls, all at initial stages of the disease. The typical sign of PSP is the supranuclear palsy of vertical gaze, absent in PD; while other oculomotor dysfunction includes slowing of vertical saccadic movements (downward movement especially), apraxia of eye opening that comes with a compensatory frontalis overactivity giving the typical “surprised” expression. Because it is a supranuclear gaze palsy, the vestibulo-ocular reflex is preserved in PSP. Other features of PSP include pseudobulbar palsy, subcortical-type dementia, frontal release signs and motor perseveration, absent in PD. Another characteristic feature of patients with PSP is “motor recklessness”, manifesting as a disinhibition to walking/standing/moving despite a lack of balance and frequent falls. Again, compare this to the festination and general praxis inhibition associated with PD. PSP is a tauopathy, associated with abnormal aggregates of tau protein, with the hallmark feature of “tufted astrocytes”; a neurodegeneration affecting subcortical structures like the SN, the subthalamic nucleus (STN), and the midbrain.
Key to diagnosing a progressive supranuclear palsy is identifying early gait instability and difficulty moving the eyes, speech and swallow abnormalities, while ruling out similar neurodegenerative disorders with specific treatments, like Wilson’s disease.
Signs to look for in PSP:
• hold head backwards (cf. PD)
• fall backwards (cf. PD)
• tremor rare
• do not generally respond to anti-Parkinsonian drugs
The most common motor features of Corticobasal Degeneration (CBD) are asymmetric rigidity and bradykinesia, usually affecting one limb; moreover, a dystonia and myoclonus (typically distal and stimulus-sensitive) can occur, differently from PD. Up to 50% of patients with CBD report an “alien-limb” phenomenon of semi-purposeful involuntary or impulsive movements, such as the assumption of postures, grabbing objects, or intercepting an unaffected limb. Tremor is only rarely seen in CBD and, where present, is an action or postural tremor (cf. resting tremor of PD). CBD is also characterized by the cortical features of dementia (frontal and parietal function) apraxia, and cortical sensory loss, which are usually absent in PD. That said, the presentation of CBD is variable and can overlap with other diseases, and its clinical diagnostic predictive accuracy is poor. Pathologically, tau proteins produce “astrocytic plaques,” and the neurodegeneration of CBD mainly affects the SN and frontoparietal cortex.
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