MRCP PACES Parkinsonism and Parkinson’s Disease

Introduction

  • Parkinsonism is defined by the UK Brain Bank criteria as bradykinesia (progressive decrement in speed and amplitude of repetitive movements) with at least two of:
    • Rigidity: sustained increase in tone on passive movement of the arm. Not dependent on speed of passive movement (in contrast to increased tone in spasticity)
    • Resting tremor
    • Postural instability

Physical signs

  • Facial expression: hypomania or “mask-like” facies. Reduced blink rate, possible drooling
    • Glabellar tap (Myerson’s sign): failure to stop blinking when forehead is tapped
    • Blepharospasm: suggestive of progressive supranuclear palsy
    • Kayser-Fleischer rings: Wilson’s disease
  • Soft speech (hypophonia): typically low volume, monotonous; may be tremulous
  • Bradykinesia: the progressive decrement in speed and amplitude of repetitive movements
    • Decrease in both speed and amplitude when opening and closing hands repeatedly
    • Demonstrated in lower limbs by asking patient to tap feet on floor repetetively
    • Patients typically have difficulty with fastening buttons
  • Resting tremor: classical presentation of Parkinson’s disease
    • Asymmetrical “pill-rolling” (due to thumb involvement) tremor usually seen at rest.
      • Typically 4 – 6 Hz
      • Best seen with the arm rested on the lap in a semi-prone position
      • Enhanced by mental activity: ask patient to count backwards from 20
      • Disappears with activity
      • Re-emergent tremor: re-appearance of tremor after a change in position following a short latent period
    • Differentiate from essential tremor, which is characterized by:
      • Symmetrical tremor, usually involving hands, head and voice
      • When involving the head (titubation): usually yes-yes or no-no motion
      • Typically 8 – 10 Hz
      • Autosomal dominant, present from young age
      • Diminishes with mental activity
      • Enhanced by maintaining posture, voluntary movement, writing
      • Made better by alcohol, beta blockers, primidone
  • Rigidity
    • Lead-pipe rigidity: constant resistance to passive movement in absence of tremor
    • Cogwheel rigidity: rigidity when the wrists / ankles are circumducted, with step-wise “clicking”. Due to rigidity with superimposed tremor
  • Distribution of symptoms
    • Asymmetrical: Parkinson’s disease / vascular Parkinsonism
    • Symmetrical: usually suggests Parkinson’s plus syndromes
    • Predominantly lower limbs: vascular Parkinsonism
    • Predominantly axial: progressive supranuclear palsy
  • Gait: Parkinsonian gait is characteristic, with the following features
    • Narrow-based gait with stooped posture
    • Slowing of gait with asymmetrically-reduced arm swing
    • Decrease in step height and length
    • Start hesitation
    • Festination (increasingly rapid and small sequential steps)
    • Freezing (sudden episodes of inability to start or continue walking)
    • Turning in numbers of steps
    • Usually able to tandem gait
  • Balance: usually preserved in early PD
    • PD patients have a tendency to fall forwards (propulsion)
    • PSP patients tend to fall backwards (retropulsion)
    • Signs of previous serious injury (long bone fractures, head injury) from falls: PSP, due to motor recklessness and loss of protective impulses during fall)
    • Pull test: retropulsion on pulling backwards, loss of normal forward arm movement
  • Red flags
    • Ataxia: cerebellar ataxia with broad-based gait is suggestive of MSA
    • Wheelchair: rapid disease progression usually a feature of Parkinson’s plus syndromes. Very unusual to need wheelchair in first three years of disease with PD
    • Gaze palsies, especially vertical gaze palsies, are suggestive of PSP
      • Downgaze usually affected before upgaze
      • May require multiple blinks to facilitate downgaze
      • Round-the-house phenomenon: abnormal trajectory with deviation from the midline upon attempting to look upwards
      • Reduced velocity of vertical saccades usually precedes overt gaze palsy
      • Vertical vestibulo-ocular reflex is usually present in early disease and can overcome oculoparesis; may be lost as disease progresses
    • Inspiratory stridor, especially during sleep: MSA
    • Severe dysphagia / dysarthria not usually present in early PD
      • MSA, PSP or CBD, especially if percutaneous gastrostomy is required.
      • Pseudobulbar dysarthria: PSP
      • Ataxic / cerebellar dysarthria: MSA (high-pitched, quivery voice)
    • Autonomic instability: orthostatic hypotension, erectile dysfunction, urge incontinence tend to be more prominent features of MSA, especially early in disease course. Carotid sinus hypersensitivity causing syncope may be common in dementia with Lewy bodies
    • Myoclonus: typically not a feature of PD
      • Polyminimyoclonus with stimulus sensitivity may be seen in the outstretched hands of patients with multi-system atrophy
      • Myoclonus confined to one limb: corticobasal degeneration
      • Myoclonus exacerbated by voluntary movement or sensory stimulation: dementia with Lewy bodies
    • Dystonia is sometimes a feature of PD, but, when present, typically involves the foot
      • PSP: focal dystonia of neck (retrocollis) and eyelid (blepharospasm)
      • MSA: often fixed and painful mixed antecollis and laterocollis
      • When occurring in PD, usually a sign of neuroleptic therapy
    • Pyramidal involvement
      • Positive Babinski sign: vascular Parkinsonism, MSA
      • Hyperreflexia: vascular Parkinsonism, MSA
      • Striatal toe: not a positive Babinski sign; due to dystonia of the extensor hallicus longus muscle, common in PD. To distinguish from positive Babinski: sustained extension of big toe (immediate return with Babinski), other toes do not fan out as they do in Babinski
    • Cognition and psychiatric symptoms
      • PD patients classically have problems with executive function (planning and execution, reasoning, problem solving), psychomotor speed and memory
      • Profound early dementia: DLB, PSP, VP
      • Motor recklessness, aggressiveness and disinhibition: PSP
        • Clapping test: ask the patient to clap hands three times, quickly. PSP patients may clap more than three times (applause sign)
      • Hallucinations: DLB
    • Apraxia: an inability to perform a skilled or learned act which cannot be explained by a comprehension disorder or elementary deficits in sensorimotor function.
      • Ideomotor apraxia: an inability to carry out a task to command, with preserved ability to do it spontaneously (the patient knows what to do, but not how to do it). For example, inability to mime drinking a sip of water from a cup (may drink from a hand instead)
      • Ideational: an inability to synthesize components of a complex task (the patient does not know what to do). For example, a patient may be able to open a matchbox, take a match out, then strike it, but be unable to do it in one fluid motion
      • Limb kinetic: disturbance of fine finger movement coordination, with difficulty copying meaningless hand movements
      • Limb kinetic apraxia tends to occur early in CBD, and patients may complain of an alien limb. As the disease progresses, all types of apraxia may manifest
    • Dysphasia: non-fluent dysphasia (e.g. inability to quickly name as many animals as possible in 1 minute) points towards CBD or PSP

Further examination

  • Postural blood pressure (autonomic dysfunction)
  • Examine olfactory system (anosmia in Parkinson’s Disease)
  • Swallowing assessment (dysphagia in MSA, PSP, CBD)
  • Handwriting assessment (micrographia)
  • Mini mental state examination (cognition)
  • Look for seborrhoea and seborrheoic dermatitis
  • Family history (genetic Parkinsonian syndromes)
  • Drug history (drug-induced Parkinsonism)

Differential diagnosis

  • Parkinson’s disease
    • Progressive neurodegenerative disease caused by degeneration of dopaminergic neurons within the substantia nigra pars compacta (SNc) of the basal ganglia.
      • Dopaminergic SNc projections relieve tonic inhibition of basal ganglia output nuclei, the internal globus pallidus (GPi) and substantia nigra pars reticulate (SNr), on the thalamus, thus enhancing the corticostriatal pathway.
      • Pathologically: aggregates of α-synuclein and other proteins called Lewy bodies are seen in affected neurons
      • Symptoms usually occur when >50 – 60% of SNc neurons degenerate
    • Bradykinesia plus two or more of:
      • Resting tremor
      • Rigidity
      • Postural instability (usually late in disease)
    • Other manifestations: anosmia, cognitive impairment, mood disorders (depression, anxiety, apathy), excessive daytime somnolence, autonomic dysfunction
    • Staging: Hoehn and Yahr scale:
      • 1: unilateral disease with minimal or no functional disability
      • 2: bilateral / midline disease without impairment of balance
      • 3: bilateral disease with mild to moderate disability, postural instability, loss of postural reflexes. Physically independent
      • 4: severely disabling disease, but still able to walk and stand unassisted
      • 5: confined to wheelchair / bed unless aided
  • Progressive supranuclear palsy (Steele-Richardson-Olszewski syndrome)
    • Most common Parkinson’s plus syndrome
    • Progressive neurodegenerative disease
      • Pathological hallmark is tau protein filamentous inclusions (neurofibrillary tangles) in glia and neurons
      • Multiple neurotransmitter pathways (cholinergic, adrenergic, dopaminergic) pathways affected
    • Tends to present with frequent, early falls (predominantly backwards), due to a combination of motor recklessness and postural instability
    • Falls frequently result in severe injuries due to loss of protective reflexes
    • Early signs include slowing of vertical saccades
    • Vertical gaze palsy usually affects downward gaze before upward gaze
    • Vertical gaze palsy can be overcome by vertical vestibulo-ocular reflex
    • Tends to affect axial muscle groups, retrocollis may be a feature
    • Response to levodopa is generally poor
    • Progression is rapid, usually survival from onset is 5 – 7 years
  • Multiple system atrophy
    • Progressive loss of neuronal and oligodendral cells at numerous sites of CNS, including basal ganglia, pontine nuclei, cerebellum and intermediolateral cord tracts
    • Variable combination of Parkinsonism with autonomic, pyramidal or cerebellar symptoms / signs
    • Sub-types:
      • MSA-P: Parkinsonian features predominate (striatonigral degeneration)
      • MSA-C: Cerebellar features predominate (olivopontocerebellar atrophy)
      • Shy-Drager syndrome: predominantly autonomic dysfunction
    • Should be suspected in patients presenting with Parkinsonism with cerebellar or predominantly autonomic symptoms (may present with syncope, urge incontinence, postural hypotension). May have disproportionate mixed laterocollis / antecollis and cold, blue hands
    • Inspiratory stridor is associated with sudden death and must be specifically asked about. Management options include tracheostomy and nocturnal CPAP.
    • Dysphagia is often prominent; may require nasogastric / PEG feeding
  • Corticobasal degeneration
    • Characterized by frontoparietal cortical degeneration, in addition to degeneration of the extrapyramidal system
    • Typically presents with extremely asymmetrical symptoms of tremor, apraxia and rigidity in an upper limb. May cause an alien limb phenomenon – independent movement of a limb.
    • Characterized by progressive gait disturbance, cortical sensory loss and stimulus-sensitive myoclonus, which can result in a jerky, useless limb (usually the hand)
    • The gait is usually slightly wide-based and apraxic
    • No benefit from levodopa, relentlessly progressive
  • Dementia with Lewy bodies
    • Lewy bodies in widespread areas of neocortex and brainstem
    • Characterized by early-onset dementia with Parkinsonism
    • Hallucinations, especially visual, paranoid delusions and overt psychosis may occur
    • Marked worsening of symptoms if neuroleptics are given
  • Drug-induced Parkinsonism
    • May be indistinguishable from PD
    • Asymmetrical bradykinesia, rigidity, tremor and gait disturbance
    • Classically caused by neuroleptics: chlorpromazine, prochlorperazine, haloperidol
      • Other drugs: metoclopramide, lithium, valproate, cinnarizine
    • Onset is dose-related, typically manifest within three weeks
    • May take up to a year to resolve following drug withdrawal; occasionally permanent
  • Wilson’s disease
    • Autosomal recessive mutation in ATP7B gene on chromosome 13, leading to impaired cellular copper transport
    • Should be suspected in every case of young-onset Parkinsonism
    • Characteristic neurological manifestations of Wilson’s are Parkinsonism with ataxia
    • Tremor is classically coarse, and present during action
    • Also associated with liver disease: hepatitis, steatosis, hepatomegaly, acute liver failure, cirrhosis.
    • Psychiatric symptoms such as depression and irritability may be prominent
    • Diagnosis:
      • Slit lamp examination for Kayser-Fleischer rings
      • Low serum caeruloplasmin
      • Raised 24 hour urinary copper excretion
    • Treatment:
      • Copper removal: chelators such as D-penicilliamine, trientine
      • Prevention of re-accumulation: chelators, zinc salts, low-copper diet
  • Vascular Parkinsonism
    • Strokes in basal ganglia region
    • Usually cause abrupt onset in Parkinsonian symptoms, with step-wise deterioration
    • Classically involves the lower limbs more than the upper limbs
    • Poor response to levodopa
    • Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL), the most common heritable cause of stroke
  • Normal pressure hydrocephalus
    • Pathologically enlarged ventricles with normal opening pressure on LP, probably due to impaired absorption of CSF
    • Classic triad of:
      • Cognitive disturbance / dementia
      • Gait disturbance
      • Urinary incontinence
    • Treatment is with therapeutic LPs or placement on a ventriculoperitoneal shunt
  • Traumatic head injury (dementia pugilistica)
  • Space-occupying lesions (large frontal meningiomas, tumours of basal ganglia)
  • Toxins: manganese, MPTP (1-methyl-4-phenyl-1,2,3,6-tetrahydropridine), carbon monoxide, mercury, organophosphates, pesticides

Investigations

  • Parkinson’s disease is a clinical diagnosis
  • Structural brain imaging to rule out:
    • NPH
    • Strokes within basal ganglia
    • Space-occupying lesions
    • Parkinson’s plus syndromes may show the following features on imaging:
      • MSA: atrophy of cerebellum and brainstem
      • PSP: atrophy and hyperintensity of midbrain and red nucleus
      • CBD: frontoparietal atrophy
  • If young: slit lamp examination, serum caeruloplasmin and 24-hr urinary copper excretion to exclude Wilson’s disease

Management

  • Multidisciplinary team approach
  • Physical therapy, occupational therapy for preservation of function
  • Speech therapy for swallowing, gastroenterology if PEG required
  • Patient education and counselling
  • Psychiatrist if depression occurs
  • Medical therapy
    • Monoamine oxidase B (MAO-B) inhibitors (selegiline, rasagiline): may improve PD symptoms and delay need for levodopa by a few months. However, does not have a major benefit, and does not appear to delay progression of disease.
      • Side effects: unlike rasagiline, selegiline is metabolized to amphetamine, and as such is associated with cognitive side-effects.
      • Serotonin syndrome: fever, tachycardia, hypertension, myoclonus and agitation; may cause hypertensive crisis
    • Amantadine can increase dopamine synthesis, and has moderate anti-Parkinsonian effects. Can provoke changes in sleep-wake cycles, congestive heart failure and orthostatic hypotension.
      • Can be favored in young people if tremor and fatigue predominate
      • Most useful in reducing levodopa-induced dyskinesias
    • Anticholinergics (trihexyphenidyl, benztropine): theoretically act to modulate balance between striatal dopamine and anticholinergic activity. Mainly used as adjuncts to levodopa to control rest tremor. Adverse effects may outweigh risks, and they are generally avoided in PD.
      • Contraindicated in narrow-angle glaucoma, dementia
      • May impair cognitive function
      • Adverse effects: tachycardia, urinary retention, constipation, blurred vision
    • Dopamine agonists
      • Cross the blood-brain barrier and primarily act on D2 receptors
      • Ergot derivatives (cabergoline, bromocriptine) – not commonly used nowadays because of concerns of pleuro-pulmonary and retroperitoneal fibrosis, fibrotic valvular heart disease
      • Non-ergot derivatives (pramipexole, ropinirole, rotigotine)
      • Suitable for younger patients and those with mild-moderate disease
      • Adverse effects:
        • Fatigue (5 – 10%)
        • Nausea (15 – 20%) +/- constipation (5 – 10%)
        • Lower limb oedema (10 – 40%)
        • Impulse control disorders (5 – 10%) – gambling, sexual activity
        • Sleep attacks (sudden onset of sleep)
      • Motor fluctuations and dyskinesias decreased compared to levodopa
    • Levodopa
      • Augments striatal dopaminergic transmission by being converted directly into dopamine, resulting in marked clinical improvement
      • Given with peripheral L-aromatic amino acid decarboxylase (L-AAAD) inhibitors carbidopa (Sinemet®) or benserazide (Madopar®) to limit peripheral breakdown of levodopa and increase CNS bioavailability. Also limits peripheral side effects of nausea and orthostasis.
      • Adverse effects:
        • Drowsiness, hallucinations
        • Nausea and vomiting
        • Orthostatic hypotension
        • Dyskinesias – appear as early as 3 – 5 years following levodopa initiation, much more severe after 5 – 10 years of therapy
      • Response fluctuations: large variations in motor performance, with normal function and peak-dose dyskinesia during “on” periods and significant weakness and bradykinesia during “off” periods.
        • Catechol-O-methyl transferase (COMT) inhibitors (entacapone, tolcapone) reduce metabolism of levodopa peripherally, increasing amount crossing BBB. They reduce response fluctuations.
          • Tolcapone associated with acute fulminant hepatic necrosis
        • Reducing the dose and increasing the frequency of levodopa can also help to avoid peak dose dyskinesias
        • Levodopa absorption is affected by food; should not be taken with meals, especially those high in protein
        • Consider sustained release preparations in patients with significant “off” periods (although effect can be variable), or those with significant peak dose dyskinesia
        • End-of-dose dyskinesia can be managed by increasing the dose and frequency of levodopa, or by adding a dopaminergic agonist, MAO-B or COMT inhibitor
        • Apomorphine is a subcutaneously-administered non-ergot dopamine agonist, which can reverse off periods
        • Amantadine can reduce peak-dose dyskinesia
      • Levodopa-sparing strategy is generally used, especially in young patients due to the above-mentioned complications
      • Should be started at minimal effective dose (50 – 100mg) 3 – 4 times per day, as appearance of dyskinesias is dose-dependent
  • Surgical therapy
    • Deep brain stimulation of the sub-thalamic nucleus reverses akinesia and controls dyskinesia. There is no permanent brain lesion, and it is therefore reversible.
      • Complications: stroke, infection (2% combined), death (0.5%)
    • Thalmotomy of the ventral intermediate nucleus to reduce contralateral tremor
    • Pallidotomy can relieve most of the cardinal symptoms of PD

Summary

This patient has Parkinsonism. There is hypomimia with infrequent blinking and hypophonia. There is bradykinesia, with a reduction in frequency and amplitude of repetitive movements. There is an asymmetrical, resting tremor which is relieved by mental activity. There is lead pipe rigidity at the elbows, and cogwheeling at the wrist. The gait is hesitant at initiation, with a stooped posture. It is narrow-based, and festinating, with a lack of normal arm swing. The patient also turns in numbers.

There are no red flags such as ataxia, vertebral gaze palsy, pyramidal signs, swallowing adjuncts, limb apraxia, antecollis or retrocollis to suggest a Parkinson’s plus disorder such as progressive supranuclear palsy, multiple system atrophy or corticobasal degeneration. There is no evidence of dyskinesias, which may imply levodopa therapy. Functionally, he is able to walk and button his shirt without aid.

The most likely diagnosis is Parkinson’s disease.

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