Parkinson's Disease and Parkinsonism

Question 1

What are movement disorders?

Answer 1

Caused by disease of:
• Basal ganglia (extrapyramidal)
• Corticospinal / pyramidal tract
• Cerebellum

Question 2

Categories of movement disorders caused by disease of the basal ganglia?

Answer 2

Hyperkinetic:
• Dystonia
• Tics
• Myoclonus
• Chorea
• (Tremor)

Hypokinetic (rigidity, bradykinesia):
• Parkinsonism
• Parkinson’s disease

Question 3

Movement disorders caused by corticospinal/pyramidal tract disease?

Answer 3

Pyramidal weakness

Spasticity

Question 4

Movement disorders caused by cerebellar disease?

Answer 4

Ataxia

Question 5

Define Parkinsonism?

Answer 5

AKA Parkinsonian syndrome

This is a clinical syndrome (set of symptoms) consisting of:
• Rigidity
• Akinesia / bradykinesia
• Resting tremor

The most common type if Parkinson’s disease

Question 6

Define dystonia?

Answer 6

Prolonged muscles spasms and abnormal posturing

Question 7

Define chorea?

Answer 7

Fragments movement that flow irregularly from 1 body segment to another, resulting in a dance-like (writhing) appearance

If the amplitude of these movements is large, it is called chorea

Question 8

List the basal ganglia?

Answer 8

Caudate nucleus

Putamen

Globus pallidus - split into internal (GPi) and external (GPe)

Subthalamic nuclei

Substantia nigra

Question 9

What is the lentiform nucleus?

Answer 9

Putamen and globus pallidus together

Question 10

What is the striatum?

Answer 10

Caudate nucleus and putamen together

Question 11

What is the corpus striatum?

Answer 11

Caudate nucleus, putamen and globus pallidus together

Question 12

Which pathways are hyperactive and hypoactive in the Parkinsonian state?

Answer 12

Hyperactive pathways:
• Striatum stimulation of GPe
• Substantia nigra stimulation of GPi
• GPi stimulation of thalamus

Hypoactive pathways:
• GPe stimulation of substantia nigra
• Striatum stimulation of GPi

Question 13

Symptoms of Parkinson’s disease?

Answer 13

Presents with:
• Resting tremor
• Muscular rigidity
• Akinesia
• Gait and postural impairment

Question 14

Sub-types of motor features in Parkinson’s disease?

Answer 14

Motor features are heterogeneous but there broadly 2 sub-types:

• Tremor dominant Parkinson’s disease (with relative absence of other motor symptoms)
• Non-tremor dominant Parkinson’s disease, e.g: akinetic-rigid syndrome and postural instability gait disorder

There is also a mixed / indeterminate phenotype

Question 15

Progression of Parkinson’s disease?

Answer 15

Characterised by worsening motor features, which initially respond well to symptomatic therapies (AKA ‘honeymoon phase’)

Advanced stages are characterised by emergence of complications related to long-term symptomatic treatment, inc:
• Motor and non-motor fluctuations
• Dyskinesia
• Psychosis

In the late stages, treatment resistant motor and non-motor features are prominent and inc:
• Postural instability 
• Freezing of gait
• Falls
• Dysphagia
• Speed dysfunction

Question 16

Occurrence of late stage symptoms in Parkinson’s disease?

Answer 16

After ~17-20 years of PD, the majority of patients will have gait freezing, falls and dementia

At this stage, half report choking

Question 17

When is the pathogenic process that causes Parkinson’s disease underway?

Answer 17

Presumed to be underway during the pre-motor phase, inc. regions of the peripheral and CNS as well as the dopaminergic neurones in the SNpc

Question 18

Progression of Parkinson’s disease depending on sub-type?

Answer 18

Course and prognosis differ with the tremor-dominant sub-type being assoc. with a slower rate of progression and less functional disability

Question 19

Non-motor features of Parkinson’s disease?

Answer 19

These are common in early Parkinson's disease and are assoc. with reduced health-related QoL:
• Olfactory dysfunction
• Cognitive impairment
• Psychiatric symptoms 
• Sleep disorders 
• Autonomic dysfunction
• Pain and fatigue 

They are often present before the onset of classical motor features (can be present for more than a decade before motor onset)

Question 20

What is rapid eye movement sleep behaviour disorder?

Answer 20

Parasomnia characterised by abnormal/disruptive behaviours that occur during rapid eye movement sleep, such as:
• Talking, shouting, laughing
• Gesturing and grabbing
• Punching and kicking
• Sitting up in bed

Question 21

Diagnosis of rapid eye movement sleep behaviour?

Answer 21

Requires overnight polysomnography to:
• Document the present of rapid eye movement without atonia, such as sustained or intermittent muscle activity (measured by electromyogram)
• Rule out mimics, such as obstructive sleep apnoea, non-rapid eye movement parasomnia and seizures

Question 22

Treatment of rapid eye movement sleep behaviour?

Answer 22

Clonazepam or melatonin at bedtime

Question 23

Complications of RBD?

Answer 23

Sleep disruption

Injuries to patient and bed partner

Patients with isolated RBD have an increased risk of developing a neurodegenerative condition

Parkinson’s disease patients with RBD tend to have a disease sub-type characterised by:
• More severe autonomic dysfunction
• Gait impairment
• Dementia

Question 24

Diagnostic criteria for Parkinson’s disease (step 1)?

Answer 24

Bradykinesia (slowness of initiation go voluntary movement with progressive reduction in speed and amplitude of repetitive actions)

+

One or more of:
• Muscular rigidity
• 4-6 Hz rest tremor
• Postural instability not caused by primary visual, vestibular, cerebellar or proprioceptive dysfunction

Question 25

Exclusion criteria for Parkinson's disease?

Answer 25

One or more of the following is suggestive of an alternate diagnosis: • Hx of repeated strokes with stepwise progression of Parkinsonian features • Hx of repeated head injury • Hx of definite encephalitis • Neuroepileptic treatment at the onset of symptoms • Negative response to large doses of levodopa • Sustained remission • Strictly unilateral features after 3 years • Early severe autonomic involvement • Early severe dementia with disturbances of memory, languate and praxis • Oculogyric crises (often a side effect of neuroepileptic drugs) • Supranucleus gaze palsy • Babinski sign • Cerebellar signs • Presence of a cerebral tumour or communications hydrocephalus on CT/MRI scan

Question 26

Pathogenesis of Parkinson's disease?

Answer 26

Loss of dopaminergic neurones within the SNpc and in many other regions, e.g: locus coeruleus Misfolded α-synuclein (insoluble and aggregated) forms intracellular inclusions (Lewy bodies) and processes (Lewy neurites) of neurons, in the brain, spinal cord and PNS

Question 27

Gross and histological appearance of Parkinson's disease?

Answer 27

Sections through the brainstem reveal loss of the normally dark pigment in the substantia nigra and locus coeruleus; this pigment loss correlates with DOPAMINERGIC NEURONE LOSS A neurohistological hallmark of Parkinson's disease are LEWY BODIES

Question 28

Method of staging Lewy pathology in Parkinson's disease?

Answer 28

Braak staging - helps to explain the non-motor symptoms of Parkinson's disease

Question 29

Non-modifiable risk factors for Parkinson's disease?

Answer 29

Older age (greatest risk factor); early onset, <40 years, increases the probability of a genetic cause Male gender Genetics

Question 30

Genetic risk factors for Parkinson's disease?

Answer 30

Increased risk assoc. with a positive FH of Parkinson's disease or tremor, e.g: • SNCA - encodes the protein α-synuclein • Mutation of LRRK2 is the most common cause of dominant Parkinson's disease • Mutation of parkin is the most common cause of recessive Parkinson's disease The greatest risk factor for Parkinson's disease is a mutation in GBA, which encodes β-glucocerebrosidase (lysosomal enzyme deficient in Gaucher's disease)

Question 31

Monogenic forms of Parkinson's disease?

Answer 31

Autosomal dominant forms include SNCA and LRRK2 Autosomal recessive forms include Parkin

Question 32

Environmental risk factors for Parkinson's disease?

Answer 32

Pesticide exposure Prior head injury Rural living β-blocker use Agricultural occupation Well water drinking

Question 33

Environmental factor associated with decreased risk of Parkinson's disease?

Answer 33

Tobacco smoking and alcohol consumption Coffee drinking NSAID use CCB use

Question 34

Treatment of Parkinson's disease?

Answer 34

No available neuroprotective or disease modifying drugs for Parkinson's disease ``` Symptomatic treatments enhance intracerebral dopamine conc. or stimulate dopamine receptors: • Levodopa • Dopamine agonists • Monoamine oxydase type B inhibitors • Amantagine (less commonly) ```

Question 35

When should treatment of Parkinson's disease be initiated?

Answer 35

Initiate when symptoms cause disability or discomfort, aiming to improve function and QoL Bradykinesia and rigidity respond reliably to dopaminergic treatment early in the disease

Question 36

Effectiveness of treatments for Parkinson's disease?

Answer 36

MAO B inhibitors are only moderately effective Levodopa and dopamine agonists are needed for more severe symptoms

Question 37

Treatment of Parkinson's disease tremor?

Answer 37

Anti-cholinergic agents can be effective for tremor: • Trihexyphenidyl • Clozapine Tremor is inconsistently responsive to dopamine replacement therapy, esp. in lower doses

Question 38

Adverse reactions of Parkinson's disease treatment?

Answer 38

Both dopamine agonists and levodopa are assoc. with nausea, daytime somnolence and oedema Dopamine agonists: • Impulse control disorders, e.g: pathological gambling, hypersexuality, binge eating, compulsive spending Levodopa provides the greatest symptomatic benefit but long-term use is assoc. with motor complications: • Dyskinesia • Motor fluctuations NOTE - there is a difference between motor symptoms and motor complications

Question 39

In which patients should dopamine agonists not be prescribed?

Answer 39

Avoid in patients with a history of addiction, OCD and impulsive personality Do not prescribe in the elderly, part. those with cognitive impairment, as it is more commonly assoc. with hallucinations

Question 40

Long-term complications of dopaminergic therapies for Parkinson's disease?

Answer 40

Motor fluctuations - alterations between periods of good motor symptom control and periods of reduced motor symptom control Non-motor fluctuations - alterations between periods of good non-motor symptom control and periods of reduced non-motor symptom control Dyskinesia - involuntary choreiform or dystonic movements, which occur most frequently when levodopa conc. is at a maximum; less commonly, it can occur at the beginning or end of a levodopa dose (AKA diphasic dyskinesia) Drug-induced psychosis - hallucinations include minor phenomena, such as: • Sense of presence • Passage hallucinations • Well-formed visual and, less commonly, non-visual (tactile, auditory, olfactory) hallucinations Illusions and delusions may also occur

Question 41

Managing the complications of motor fluctuations and dyskinesias, due to long-term dopaminergic therapy?

Answer 41

Pharmacological - to reduce dopamine fluctuations, additionally prescribe: • A dopamine agonist • Monoamine oxidase type B inhibitory (MAO B inhibitor) • Catechol-O-methyltransferase inhibitor (COMT inhibitor) Direct delivery of a stable levodopa-carbidopa gel into the duodenum, via percutaneous endogastric gastrostomy tube attached to portable infusion pump Subcutaneous infusion of apomorphine (potent dopamine agonist) Non-dopaminergic treatment can be helpful: • Amantadine • Clozapine

Question 42

Managing the complication of psychosis, due to long-term dopaminergic therapy?

Answer 42

Most efficiently managed with clozapine; alternatively, quetiapine may be used These are both atypical anti-psychotics; the use of other neuroepileptics should be avoided

Question 43

Treatment of psychosis for PD in those who have dementia?

Answer 43

Rivastigmine (an acetylcholinesterase inhibitor) is the treatment of choice for late-stage dementia in those who have PD It may reduce visual hallucinations and delusions in these patients

Question 44

Treatment of depression assoc. with PD?

Answer 44

Anti-depressants; specifically, tricyclics are favoured, e.g: desipramine and nortriptyline SSRIs, e.g: citalopram, are also an option

Question 45

Surgical treatment options for PD?

Answer 45

Deep brain stimulation for treatment of motor symptoms/complications This targets either then subthalamic nucleus or globus pallidus internus

Question 46

Summary of pharmacological treatments of non-motor symptoms and complications of PD?

Answer 46

ADD TABLE

Question 47

Motor symptoms of Parkinson's disease?

Answer 47

Bradykinesia Resting tremor Rigidity Postural and gait impairment NOTE - these comprise the clinical syndrome of Parkinsonism

Question 48

Define bradykinesia?

Answer 48

Slowness of movement with progressive loss of amplitude or speed during attempted rapid alternating movement of body segments

Question 49

Assessment of bradykinesia in PD patients?

Answer 49

Ask the perform some repetitive movements as quickly as possible (opening and closing the hand, foot tapping) OR Global assessment of spontaneous movements (standing up)

Question 50

Other signs that indicate bradykinesia?

Answer 50

Hypomimia (decreased facial expression and eye blinking) Hypophonia Micographia (progressively smaller handwriting)

Question 51

Define rest tremor (AKA Parkinsonian tremor)?

Answer 51

Rhythmic oscillatory involuntary movement of affected body part at rest This vanishes with active movement and typically reappears after a few seconds when arms are outstretched (re-emerging tremor)

Question 52

Body regions affected by Parkinsonian tremor?

Answer 52

Most distinguishing resting tremor is 'pill-rolling' type Finger flexion-extension or abduction-adduction Tremor can also affect lower limbs, jaw and tongue but a head tremor is atypical

Question 53

How is Parkinsonian tremor best observed in clinical practice?

Answer 53

While the patient is focused on a particular mental task (counting backwards from 100)

Question 54

Define rigidity in PD?

Answer 54

Increased muscle tone felt during examination by passive movement; resistance is felt through the full range of movement There is no increase in rigidity with a higher mobilising speed This distinguishes rigidity from spasticity (which occurs due to UMN lesions)

Question 55

What is cog-wheel rigidity?

Answer 55

Rigidity + resting tremor = 'cog wheel' rigidity (esp. at the wrist) A characteristic feature of Parkinson's disease

Question 56

Other features of rigidity in PD?

Answer 56

+ve Froment's manoeuver (rigidity increases in the body segment being examined due to voluntary movement of other body parts)

Question 57

Describe the postural and gait impairment in PD

Answer 57

Stooped posture owing to impaired postural reflexes; this increases the risk of falls NOTE - camptocormia is extreme anterior truncal flexion

Question 58

Features of the postural and gait impairment in PD?

Answer 58

Decreased arm swing Slow turning with multiple small steps Freezing Festinations (very fast succession of steps and difficulties stopping)

Question 59

How to clinically assess for postural and gait impairment in PD?

Answer 59

Assess both in an open space as well as while passing through narrow doorways or spaces Pull test

Question 60

Occurrence of non-motor features in PD?

Answer 60

Some features, e.g: hyposmia, REM, constipation, depression, occur early in PD Others, e.g: dementia, hallucinations, occur late in the disease but are very commonly at this late stage

Question 61

Hx taking from a potential PD patient?

Answer 61

Which symptoms have emerged and their sequence; consider the perceived anatomical inv. Inquire about pre-motor symptoms, e.g: sleep-related REM sleep behaviour, loss of smell and constipation Past and present medical and drug history Exposure to environmental toxins, e.g: manganese, pesticides FH (esp. any neurological conditions and note ethnicity)

Question 62

Examination of PD patients?

Answer 62

Neuro exam Check for an asymmetric pill-rolling tremor and bradykinesia? No features other than those for Parkinsonism, i.e: sensory, pyramidal and cerebellar signs should be absent No dementia early in the disease course No other movement disorders, e.g: tics, chorea and myoclonus Full range of eye movements with normal latency, speed and accuracy

Question 63

Ix for PD?

Answer 63

TFTs and FBC (rule out hypothyroidism and anaemia) Structural brain imaging Consider dopamine functional imaging: • PET with fluoro-dopa • Dopamine transporter (DAT) imaging with single-photon emission CT Positive levodopa challenge Genetic testing (where appropriate)

Question 64

Disadvatages of dopamine functional imaging?

Answer 64

Unable to distinguish PD from other causes of degenerative Parkinsonism NOTE - it should be normal in essential tremor, dystonic tremor and psychogenic parkinsonism

Question 65

Red flags in a PD diagnosis?

Answer 65

Absence of asymmetry of symptoms Severe axial or lower limb inv. Frequent falls Fast disease progression Eye movement disorder, e.g: supranuclear palsy, dysmetric or slow saccades) Other unexpected movement disorder, e.g: tics, myoclonus or chorea Pyramidal or cerebellar dysfunction Bulbar or pseudobulbar features Apraxia Severe cognitive deterioration or psychosis Marked autonomic dysfunction Negative levodopa challenge

Question 66

What is vascular parkinsonism?

Answer 66

A type that predominantly affects the lower limbs (AKA lower body Parkinsonism) Rest tremor is uncommon in this and their is a poor response to levodopa Other signs of vascular brain lesions may be present, e.g: • Spasticity • Hemiparesis • Pseudobulbar palsy Structural brain imaging is the main guide to the diagnosis

Question 67

What is drug-induced parkinsonism?

Answer 67

A type of parkinsonism that tends to be symmetrical and often has a coarse postural tremor; occurs due to any drug that blocks the action of dopamine, esp. NEUROEPILEPTIC drugs Symptoms emerge after drug exposure; improvement/resolution of symptoms within a few months of complete drug withdrawal These patients may have other drug-induced disorders: • Orolingual dyskinesias • Tardive dystonia • Akathisia

Question 68

Which tremor disorder may be confused for PD?

Answer 68

Essential tremor is often confused with tremulous PD This is often autosomal dominant with a mean onset of 15 years

Question 69

Signs of essential tremor?

Answer 69

Symmetric, postural or kinetic tremor that is infrequently observed at rest Alcohol responsiveness If a head tremor is present, it will be mild

Question 70

What is multi-system atrophy?

Answer 70

A common cause of degenerative Parkinsonism with an onset in 60s-70s

Question 71

Core triad of multi-system atrophy?

Answer 71

1. Dysautonomia 2. Cerebellar features 3. Parkinsonism

Question 72

Other symptoms of multi-system atrophy?

Answer 72

Jerky postural tremor Pyramidal signs: • Generalised hyperreflexia • Extensor platar responses

Question 73

Other features suggestive of multi-system atrophy?

Answer 73

Severe dysarthria or dysphonia Marked antecollis Inspiratory sighing Orofactial dystonia

Question 74

Ix for multi-system atrophy?

Answer 74

Sub-optimal and short-lived response to levodopa in 1/3rd of patients MRI may shows hot cross bun sign (cerebellar and pontine atrophy);

Question 75

What is progressive supranuclear palsy and a distinguishing feature from PD?

Answer 75

Symmetric akinetic-rigid syndrome with predominantly axial inv. Tremor is infrequent in these patients and there is no response to levodopa

Question 76

Symptoms of progressive supranuclear palsy?

Answer 76

Gait and balance impairment (early falls) Vertical gaze supranucleus palsy Pseudobulbar symptoms Retrocollis Continuous activity of the frontalis muscle with eyes wide open Frontal - subcortical cognitive deficits Some patients may present with Parkinsonism (AKA PSP-parkinsonism)

Question 77

What is fragile X-tremor ataxia syndrome (FXTAS)?

Answer 77

Late-onset (>50 years) neurodegenerative disorder in patients with an abnormal number of CGG repeats in the FMR1 gene, in the pre-mutation range The disease progresses slowly

Question 78

Core symptoms of FXTAS?

Answer 78

Cerebellar gait ataxia Postural/intention tremor Variably, Parkinsonism may occur Dysautonomia Cognitive decline of frontal type Peripheral neuropathy Milder symptoms may be present in females with pre-mutation (X-linked inheritance), often premature ovarian failure and menopause

Question 79

Ix for FXTAS?

Answer 79

MRI shows T2 hyperintensities in the middle cerebellar peduncles (AKA MCP sign) Confirmed by molecular testing

Question 80

Consequences on children of those carrying FXTAS premutations?

Answer 80

May have classical fragile X syndrome