Parkinsons disease

Question 1

What are the different areas of the brain which can be affected by pathology which result in movement disorders ?

Answer 1

Corticspinal/pyramidal tract can be affected - this results in UMN features such as pyramidal weakness and spasticity

Basal ganglia can be affected, resulting in either hyperkinetic or hypokinetic signs:

Hyperkinetic disorders are also called dyskinesias. There are five forms of dyskinesias which include:

1. Dystonia - Prolonged muscle spasms and abnormal postures
2. Tics - a habitual spasmodic contraction of the muscles, most often in the face.
3. Myoclonus - spasmodic jerky contraction of groups of muscles.
4. Chorea - Fragments of movements flow irregularly from one body segment to another causing a dance-like appearance called Ballismus: if amplitude of these movements is large
5. Tremor - unintentional, rhythmic muscle movement involving to-and-fro movements (oscillations)

Hypokinetic (rigidity and bradykinesia - slow movement) disorders:

1. Parkinsonism
2. Parkinson’s disease

Cerebellum - results in ataxia (incoordination)

Question 2

What is the classic triad of parkinsonism ?

Note parkinsonism = a general term that refers to a group of neurological disorders that cause movement problems similar to those seen in Parkinson’s disease

Answer 2

1. Bradykineasia/ hypokinesia
2. Ridigity/ increased tone
3. Rest Tremor
4. Also postural and gait impairment

Question 3

What are the different causes of parkinsonism ?

Answer 3

• Idiopathic PD (this is parkinsons disease)
• Drugs e.g. neuroleptics (antipsychotics), metoclopramide, prochlorperazine
• Rarely trauma/boxing
• Parkinsons plus syndromes

Question 4

Define what parkinsons disease is

Answer 4

A common and complex neurodegenerative disease defined by the clinical motor features of parkinsonism

PD usually presents asymmetrically (I think e.g. the main tremor is usually in one arm etc)

Question 5

What are the signs and symptoms of bradykinesia ?

Answer 5

• Slow to initiate and carry out movements - with progressive loss of amplitude or speed during attempted rapid alternating movement
• Hypomimesis - reduced facial expression
• Decreased eye blinking
• Monotonous Hypophonia - lacks variation in tone or pitch and is soft spoken
• Micographia (progressively smaller handwriting from initiating writing)
• Difficulty doing up buttons or cleaning teeth

Question 6

Describe the rest temor in parkinsonism

Answer 6

• Defined as a rhythmic oscillatory involuntary movement of affected body part at rest that vanishes with active movement
• Tremor is unilateral
• Typically reappears after a few sec when arms held outstreched (‘reemerging tremor’)
• Tremor frequency in low to mid-range (4-6 Hz)
• Most distinguishing resting tremor is “Pill-rolling”-type or Finger flexion-extension or abducLon-adducLon

Question 7

Describe rigidity in parkinonsim

Answer 7

• Increased muscle tone felt during examination by passive movement
• Resistance is felt throughout full range of movement
• “cog wheel” rigidity start-and stop movements through the range of motion of a joint

Question 8

What are the postural and gait impairment problems suggestive of parkinsonism ?

Answer 8

• Stooped posture
• Parkinsonian gait is slow, occurs at narrow base with short, shuffling steps
• Decreased arm swing
• Slow turning with multiple small steps
• Freezing - can occur which is when they stop in places and are unable to move themselves because their muscle responses are now so slow
• Festination (very fast succession of steps and difficulLes stopping)

Question 9

What are some of the non-motor features of parkinsons disease (idiopathic parkinsons disease)

Answer 9

Early non-motor features:

• Hyposmia - reduced smell
• REM
• Constipation
• Depression
• pain and fatigue
• cognitive impairment

Later non-motor features:

• Dementia - this occurs in >80% of patients after 20yrs
• Hallucinations

Question 10

Describe the typical disease progression in someone with parkisons disease

Answer 10

1. Non-motor symptoms can be present for upto a decade
2. Motor symptoms present (this is when it gets diagnosed as parkinsons disease)
3. Progression of PD is characterised by worsening motor features which initially respond well to symptomatic therapies
4. Advanced stages of PD characterised by the emergence of complications related to long-term symptomatic treatment such as motor and non-motor fluctuations, dyskinesia, and psychosis
5. In the late stage of PD treatment resistant motor and non-motor features are prominent and include axial motor symptoms such as postural instability, freezing of gait, falls, dysphagia, and speech dysfunction (note dementia also very very common)

Question 11

What is the average age of onset of parkinsons disease ?

Answer 11

60

Question 12

What is rapid eye movement (REM) sleep disorder ?

Answer 12

It is a parasomnia (disorder characterised by abnormal or unusual behaviour during sleep), characterised by abnormal or disruptive behaviours such as laughing, talking, shouting, gesturing, grabbing, punching, kicking, sitting up in bed. These behaviours occur during rapid eye movement (REM) sleep and are often related to dream enactment

Question 13

How is REM sleep disorder diagnosed and treated ?

Answer 13

Diagnosis = overnight polysomnography

Treatment = clonazepam or melatonin at bedtime.

Question 14

How is parkinsons disease diagnosed ?

Answer 14

It is a clinical diagnosis:

Bradykinesia + one or more of the following:

1. Muscular rigidity
2. 4-6Hz resting tremor
3. Postural instability not caused by primary visual, vestibular, cerebellar or proprioceptive dysfunction

Question 15

Describe the pathological process of parkinsons disease

Answer 15

Pathological hallmark - consists of prominent dopaminergic neuron loss in the substantia nigra pars compacta (SNpc) with α-synuclein-containing Lewy bodies and Lewy neurites

Loss of dark pigment in the substantia nigra correlates to loss of dopaminergic cell loss

Note that neuronal loss in PD does affect other areas of the brain including locus ceruleus, nucleus basalis Meynert etc etc

Question 16

What genetic mutations are associated with an increased risk of PD and which genetic mutation in particular is associated with the greatest risk for PD ?

Answer 16

• LRRK2 and parkin are the most common causes of dominantly and recessive PD,
• SNCA also increases risk
• The greatest genetic risk factor for PD is mutations in GBA

Question 17

Do drugs in the treatment of PD slow disease progression ?

Answer 17

No - they are symptomatic treatments and do not slow the disease progression

Symptomatic treatments enhance intracerebral dopamine concentrations or stimulate dopamine receptors

Question 18

What is the treatment of parkinsons disease ?

Answer 18

Offer levodopa to people in the early stages of Parkinson’s disease whose motor symptoms impact on their quality of life. - usually people are started on the levodopa (note its always given with a COMT e.g. carbidopa, entacapone, tolcapone

Consider a choice of dopamine agonists, levodopa or monoamine oxidase B (MAO‑B) inhibitors for people in the early stages of Parkinson’s disease whose motor symptoms do not impact on their quality of life. (go more for MAO-B or dopamine agonist here, as want to hold off giving levodopa if possible, dopamine agonist I think preferred out of the 2)

If a person with Parkinson’s disease has developed dyskinesia and/or motor fluctuations, including medicines ‘wearing off’ Offer a choice of dopamine agonists, MAO‑B inhibitors or catechol‑O‑methyl transferase (COMT) as an ajunct to carbidopa/levodopa

• Examples of dopamine agnosits = apomorphine, pramipexole, ropinirole and rotigotine.
• Other options of dopamine agnoists ‘ergot’ types ergot’ types include bromocriptine,pergolide and cabergoline
• monoamine oxidase B (MAO‑B) inhibitors = rasagiline or selegiline)

Question 19

What is the purpose of giving levodopa with carbidopa ( a dopa-deoxycarbxylase inhibitor)?

Answer 19

The deoxycarboxylase inhibitor blocks enzymes from breaking down drug (levodopa)

Question 20

What drug may be useful in the treatment of mild parkinsons with a prominent tremor (as dopamine replacement therapy is not great for treating tremor esp in treatment of mild disease as lower doses used)? (not used often as plenty of side effects in elderly)

Answer 20

Anti-cholinergics - trihexyphenidyl, or clozapine

Question 21

What side effects are both dopamine agonists and levodopa both associated with ?

Answer 21

nausea, daytime somnolence (sleepiness), and oedema

Question 22

What patients should dopamine agonists be avoided in and why ?

Answer 22

• should be avoided in patients with a history of addiction, obsessive-compulsive disorders and impulsive personality
• Impulse control disorders, including pathological gambling, hypersexuality, binge eating, compulsive spending can occur in patients on dopamine agonists
• Also more commonly associated with hallucinations

Question 23

What are the long-term complications of dopaminergic therapies for PD?

Answer 23

Motor fluctuations & Non-motor fluctuations::

• Alterations between periods of good motor symptom control and periods of reduced motor symptom control
• Alterations between periods of good non-motor symptom control and periods of reduced nonmotor symptom control

Dyskinesias:

• Most frequently when levodopa concentraLons are at their maximum (peak-dose)

Drug induced psychosis:

• Hallucinations may be minor but also well-formed visual and less-commonly non-visual (tactile, auditory, olfactory) hallucinations. Other psychotic features might include illusions and delusions (often with paranoia)

Also dry mouth, anorexia, palpitations, postural hypotension

Question 24

What is motor fluctuations and dyskinesias in PD thought to signify and what does the presence of this mean for treatment ?

Answer 24

Thought to result from the pulsatile stimulation of striatal dopamine receptors in later disease stages

When this is present this is when you would add either of the following to the current treatment with levodopa/carbidopa):

1. A dopamine agonist - ropinirole or pramipexole
2. Monoamine oaxidase type B inhibitor (MAO B inhibitor) - rasagiline, selegiline
3. Catechol-O-methyltransferase inhibitor (COMT inhibitor) - carbidopa, entacapone, tolcapone

Question 25

How are each of the following non-motor problems in PD treated:

1. Psychosis (think about hallucinations and delusions etc)
2. Depression
3. Dementia

Answer 25

1. Psychosis (think about hallucinations and delusions etc) - use antipsychotics (also called neuroleptics) - only use clozapine 1st line or quetiapine 2nd line - other antipsychotics may worsen motor symptoms in PD
2. Depression - treat as normal guidelines
3. Dementia (lewy body) - rivastigmine

Question 26

What surgical treatments may be considered in patients in PD not responsive to pharmacological management ?

Answer 26

Deep brain stimulation for treating motor symptoms / complications is well established targeting either the subthalamic nucleus or globus pallidus internus

Question 27

What is a very good reponse to levodopa treatment suggestive of ?

Answer 27

PD - basically initially treatment with it is very very effective in treating motor symptoms but as the disease progresses its effectiveness decreases, this initial great response can be used to help diagnosis

Question 28

What investigations can be done to aid in the diagnosis of PD if it is not clear from history and clinical exam ?

Answer 28

Rule out treatable conditions of asthenia (hypothyroidism, anaemia)

Structural brain imaging - mainly MRI this will be normal in PD helps distinguish from other diseases

Possibly dopamine funcLonal imaging:

• PET with fluoro-dopa (limited availability and high cost)
• Dopamine transporter (DAT) imaging with single-photon emission CT (DAT-SPECT)

Dopamine functional imaging is unable to distinguish PD from other causes of degenerative Parkinsonism, but should be normal in essential tremor, dystonic tremor, psychogenic parkinsonism

Positive levodopa (or s.c. apomorphine) challenge

Genetic testing where appropriate

Note that these are all considered when diagnosis is not clear, otherwise it is a CLINICAL diagnosis

Question 29

What are the main differential diagnosis for someone presenting with parkinsonism like symptoms ?

Answer 29

Parkinsons-plus syndromes + drug induced parkinsonism:

1. Vascular parkinsonism
2. Tremor disorder
3. Multi-system atrophy
4. Progressive supranuclear palsy
5. Fragile X-tremor ataxia syndrome (FXTAS)

Question 30

What are the features suggestive of a vascular parkinsonism ?

Answer 30

• Parkinsonism affects predominantly lower limbs (“lower body” Parkinsonism) - so the features of parkinsonism but only in the lower limbs
• Rest tremor is uncommon
• Other signs of brain vascular lesions might be present (spasticity - some muscles continuously contracted , hemiparesis - weakness of one entire side of the body including arm, trunk and leg, and pseudobulbar pasly - speech problems, dysphagia etc)
• Poor levodopa response
• Structural brain imaging will guide diagnosis

Pic shows spasticity

Question 31

What are the features suggestive of a drug induced parkinsonism ?

Answer 31

• Parkinsonism tends to be symmetrical
• Often coarse postural tremor
• Series of events is important: emergence of symptoms after drug exposure and Improvement / resolution within few months of complete drug withdrawal
• Causes are any drug that blocks the action of dopamine (especially neuroleptic/antipsychotic drugs)

Question 32

What are the features suggestive of a tremor disorder ?

Answer 32

Essential tremor is quite distinct and is often confused with PD treemor:

• It is symmetric, postural (occur when person maintains a position against gravity) or kinetic (occuring during voluntary movement)
• Tremor has higher frequency (up to 12 Hz)
• Tremor not at rest
• Often autosomal dominant inheritance with mean onset of 15 years
• Alcohol responsiveness
• May have a head tremor if present usually mild

Question 33

What features are suggestive of multi-system atrophy ?

Answer 33

• Common cause of degenerative Parkinsonism
• Age on onset in late 6th or 7th decades
• Core triad of dysautonomia (ANS problems such as tachycardia, orthostatic hypotension, constipation, erectile dysfunction etc), cerebellar features and Parkinsonism
• Jerky postural tremor and pyramidal signs – generalised hypereflexia and extensor plantar responses
• Suboptimal and short lived Levodopa response in 1 in 3 patients
• Severe dysarthria or dysphonia
• MRI – cerebellar and pontine atrophy ‘‘hot cross buns’’ sign

Question 34

What are the features suggestive of a progressive supranuclear palsy?

Answer 34

• Parkinsonism - bradykinesia prominent
• Gait and balance impairement (early falls) - stiff broad based gait
• Tremor uncommon
• Cognitive impairment - fronto-temporal
• Vertical gaze supranuclear palsy - downward gaze more impaired than upward
• Continuous activity of the frontalis muscle with eyes wide open (staring)
• No response to levodopa

Question 35

What are the features suggestive of Fragile X-tremor ataxia syndrome (FXTAS)?

Answer 35

• Late-onset (>50 years) neurodegeneraLve disorder in pts with an abnormal number of CGG repeats in the FMR1 gene, in the premutaLon range (55-200)
• Core symptoms include cerebellar gait ataxia, postural / intenLon tremor, variably Parkinsonism, dysautonomia, cogniLve decline of frontal type, and peripheral neuropathy
• Slow disease progression
• Milder symptoms in females with premutaLon (X-linked inheritance), often premature ovarian failure and menopause
• MRI with T2 hyperintensities in the middle cerebellar peduncles (MCP sign)
• Confirmation by molecular testing
• Children of FXTAS premutaLon carriers may have classical Fragile X syndrome