PD and BG drug therapy COPY

Question 1

DISORDERS OF MOVEMENT

i) which two categories can these be placed in?
ii) what can hyperkinetic movements be further classified into?
iii) give three examples of hyperkinetic jerky movement disorders
iv) give two examples of hyperkinetic non jerky movements
v) what type of conditions are hypokinetic? give two examples of these and define them

Answer 1

i) hyper or hypokinetic
ii) hyperkinetic can either be jerky or non jerky
iii) hyperkinetic jerky = tics, chorea and myoclonus
iv) hyperkinetic non jerky = dystonia (abnormal posture) and tremor (oscillating movement)
v) hypokinetic conditions = parkinsonian such as ataxia (disturbance of co-ord) and apraxia (disturbance of planning)

Question 2

HYPOKINETIC MOVEMENTS

i) what is ataxia? disruption in which area causes this?
ii) what is apraxia? disruption in which area causes this?

Answer 2

i) ataxia is disrupted co-ordination = cerebellar disruption
ii) apraxia is disruption in planning therefore disturbance between sensory and motor cortex

Question 3

BALLISMUS/HEMIBALLISMUS

i) what is seen in ballismus? how does this differ from hemiballismus
ii) what is seen in hemiballismus and what is the most common cause?
iii) in HB what goes wrong in relation to basal ganglia pathways? which pathway is favoured?
iv) explain how this manifests if there is a lesion in the subthalamic nucleus

Answer 3

i) ballismus = high amplitude flailing of limbs and large amplitude PROXIMAL movement of limbs - differs from hemiball as affects both sides of the body and HB only affects one side
ii) hemiballismus = jerky hyperkinetic movements and negative symptoms such as numbness that affect one side of the body
iii) HB = disrupted balance between direct and indirect pathway - the direct pathway is favoured
iv) lesion in the STN will decrease excitation in the GPi therefore the GPi will cause less inhibition on the thalamus and this increases movement

Question 4

what kind of movement disorder may this cause?

will the abnormal movement be on the same or contralateral side to the lesion?

will this cause positive or negative symptoms?

Answer 4

stroke causes hemiballismus

movement disorder will be on the contralateral side to the lesion

causes negative symptoms such as numbness

Question 5

TIC DISORDERS

i) what are they?
ii) give an example of a simple or complex associated actions
iii) what other symptom may they be associated with? is this common?
iv) what may make it worse?
v) what makes it better? what does this imply?
vi) name a condition that on the more severe end of the spectrum of tic disorders

Answer 5

i) brief repetitive stereotyped movements with premonitionary urge (eg feel urge to sneeze) plus a motor disorder

ii) simple = blinking or coughing
complex = jumping or twirling

iii) may also be associated with swearing (coprolalia) but this is rare
iv) anxiety or fatigue makes it worse
v) distraction and concentration makes it better - this implies that is not completely under voluntary control
vi) more severe condition = tourettes

Question 6

CAUSES OF TIC DISORDERS

i) what % of people have ADHD, OCD and anxiety
ii) which basal ganglia loops may be dysfunctioning if the tic disorder is associated with OCD or ADHD?
iii) is more likely due to genes or environment?
iv) after which event may it occur? explain

Answer 6

i) 50% have ADHD, 33% OCD and 50% anxiety
ii) dysfunction in limbic or prefrontal basal ganglia loops may be associated with ADHD or OCD
iii) due to a mix of genes and the environment
iv) may occur after an infection due to molecular mimickry - antibodies are made against neurons

Question 7

CHOREA

i) what is it?
ii) are the proximal or distal limbs affected?
iii) how will the patient appear?
iv) what will happen if you ask the patient to hold their tongue out? what does this demonstrate?
v) what are the two most common causes? explain why
vi) how will a lesion in the STN cause this? what BG pathway is favoured?

Answer 7

i) jerky, brief, irregulat contractions that are not repetitive or rhymic but flow from one muscle to the next
ii) affects distal limbs - writhing movement
iii) patient will appear fidgety and restless (dance like movment)
iv) ask patient to hold tongue out - cant do it = motor impersistence
v) two most common causes are degerative (HD) or drugs (neuroleptics - DA agonists)
vi) lesion in STN will cause decrease GPi excitation which decreases thalamic inhibition which increases movement - favours the direct pathway

Question 8

HUNTINGTONS DISEASE GENETICS

i) what is the genetic cause?
ii) is it autosomal dominant or recessive?
iii) is there complete penetrance?
iv) what is anticipation?
v) how does the length of the number of repeats affect disease onset?
vi) how does the repeat sequence change as you go down generations?

Answer 8

i) trinucleotide repeat on chromosome 4
ii) auto dominant
iii) complete penetrance (anyone who carries the gene will express the pheno)
iv) anticipation = the number of repeats increases with generations
v) increase in number of repeats with each generation will cause earlier onset and more severe disease
vi) as you go down generations the repeat sequence tends to enlarge

Question 9

HUNTINGTONS CLINICAL PRESENTATIONS

give examples of

i) cognitive
ii) behavioural
iii) physical

symptoms

iv) what type of movement disorder is HD? how is this characterised?
v) what is dyskinesia?
vi) which medical team are often required to intervene?

Answer 9

i) cognitive = inability to make decisions or multitask and general slowness of though
ii) behavioural = irritability, depression, apathy, anxiety and delusions
iii) physical = chorea, motor persistence, dystonia, abnormal eye movements due to oculomotor BG loop disruption
iv) HD = chorea (dance like movements) which is characterised by overactive DA
v) dyskinesia is involuntary muscle movements
vi) often requires neuropsychiatry

Question 10

MYOCLONUS

i) what is the main thing that characterises this?
ii) is it a brief or prolonged movement?
iii) are movements positive or negative?
iv) what will be seen if you ask the patient to lift their hands?
v) what is the possible pathophysiology?
vi) which system is probably affected?

Answer 10

i) jerk
ii) brief movement with rapid onset and offset
iii) movements are both positive (muscle contraction) and negative (muscle inhibitions)
iv) ask patients to lift hands and they will just lose tone
v) possible pathophysiology is an imbalance between excitatory and inhibitory NTs (explains why it can be treated with anti-epileptics)
vi) probably affects the motor control system at multiple levels

Question 11

CAUSES OF MYOCLONUS

what are the three main causes of myoclonus? what are each of these associated with?

Answer 11

1) juvenile myoclonic epilepsy = early morning jerks
2) brain hypoxia = post cardiac arrest
3) prion disease = cardinal feature is a myoclonic jerk

Question 12

DYSTONIA

i) what type of movement disorder is this?
ii) what postures are characteristic of dystonia?
iii) what disease is this a feature of?
iv) name three brain areas that may be disrupted in dystonia
v) give five possible causes
vi) blocking of which receptors may cause dystonia? which drug do som dystonias respond to?

Answer 12

i) hyperkinetic non jerky
ii) abnormal twisting, tremor, arm held in flexed position
iii) feature of huntingtons disease
iv) may be due to disruption in motor cortex, supplementary motor areas, cerebellum and basal ganglia
v) possible causes = stroke, brain injury, encephalitis, PD and HD
vi) blocking DA receptors can cause dystonia and some can be LDOPA response (suggests DA pathway plays a part)

Question 13

TREMOR

i) what kind of movement disorder is this?
ii) give three types based on the moment of occurence
iii) what is the most common type of tremor? what does this particularly affect?
iv) how can this type of tremor be tested?

Answer 13

i) hyperkinetic non jerky
ii) rest, postural or kinetic
iii) most common type is essential tremor = simple kinetic and only really affects the hands
iv) essential tremor can be tested by the finger to nose test

Question 14

PATHOPHYS OF TREMOR

i) what is the postulated theory?
ii) what causes tremor in PD in relation to NTs/brain area?
iii) dysfunction of which NT/brain area is involved in essential tremor?
iv) how are circuits between flexors and extensors affected?

Answer 14

i) suggested theory is increased activity in the cerebellothalamocortical circuit
ii) tremor in PD due to DA dysfunction in the globus pallidus
iii) essential tremor - due to GABA dysfunction in the cerebellum
iv) oscillating circuits between flexors and extensors are normally dampened

Question 15

what is a new treatment for essential tremor?

how does this work?

why is it good?

what would previously have been used?

Answer 15

MRI focused ultrasound therpay

works by firing US beams into the head while circulating cooling water to prevent burning - ablates a specific brain area

good because it is non invasive

may have previously done deep brain stimulation

Question 16

DRUG TREATMENT FOR HYPERKINETIC MOVEMENT DISORDERS

i) which pathway predominates in these disorders?
ii) give three examples of these disorders
iii) what type of agent may be used to treat? give four examples of these drugs
iv) give two other types of agents that may be used to treat and give an example of each
v) give two acute/sub acute/long term problems that these agents may cause

Answer 16

i) the direct pathway predominates
ii) myoclonus, tics, chorea
iii) DA receptor blockers (typical APs) such as haloperidol, chlorpromazine, pimozide and risperidone (EP SEs)
iv) other agents are DA depeleting agents such as tetrabenazine and atypical anti psychotics such as clozapine

v) acute = oculogyric crisis and neuroleptic malignant syndrome
- sub acute (wks and months) = parkinsonism
- long term (months/years) = tardive dyskinesias

Question 17

ACUTE PROBLEMS FROM DA BLOCKING AGENTS

i) name two acute problems due to DA blockers
ii) how quickly do each of these develop?
iii) how are these characterised?

Answer 17

i) ocuclogyric crisis and neuroleptic malignant syndrome
ii) both start hours to days after treatment
iii) oculogyric crisis - fixed stare, upward dev of eyes, neck/trunk extension, jaw spasm, dystonia

NMS - rigidity/muscle breakdown (raised creat phosphokinase) , fever, autonomic instability (BP and pulse are volatile), confusion

Question 18

what side effect of DA blockers is this posture characteristic of?

Answer 18

oculogyric crisis

Question 19

TARDIVE DYSKINESIA

i) define
ii) when may this be seen?
iii) why is this seen?
iv) give three postures that may be observed
v) how is this treated?
vi) movements seen are similar to what other condition?

Answer 19

i) stiff jerky movements of face that cant be controlled, excessive movement
ii) may be seen when taking anti psychotics
iii) seen due to supersensitivity of DA receptors (DA receptors are shut down to they upregulate)
iv) face/mouth movement, dystonic trunk, excess movement
v) treat by gradually withdrawing the offending agent then sub with an atypical AP or DA depleting agent/benzo
vi) movements are similar to those seen in HD

Question 20

name three jerky hyperkinetic movement disorders

name two non jerky movement disorders

Answer 20

jerky - myclonus, tic, chorea, ballisumus

non jerky - tremor and dystonia

Question 21

HYPOKINETIC MOVEMENT DISORDERS

i) what is the umbrella term used for the symptoms seen?
ii) name the triad of symptoms. which one of these must be seen to have a hypokinetic disorder?
iii) what is akinesia?
iv) name two physical signs and give examples of each

Answer 21

i) parkinsonism - conditions that can mimic PD (akinetic rigid movement)

ii) bradykinesia, rigidity and tremor
- bradykinesia must be present to have a hypokinetic disorder

iii) akinesia is difficulty initating voluntary movement
iv) slowness and poverty of movement (loss of facial expression and arm swing)

Question 22

KEY FEATURES OF HYPOKINETIC MOVEMENT DISORDERS

i) name the three key features
ii) which one must be present for a diagnosis?
iii) explain how to test each feature

Answer 22

i) bradykinesia, rigidity and tremor
ii) must have bradykinesia for a diagnosis
iii) bradykinesia - get patient to tap hand and the tap will get slower and smaller over time

rigidity - move arm and you will feel the rigidity

tremor - sit patient down and ask them to close eyes and count from 20-1 (see tremor)

Question 23

NON MOTOR SYMPTOMS - HYPOKINETIC DISORDERS

i) how are non motor symptoms explained?
ii) give five non motor symptoms
iii) do these occur before or after motor symptoms?

Answer 23

i) explained by different loops travelling through the basal ganglia eg oculomotor and limbic loop
ii) depressed mood, dementia, postural hypertension, hypersalivation (autonomic involvement), sleep disturbance, reduced sense of smell
iii) these occur before motor symptoms

Question 24

PARKINSONS DISEASE PATHOPHYSIOLOGY

i) what causes reduced movement in relation to BG pathways?
ii) where are DA neurons lost? which BG pathways does this affect?
iii) what will lack of dopamine cause from the striatum onwards? what does this result in?

Answer 24

i) reduced activation of the directt pathway and increased activation of the indirect pathway
ii) DA neurons are lost between the striatum and the substantia nigra

iii) lack of DA causes the striatum to have less inhibition on GPe
- GPe activates the STN
- STN activates GPi which inhibits the thalamus
- Increased thalamic inhibition causes reduced movements

Question 25

PARKINSONS DISEASE

i) which cells and where are primarily affected?
ii) what % cell loss is seen at disease onset
iii) what is the histopathological hallmark?
iv) what are the three main categories of causes of parkinsonism?

Answer 25

i) DA neurons in the substantia nigra
ii) 70% cell loss seen at disease onset
iii) lewy bodies and intraneuronal protein inclusions are seen histopathologically
iv) neurodegenerative, secondary and genetic

Question 26

CAUSES OF PARKINSONISM

i) what % does parkinsons disease account for?
ii) which two symptoms may be seen before motor symptoms?
iii) name three types of atypical parkinsonism
iv) name four secondary causes of parkinsonism
v) name one genetic cause of parkinsonism

Answer 26

i) PD accounts for 80% of parkinsonism
ii) see cognitive impairement and dementia before motor symptoms

iii) MSA = multiple system atrophy
PSP = progressive supranuclear palsy (eyes in fixed state)
CBD = corticobaasal generation

iv) drugs (antipsychotics are DA antag), stroke, hydrocephalus, metal deposition disorders
v) wilsons disease

Question 27

LDOPA

i) what converts LDOPA to dopamine? (A)
ii) what breaks down dopamine? (B & C)
iii) which of these may be inhibited to help treat symptoms of PD

Answer 27

i) DOPA decarboxylase
ii) COMT and MAO B
iii) inhibiting COMT and MAO B may help to treat symptoms

Question 28

EARLY DRUG THERAPIES FOR PD

i) name an anti-flu agent that can be used to treat PD - what receptor does it agonise?
ii) name another class of drug that targets DA balance. how does this work? what are the side effects? which patients would not be given this?
iii) which drugs prevent DA breakdown?

Answer 28

i) Amantidine - glutamate agonist

ii) anti cholinergics (procyclidine) - need a balance between Ach and DA but limited by side effects:
- confusion, urinary retention and dry mouth
- dont give to patients with cognitive impairments as it causes confusion

iii) MAO inhibitors prevent DA breakdown

Question 29

ACH AND DA BALANCE IN THE BG

i) which area is rich in Ach and DA?
ii) what effect will a reduction in DA in the BG have on Ach?
iii) how can this be counteracted?

Answer 29

i) the striatum is rich in DA and Ach
ii) reduction of DA will cause a functional excess of Ach
iii) this can be counteracted by reducing Ach effects by anti-cholinergics/muscarinics

Question 30

MAO INHIBITORS

i) what do they do?
ii) what are the two isoforms of MAOs? give an example of each
iii) what are two downsides to using non selective MAOIs? what may they be used to treat?
iv) give an example of a more selective MAOI - why may this be used?

Answer 30

i) prevent breakdown of monoamine chemical neurotransmitters

ii) MAO A - 5HT, adrenaline and noradrenaline
MAO B - dopamine

iii) non selective MAOIs have lots of side effects and need dietary restriction (risk of hypertension)
- may be used to treat depression
iv) selective MAOI = selegilline and rasagilline
- may be used as no dietary restriction required

Question 31

LDOPA TREATMENT

i) where do you get side effects? how is this counteracted?
ii) give two examples of LDOPA drugs
iii) how is a narrow range of DA levels maintained?
iv) what does too much DA cause?
v) how does duration of LDOPA benefit vary throughout disease?

Answer 31

i) ge side effects in the periphery so give a DOPA decarboxylase inhibitor that works peripherally to prevent LDOPA > DA
ii) madopar and sinemet
iii) narrow DA range is maintained by giving small dose intervals
iv) too much DA causes dyskinesia (involuntary muscle movements)
v) as disease progresses there is decreased duration of clinical benefit and DA range gets more narrow

Question 32

ENHANCING EFFECTS OF LDOPA IN ADV DISEASE

i) what drug can prolong effects of LDOPA before you neeed another dose? give two examples
ii) how does this drug work? what are the side effects?
iii) name a route of admin that allows a more narrow range of DA
iv) name one advantage and three disadvantages of this route

Answer 32

i) COMT inhibitors eg entacapone and tolacapone

ii) works by reducing peripheral metab of LDOPA and extends effects
- side effects are diarrhoea, liver disease and can make dyskinesia worse

iii) Duodopa (through duodenum)

iv) adv is that it is directly delivered to duo
disadv is that is it is affected by poor gastric motil/constipation, it has unpredictable bioavailabilitty (harder to hit narrow therpeutic window), expensive, doesnt affect disease progression

Question 33

DOPAMINE AGONISTS

i) what does this bypass?
ii) how does it work? give two advantages
iii) name four different types and give an example of each
iv) what is the effect of them?
v) give two disadvantages

Answer 33

i) bypasses degenerating nigrostriatal neurons
ii) works by directly activating DA receptors so no need for enzymatic conversion

iii) Ergot - pergolide NO LONGER USED DUE TO CARDIAC/PULM FIBROSIS
Non Ergot - pramipexole
Patch - rotigotine
Subcutan infusion - apomorphine

iv) all reduce frequency of motor complications
v) disadv are dopamine dysregulation syndrome (10%), impulsive disorders such as gambling and shopping

Question 34

APOMORPHINE INFUSION

i) what type of drug is this?
ii) how effective is it and how quickly does it work?
iii) how does it reduce dyskinesia?
iv) how is this thought to work?
v) give a disadvantage. what patients may this be unsuitable for?

Answer 34

i) DA agonist
ii) very effective and works instantly
iii) reduces dyskinesia by continuous DA stimulaiton
iv) thought to work by continuous DA stim as pulsatile DA stim is thought to prime the BG for motor complications

v) disadv = skin nodules
may also not be suitable for patients with poor manual dexterity as need to use a pump to admin

Question 35

NON DRUG TX FOR PD

i) name two therapies that can be used if drugs dont work
ii) how do they work?
iii) do they alter disease progression? do they effect non motor symptoms?

Answer 35

i) deep brain stimulatioon and MRI focused US
ii) DBS - works by high frequency stimulation inhibiting neurons by blocking depolarisation and blocking abnormally synchronous BG rhythms

MRI US - ablates the faulty part of the circuit by firing US waves at it

iii) DBS does not alter disease prgoreession and has no effect on motor symptoms