Basal Ganglia disorders

Question 1

What is the classic triad in Parkinson’s Disease (PD)? [4]

Describe other characteristic symptoms that PD patient may face [4]

State 4 psychiatric features of PD

Answer 1

A clinical syndrome of Bradykinesia + atleast one of:

• Tremors
• Rigidity
• Postural Instability

Other characteristic features:

• Mask-like face
• Micrographia
• Impaired sense of smell
• Postural hypotension (autonomic dysfx)
• Pyschiatric
  
  • Depression
  • Psychosis
  • Dementia
  • Sleep disturbance

Question 2

Causes of Parkinsonism

Answer 2

Causes of Parkinsonism
* Parkinson’s disease
* drug-induced e.g. antipsychotics, metoclopramide
* progressive supranuclear palsy
* multiple system atrophy
* Wilson’s disease
* post-encephalitis
* dementia pugilistica (secondary to chronic head trauma e.g. boxing)
* toxins: carbon monoxide, MPTP

Question 3

Describe manifestation of bradykinesia [2]

Describe tremor [2]

Explain why there is cogwheel rigidity [2]

Answer 3

Bradykinesia is apparent through:

• Gait: short, shuffling steps with reduced arm swinging
• Difficulty initiating movement

Tremor

• worse when stressed or tired, improves with voluntary movement
• typically ‘pill-rolling’, i.e. in the thumb and index finger

Cogwheel rigidity:

• Lead pipe > cogwheel due to superimposed tremor
  Lead pipe rigidity is defined as a constant resistance to motion throughout the entire range of movement. Cogwheel rigidity refers to resistance that stops and starts as the limb is moved through its range of motion.

Question 4

Dopamine is the main neurotransmitter involved in Parkinson’s, where in the brain does it take effect?

Answer 4

Brain stem

• Vomiting Centres

Basal Ganglia

• Initiating/Controlling Movement

Limbic System & Frontal Cortex

• Reward Centres

Question 5

How/where is dopamine synthesised?

Answer 5

Dopamine is synthesised in both the brain and periphery but only its precursors can cross the BBB. Tyrosine -> DOPA -> Dopamine

Question 6

If Dopamine itself can’t cross the BBB how do we deliver it as a drug?

Answer 6

We give DOPA as a precursor. We have to block the AAAD enzyme in the liver to prevent the DOPA being converted to dopamine before it reaches the Brain

Question 7

Explain the variety of dopamine receptors?

Answer 7

D1-D5 receptors (All metabotropic i.e. G-protein coupled)
Different receptors appear in different parts of the brain

Question 8

What drug categories are there for Parkinson’s?

Answer 8

Dopamine Precursors

Dopamine Agonists

Dopamine breakdown Inhibitors (used to extend half life of levodopa)

Question 9

What enzymes are targeted by Dopamine breakdown Inhibitors?

Answer 9

MAO-B COMT

Question 10

What is used as a dopamine precursor?

Answer 10

Levodopa

Question 11

How do we extend levodopa’s half life?

Answer 11

• MAO-B inhibitors
• COMT inhibitors
• Slow Release Levodopa

Question 12

List some dopamine breakdown inhibitors?

Answer 12

MAO-B inhibitors: Selegiline, Rasagiline & Safinamide COMT inhibitors: Entacapone & Tolcapone

Question 13

We also use enzyme inhibitors to reduce Levodopa consumption in the periphery, how and why?

Answer 13

Carbidopa & Benserazide are AAAD inhibitors preventing conversion of Levodopa -> Dopamine in the periphery. This allows more oral levodopa to reach the brain and reduces PNS side effects

Question 14

List some dopamine agonists?

Answer 14

Ergots - Stimulate fibrosis and very dirty so no longer in use Non-ergots - Not as effective as Levodopa Apomorphine - Heavily stimulates brainstem dopamine receptors making it a powerful emetic

Question 15

What are the benefits of dopaminergic drugs?

Answer 15

Improves motor features of parkinson’s: - Bradykinesia - Rigidity - Tremor But doesnt improve things like cognition, balance or dysarthia

Question 16

Given the side effects of dopaminergic drugs, what could dopamine antagonists be used for?

Answer 16

N&V Long-term psychosis treatment

Question 17

Domperidone is a notable dopamine antagonist, what is it used for?

Answer 17

As an anti-emetic because it doesnt cross the BBB, but the vomiting centre in the medulla is actually outside it. This means domperidone won’t treat psychosis but will be anti-emetic without worsening parkinson’s. Hence its used in conjunction with apomorphine to prevent the emetic effect of the dopamine agonist

Question 18

Explain pathogenesis of PD

Answer 18

Neuronal Degeneration in the substantia nigra, particular its dopaminergic inputs to the striatum.

Dopamine is involved in enhancing the basal ganglia’s direct & indirect pathways without it it can be impossible to initiate the right movements and stop the wrong ones.

Question 19

How do you diagnose parkinsonism?

Answer 19

• Clinical diagnosis
• Should be slowly progressive (over 5-10 yrs)
• Symptoms will often be assymetric
• Response to treatment

Question 20

Describe investigations used to diagnose PD

Answer 20

Dopamine Transporter SPECT (a functional imaging technique)
* DaTSCAN: an ioflupane radioisotope is injected into patients.
* A gamma camera produces SPECT images, which demonstrate the isotope’s high affinity for the dopamine transporter, particularly in the striatum.
* Patients with Parkinson’s disease may demonstrate either unilaterally or bilaterally reduced uptake.
* Dopaminergic drugs can influence the scan and it must therefore be interpreted in this context.

L-DOPA challenge:
* patients are assessed before and after a large dose of levodopa (200-400 mg), using a validated measure
* such as a timed walk and/or unified Parkinson’s disease rating scale (UPDRS) score.
* Improvement with levodopa, though not diagnostic of Parkinson’s disease, is a useful guide to the likely efficacy of dopaminergic therapy.

Question 21

What causes huntington’s?

Answer 21

Its a hereditary genetic disorder
It occurs by profound loss of the caudate, putamen and globus pallidus
You lose the inhibitory effect of the basal ganglia and lots of violent, innapropriate movements are initiated

Question 22

What are the symptoms of huntington’s?

Answer 22

• Hyperkinesia
• Dementia
• Personality disorders

The characteristic chorea is spontaneous, uncontrolled, rapid flicks and major movements with no purpose

Question 23

What are the complications of parkinson’s?

Answer 23

• Depression
• Dementia (E.g. Lewy Body)
• Speech and balance issues
• Autonomic (E.g. problems controlling BP & continence)

Question 24

How does PD initially present in symmetry of symptoms?

Answer 24

Parkinson’s disease classically presents asymmetrically, so very symmetrical initial presentations suggest alternative causes (e.g. essential tremor, dystonic tremor, drug induced tremor, vascular Parkinsonism, normal pressure hydro- cephalus). Later in the disease duration, the signs may appear more symmetrical.

Question 25

How does PD initially present in symmetry of symptoms?

Answer 25

Parkinson’s disease classically presents asymmetrically, so very symmetrical initial presentations suggest alternative causes (e.g. essential tremor, dystonic tremor, drug induced tremor, vascular Parkinsonism, normal pressure hydro- cephalus). Later in the disease duration, the signs may appear more symmetrical.

Question 26

Describe early presentation of PD [4]

Answer 26

◆ Anxiety – may precede motor symptoms by decades.
◆ Olfactory decline/anosmia – an early but non-specific sign.
◆ Rapid eye movement (sleep) behavioural disorder (REM-BD) – strongly predictive of future
neurodegenerative pathology.
◆ Cognitive impairment – often of frontostriatal executive dysfunctio

Question 27

Late presentation of PD

Answer 27

◆ Worsening of symptoms and spread to involve the contralateral limbs.
◆ Cognitive problems become more apparent with poor memory and visual hallucinations.
◆ Systemic symptoms such as constipation, dysphagia, sleep disorder and autonomic failure (espe-
cially orthostatic hypotension and thermodysregulation) become as important and disabling (or more so) than the motor disability.

Question 28

Describe a festinating gait

Answer 28

Latin festinare [to hurry]
Festination is the shortening of each step in a long gait sequence, together with an increase in gait speed and involuntary forward-leaning of the trunk

Question 29

Prognosis of PD

Answer 29

55% of patients die within 10 years of diagnosis, with pneumonia being the commonest cause of death. Of the patients that survive:
* 68% have postural instability (predictors include age, non-tremor-dominant motor phenotype and comorbidity).
* 46% have dementia (predictors include age, motor impairment, ‘posterior-cortical’ cognitive deficits and MAPT [microtubule-associated protein tau] genotype).
* 23% are free of postural instability/dementia.

Question 30

Management of PD

Management of wearing off or on-off phenomena

Answer 30

later in the disease when fluctuations in symptoms become problematic, duodenal administration has been shown to provide more steady plasma levels and an improved clinical state.

Question 31

What is the difference between on-off phenomena and wearing off phenomena

Answer 31

on-off ’ phenomena with a switch between mobility and immobility with end-of-dose or ‘wearing off’ [worsening of motor function

Question 32

Name medications used in PD that are not levodopa
What side effects are dopaminergic therapies associated with? [3]

Answer 32

• bromocriptine, cabergoline, pergolide, ropinirole, pramipexole) available in oral form.
• These agents are associated with a susceptibility to impulse control disorders- dangers of pathological gambling, extramarital affairs, compulsive hoarding/collecting and punding.
• dopamine dysregulation syndrome - patients seek ever higher, more frequent doses of their dopaminergic drugs despite no apparent clinical benefit.
• The ‘ergot’-derived dopamine agonists, bromocriptine, cabergoline and pergolide have been associated with pulmonary, retroperitoneal and pericardial fibrotic reactions, and cardiac valvulopathy.

Question 33

Describe MOA of carbidopa and benserazide

Answer 33

This may be achieved by administration of levodopa in concert with a peripheral dopa decarboxylase inhibitor (either carbidopa or benserazide) to prevent its peripheral breakdown

Question 34

Describe 2 non-dopaminergic therapies

Answer 34

• Amantadine:
  ◆ Weak agonist at the NMDA-R that increases dopamine and norepinephrine release.
• Anticholinergics, e.g. trixhexyphenidyl/benzhexol, orphenadrine, procyclidine:
  ◆ Useful for treatment of tremor.
  ◆ Considerable anticholinergic side effect burden.

Question 35

Symptomatic tx of PD

Describe 3 treatments of non motor symptoms - orthostatic hypotension, cholinesterase inhibitors, neuroleptics

Answer 35

• Fludrocortisone (a mineralocorticoid), midodrine (α1-receptor agonist) and droxidopa (amino acid prodrug of norepinephrine that crosses the blood–brain barrier) for symptomatic orthostatic hypotension.
• Cholinesterase inhibitors (e.g. rivastigmine, galantamine and donepezil) for dementia.
• Neuroleptics for hallucinations or psychosis, taking care to avoid excessive dopamine antagonism that may worsen Parkinson’s disease symptoms; hence, quetiapine is most commonly employed.

Question 36

Name 6 other Parkinsonian syndromes

Answer 36

Parkinson’s disease with dementia
Dementia with Lewy bodies
Multiple system atrophy
Progressive supranuclear palsy (Steele–Richardson–Olszewski syndrome)
Corticobasal degeneration
Atypical parkinsonism

Question 37

Parkinsons disease with dementia and DLB

Answer 37

Parkinsons disease with dementia
* cognitive impairment, REM-BD, memory impairment are main features

DLB
* should be considered when cognitive disturbance presents early in the disease process, particularly if present before the motor disorder.
* may be part of disease process of Parkinsons
* sensitive to levodopa

Possible same pathophysiology

Question 38

Multiple system atrophy

Answer 38

• Early autonomic involvement (postural hypotension, urinary incontinence and male impotence)
• and/or cerebellar symptoms/signs with Parkinsonism should provoke consideration of this diagnosis.
• Parkinson- ism (MSA-p) or cerebellar signs (MSA-c) may predominate.
• Cognition is often preserved.
• The response to levodopa is often poor. Head drop is common.
• The primary neuropathology is of α-synuclein inclu- sions.

Question 39

Chronic management of Parkinsons disease

When would increasing the dose L-dopa be indicated?
When would increasing the frequency of L-dopa be indicated?

Answer 39

Increasing the dose of L-dopa is required when ‘off’ symptoms (bradykinesia, rigidity, freezing) do not respond to the starting dose
Increasing the frequency of L-dopa, which has a short half-life, is required when patients become ‘off’ in between doses. As the disease progresses the on period after each dose becomes shorter.