PH2113 - Neurodegenerative Disease and Epilepsy 7

Question 1

What is the initial treatment for Multiple Sclerosis?

Answer 1

Gold standard
- high dose short term corticosteroids for relapsing-remitting
- intravenous methylprednisolone
- 500mg - 1g daily, 3 - 5 days
OR
- high dose oral methylprednisolone
- 500mg - 2g daily, 3 - 5 days
May help restore integrity of Blood-Brain Barrier, suppress inflammation, circulating immune cells (activated lymphocytes) and activity of toxic cytokines
Does NOT affect long-term course of disease
- reduce duration of a relapse by few weeks
- no effect on disability accrued

Side effects
- weight gain
- skin thinning
- hypertension
- diabetes
- osteoporosis
- Cushing’s syndrome

Gradual withdrawal needed if in long term use

Question 2

What are the treatments for Multiple Sclerosis?

Answer 2

15 disease modifying agents for Relapsing-Remitting Multiple Sclerosis
- interferon beta (5)
- glatiramer acetate (2)
- monoclonal antibodies
- natalizumab
- alemtuzumab
- daclizumab
- ocrelizumab
- chemotherapeutic agents
- mitoxantrone
- small molecule oral agents
- fingolimod
- dimethyl fumarate
- teriflunomide

Question 3

Give examples of interferon treatments for Multiple Sclerosis

Answer 3

Generally safe – only partially effective

Betaferon
- interferon beta-1b
- sub cut 0.25mg alternating days
Avonex
- interferon beta-1a
- intramuscularly 30ug once a week
Rebif
- interferon beta-1a
- sub cut 22 or 44ug 3 x a week

Question 4

How does interferon-beta treat Multiple Sclerosis?

Answer 4

Thought to inhibit some of the downstream effects of interferon-gamma
- proinflammatory cytokine
Beneficial effect on Blood-Brain Barrier by inhibiting MMPs
- affecting migration of lymphocytes across Blood-Brain Barrier
- altering balance of pro-inflammatory Th1 response to suppressor Th2 response

Question 5

What are the side effects of using interferon-beta to treat Multiple Sclerosis?

Answer 5

Flu-like symptoms
Injection site reactions
Nausea
Blood disorders
Depression
Mild lymphpaenia

Question 6

What are the contraindications of using interferon-beta to treat Multiple Sclerosis?

Answer 6

Severe depressive illness
Liver disease

Question 7

What is the mechanism of using Copaxone (a protein drug) to treat Multiple Sclerosis?

Answer 7

Mixture of polypeptides
- resembling MBP
- glutamic acid
- lysine
- alanine
- tyrosine
Sub-cut 20mg once per day
Thought to block interaction of activated T cells with myelin
Altering the balance of proinflammatory Th1 response to suppressor Th2
Induction of a specific Th2 (CD4+) population in the periphery
- may enter the CNS
- reactivated by cross reactivity with myelin antigens
Secrete anti-inflammatory cytokines
- damage the local inflammatory process
- bystander suppression
Response against one Ag is suppressed when it is presented in the context of an Ag to which tolerance is already established

Question 8

What are the statistics for the onset and incidence of Huntington’s disease?

Answer 8

Typical onset
- 30 - 50 years of age
15 - 20 years from diagnosis to death
Incidence of 3-7 per 100,000

Question 9

What are the main symptoms of Huntington’s disease?

Answer 9

Hallmark symptoms include:
Uncontrolled movement of the arms, legs, head face and upper body. Also causes a decline in thinking and reasoning skills, including memory, concentration, judgement and ability to plan and organise

First motor signs:
- Abnormal eye movements
- Inappropriate hand and toe movements
- General restlessness
Midcourse
- Onset of involuntary movements
- Hypertonic rigidity and dystonia
Late stage
- Impaired voluntary movements
- Rigidity
- Bradykinesia
- Convulsions
- Weight loss

Question 10

What are the motor deficits of Huntington’s disease?

Answer 10

First motor signs
- abnormal eye movements
- inappropriate hand and toe movements
- general restlessness
Midcourse
- onset of involuntary movements
- chorea
- hypertonic rigidity and dystonia
- slow abnormal movements with increased muscle tone
Late stage
- impaired voluntary movements
- rigidity
- bradykinesia
- dystonia
- convulsions
- weight loss
Death
- pneumonia
- choking
- chronic skin ulcers
- nutritional deficits

Question 11

What are the cognitive deficits of Huntington’s disease?

Answer 11

Executive function
- planning
- cognitive flexibility
- abstract thinking
- rule acquisition
Perceptual and spatial skills
- self
- surrounding environment
Memory
Learning
- new skills is affected

Question 12

What are the psychiatric symptoms of Huntington’s disease?

Answer 12

Vary more than cognitive and physical
- blunting
- egocentrism
- anxiety
- depression
- aggression
- compulsion
- additions
- alcoholism
- gambling
- hypersexuality

Question 13

What is the pathology of Huntington’s disease?

Answer 13

10 - 20% reduction in brain weight
Decreased striatal volume and cell death
Decreased cortical volume and cell death
Increased ventricle size
Proteinous inclusions throughout brain
- huntingtin protein
Loss of GABAergic medium spiny neurones
- especially in caudate and putamen

Question 14

What is the pathway in Huntingtin’s disease?

Answer 14

Loss of neurones from the striatum to the globus pallidus
- chorea
Imbalance between D1 and D2 receptors

Question 15

How is Huntington’s disease inherited?

Answer 15

Autosomal dominant gene mutation
- 50% chance of passing it on
- almost 100% penetrance
- gene affected encodes the protein huntingtin
- gene identified in 1993

Question 16

What is Huntingtin?

Answer 16

Protein widely expressed in brain and periphery
- neocortex
- striatum
- cerebellar cortex
- hippocampus
Does not explain Huntington’s disease cell death patterns!

This gene is Essential for embryonic development
- mainly in the cytoplasm but also nuclear
- transcription
- intracellular transport
- intracellular signalling
- metabolism

Question 17

What is the mutation to the gene to cause Huntington’s disease?

Answer 17

The lengthened CAG repeat increases capacity of protein to aggregate in vitro producing insoluble polymers
- > 39 glutamines

Polymers may be pathogenic trigger
Aggregates may be protective

The shorter fibrils are likely to be the to be the toxic element as they grow.

Effects of the mutant protein
- Alters endocytic and secretory pathways
- Proteosomal function
- Calcium handling and mitochondrial function
- Reduced transport of growth factors

Triggers apoptotic cascades, free radical production (causes oxidative stress) glutamate toxicity

Question 18

What is the mechanism of pathology in early disease for MS ?

Answer 18

We lose neurones in d2 pathway predominantly. imbalance between direct and indirect pathways causing less inhibition of the thalamus. therefore more activation of the cortex causing excessive involuntary movement.

As d1 spiny neurones catch up and also start to perish we also see a loss of drive through the D1 pathway and get a complete reduction in movement.