Migraine

Question 1

Define primary and secondary headaches

Answer 1

Primary headaches are headaches not caused by another medical condition

Secondary headaches are caused by problems elsewhere

Question 2

What headaches are primary?

Answer 2

Migraine
Tension-type headache
Cluster headache

Question 3

How many people does migraine affect? which gender? Age group?

Answer 3

1 in 7 people in the UK
More common in women than in men

Affects people during their most productive years 18-55 years

Question 4

What is a migraine?

Answer 4

a complex neurological disorder with no known cause or cure

Ranked #19 by WHO among all diseases world-wide causing disability

Question 5

What are the two major sub types of migraine?

Answer 5

Migraine without aura:
most common
higher attack frequency
usually more debilitating

Migraine with aura:
classed same as without aura in addition to visual and /or sensory disturbances

Question 6

What is the diagnositic criteria for migraine without an aura?

Answer 6

At least five headache attacks lasting between 4-72 hours (untreated or unsuccessfully treated
Headache must have at least two of the following characteristics:
1. unilateral location
2. pulsating quality
3.moderate or severe pain
4. aggravation by or causing avoidance of routine physical activity e.g walking

During the headache at least one of the following:

1. nausea and/or vomiting
2. photophobia and phonophobia (fear of loud sounds)

Headache not attributed to another disorder

Question 7

What is the diagnositic criteria for migraine with an aura?

Answer 7

At least two headache attacks (as characterized for without aura)lasting between 4-72 hours
Patients must have no motor weakness and have aura consisting of:
1. fully reversible visual symptoms including positive features e.g., flickering lights, spots or lines
2. fully reversible visual symptoms including negative features e.g., loss of vision
3. fully reversible sensory symptoms including positive features e.g., pins and needles
4. fully reversible sensory symptoms including negative features e.g., numbness
5. fully reversible dysphasic speech disturbance

At least two of the following:
1. visual symptoms and/or
unilateral sensory symptoms
2. at least one aura symptom develops gradually over ≥5 minutes and/or different aura symptoms occur in succession over ≥5 minutes
3. each symptom lasts
≥5 and ≤60 minutes

Migraine without aura begins during the aura or follows aura within 60 minutes
Headache not attributed to another disorder

Question 8

When can migraines kill? (4)

Answer 8

1. Status migrainosus
>72 h attack; rule out stroke
2. Migrainous infarction
Aura >1 h; rule out stroke
3. Persistent aura without infarction
Aura >1 week; rule out stroke
4. Migraine aura-triggered seizure
Seizure follows a migraine

Question 9

What Triggers Migraine Attacks?

Answer 9

Migraine is an inherited tendency to headache and cannot be cured
Over 100 triggers identified
Chocolate
Caffeine 
Sleeping late
Alcohol
Environmental e.g strip lighting

Question 10

What is the current migraine theory?

Answer 10

Activation and sensitization of the trigeminovascular pain pathway
Innervates cranial tissues, in particular the meninges and their large blood vessels
A phenomenon called “Cortical Spreading Depression” is the neurophysical correlate of migraine aura

Question 11

What is cortical spreading depression?

Answer 11

Cortical Spreading Depression is a slowly propagating wave of strong neuronal and glial depolarization

Question 12

What is Familial Hemiplegic Migraine Type 1?

Answer 12

Mutation of neuronal Cav2.1 channel
Mutated channels have a gain of function-increased open probability
Shifted activation to more negative voltages
Higher propensity to propagate CSD

Question 13

What are the common prescriptions for migraines although usually used for something else?

Answer 13

Beta Blocker/Calcium channel blockers
Narcotic analgesics e.g. codeine
Tricyclic antidepressants
Ergots (Discovered in 1920s; originally used to stop bleeding after a woman gave birth)

Triptans - an actual migraine drug

Question 14

How are 5-Hydroxytryptamine used in treatment?

Answer 14

Slow intravenous infusions of 5-HT could abort a migraine attack
Lead to the discovery of “Triptans”: 5-HT1D/B/F receptor agonists

e.g. sumitriptan (1st gen)
Zolmitriptan, Rizatriptan (2nd gen)

Question 15

What makes 2nd gen triptans different to 1st gen?

Answer 15

have higher oral bioavailability and longer plasma half-life

Question 16

What is the proposed mechanism of action of triptans?

Answer 16

constriction of cranial
arteries - 5-HT1B/D
receptors

inhibitory actions
on the CNS - 5-HT1B/D
receptors

inhibition of
presynaptic TG
neurons - 5-HT1B/D/F
receptors

Question 17

What are triptans contraindicated in?

Answer 17

Contraindicated in patients with coronary or cardiovascular disease, hypertension or that are pregnant

Question 18

What is the caution with using triptans?

Answer 18

Overuse can cause severe rebound attacks-medication-overuse headaches

Question 19

What additional treatments are there?

Answer 19

Simple analgesics

Anti-emetics e.g. metoclopramide are often taken with other medications to hasten absorption

Ergots e.g., ergotamine, dihydroergotamine also act on 5-HT1 receptors but are only partial agonists

Opioid medications e.g., codeine can be used for patients with contraindications for triptans and ergots. Can be habit forming used a last resort

Question 20

What sort of prophylactic treatments are there?

Answer 20

Considered for patients suffering 4+ attacks per month

Preventive medications aim to reduce the frequency, severity and length of migraines and may increase the effectiveness of symptom-relieving medicines used during migraine attacks

b-blockers e.g., metoprolol, propranolol: unclear how they work as they cause dilation of blood vessels

Tricyclic anti-depressants e.g., amitriptyline, nortriptyline work by preventing reuptake of 5-HT and antagonizing 5-HT2 receptors

Anti-convulsants e.g., sodium valproate, gabapentin

Non-steroidal anti-inflammatory drug (NSAID) e.g., Naproxen

Calcium channel blockers e.g., verapamil

Question 21

What additional treatments are there? part 2

Answer 21

Anti-serotonergic (Anti 5-HT) drugs e.g., Pizotifen, Methysergide work by antagonizing 5-HT2 receptors

Methysergide is a semi synthetic ergot alkaloid. It should only be administered under hospital supervision because of the side effects (retroperitoneal fibrosis and fibrosis of heart values and pleura)

Botulinium toxin A (Botox®) licensed for the treatment of chronic migraine (15+ attacks per month)

Mechanism of action is yet unknown, but thought to work by relaxing muscles and by inhibiting the release of peripheral nociceptive neurotransmitters e.g., CGRP

Question 22

What role does calcitonin gene-related peptide play?

Answer 22

Molecular mediator of migraine

Question 23

What is calcitonin gene-related peptide?

Answer 23

a multifunctional 37 amino acid neuropeptide
a potent vasodilator and is involved in neurogenic inflammation and nociception
Increased levels of CGRP in serum and saliva of migraineurs during attacks
Injection of CGRP into migraineurs can cause delayed migraine-like headaches

Question 24

Using the CGRP receptors as molecular targets, what drugs are out there in trials?

Answer 24

CGRP receptor antagonists the so-called “Gepants” have been promising in clinical trials
Olcegepant: first CGRP receptor antagonist to enter trials- Efficacious in Phase II clinical trials: i.v. only, poor oral availability

Telcagepant: reached Phase III trials before termination due to high liver transaminases

Question 25

With the development of monoclonal antibodies to treat migraines. what are the requirements?

Answer 25

Monoclonal antibodies have to be injected (intravenous or subcutaneous)
Must be humanized or fully human antibodies
Long-term consequences of injecting antibodies, unknown