Migraine (spring)

Question 1

what is a primary and a seconday headache?

Answer 1

primary headaches are headaches not caused by another medical condition.

secondary headaches are caused by problems elsewhere

Question 2

give examples of primary headaches

Answer 2

migraine

tension-type headache

cluster headache

(other primary headaches)

Question 3

what is a migraine?

Answer 3

a complex neurological disorder with no known cause or cure

Question 4

what are the two types of migraine and when do they occur?

Answer 4

episodic migraine- occurs on less than 15 days per month and can be further subdivided into low frequency (1–9 days per month) and high frequency (10–14 days per month)

Chronic migraine- occurs on 15 or more days per month

Question 5

what is the difference between migraine without aura and migraine with aura?

Answer 5

Migraine without aura:

• most common
• higher attack frequency
• usually more debilitating

migraine with aura:

• headaches classed as for without aura
• additional visual or sensory disturbances

Question 6

what is the diagnostic criteria for a migraine

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:

• unilateral location
• pulsating quality
• moderate or severe pain intensity
• aggravation by or causing avoidance of routine physical activity (e.g. walking or climbing stairs)

During headache at least one of the following

• nausea or vomiting
• photophobia and phonophobia

Headache not attributed to another disorder

Question 7

what is the diagnostic criteria for a migraine with 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:

• fully reversible visual symptoms including positive features e.g., flickering lights, spots or lines
• fully reversible visual symptoms including negative features e.g., loss of vision
• fully reversible sensory symptoms including positive features e.g., pins and needles
• fully reversible sensory symptoms including negative features e.g., numbness
• fully reversible dysphasic speech disturbance

At least two of the following:

• visual symptoms or unilateral sensory symptoms
• at least one aura symptom develops gradually over ≥5 minutes or different aura symptoms occur in succession over ≥5 minutes.
• each symptom lasts ≥5 and ≤60 minutes

Migraine with aura begins during the aura or follows aura within 60 minutes

Headache not attributed to another disorder

Question 8

what complications could arise with a migraine?

Answer 8

Status migrainosus - >72 h attack

Migrainous infarction (stroke) - Aura >1 h, blood vessels narrow O2 drops

Persistent aura without infarction - Aura >1 week

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

Migraine can be modified and controlled by lifestyle adjustment and the use of medicines

Over 100 triggers identified and can include: chocolate, alcohol, caffeine, sleeping late, and environmental triggers (strip lighting)

Question 10

Pathophysiology of migraines?

where did present understanding come from?

Answer 10

Migraine is a complex genetic disorder

Likely a polygenic multifactorial inheritance

Present understanding derived from familial hemiplegic migraine (FHM): a rare monogenic, autosomal dominant form of migraine with aura

Question 11

what is the current Migraine Theory?

Answer 11

Migraine is a neurovascular disease

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

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

Question 12

Common Prescriptions for Migraineurs… complete the table

Answer 12

Question 13

First Line Acute Treatments for migraine (give doses too)

Answer 13

• Aspirin (900 mg): first-line treatment for patients with acute migraine.
• Ibuprofen (400 mg): first-line treatment for patients with acute migraine. If ineffective, the dose should be increased to 600 mg.
• Triptans: first-line treatment for patients with acute migraine. The first choice is sumatriptan (50-100 mg), but others should be offered if sumatriptan fails.
• Combination therapy using sumatriptan (50-85 mg) and naproxen (500 mg).
• Often prescribed with anti-emetics e.g., Metoclopramide (10 mg) or prochlorperazine (10 mg).

Question 14

what did 5-Hydroxytryptamine lead the discovery of?

give examples

what are they used for?

Answer 14

Triptans: 5-HT1D/B/F receptor agonists

• e.g., Sumatriptan (1st generation)
• e.g., Zolmitriptan, Rizatriptan, Naratriptan (2nd generation) (have higher oral bioavailability and longer plasma half-life)

Do not prevent migraines-provide relief

Question 15

moa of triptans?

Answer 15

constriction of cranial arteries (5-HT_1B/D receptors)

inhibitory actions on the CNS (5-HT_1B/D receptors)

inhibition of presynaptic TG neurons (5-HT_1B/D/F receptors)

Question 16

in which patients are triptans contraindicated?

what happens if triptans are overused?

Answer 16

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

Overuse can cause severe rebound attacks-medication-overuse headaches

Question 17

Prophylactic Treatment for Migraine:

in which patients?

aim?

which drugs and how do they work?

Answer 17

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., propranolol (80-160 mg, daily): unclear how they work as they cause dilation of blood vessels
• Topiramate (50–100 mg daily): blocks voltage-dependent sodium and calcium channels; mechanism of action for migraine unclear
• Tricyclic anti-depressants e.g., amitriptyline, (25-150 mg at night), thought to work by preventing reuptake of 5-HT and antagonizing 5-HT2 receptors
• Anti-convulsants e.g., sodium valproate (400-1500 mg daily); voltage-dependent sodium channels
• Candesartan (16 mg daily); angiotensin II receptor antagonist
• Botulinum toxin A is recommended for the prophylactic treatment of patients with chronic migraine where medication overuse has been addressed and patients have been appropriately treated with three or more oral migraine prophylactic treatments

Question 18

what is CGRP?

what happens to CGRP levels during migraine attacks?

Answer 18

Calcitonin Gene-Related Peptide is a multifunctional 37 amino acid neuropeptide; derived from alternative processing of the calcitonin gene.

it is a potent vasodilator and is involved in neurogenic inflammation and nociception

Increased levels of CGRP in serum and saliva of migraineurs during attacks. CGRP receptors are present at sites relevant to migraine

Question 19

What can mice tell us about migraines and how are they used?

Answer 19

humanized CGRP receptor mice; express human RAMP1

important as CGRP receptors are species specific

CGRP injected mice spent more time in the dark and Anti-CGRP receptor drugs prevent dark seeking behaviour

Question 20

describe how CGRP Receptors are used as Molecular Targets for the Treatment of Migraine?

Answer 20

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.

• Additional drawbacks include short duration of effect

Additional CGRP receptor antagonists are currently being developed and trialed

Question 21

development of Monoclonal Antibodies to Treat Migraine?

how are Monoclonal Antibodies used?

what is an issue with using Monoclonal Antibodies?

Answer 21

• anti-CGRP antibodies
• an anti-CGRP receptor antibody

Monoclonal antibodies have to be injected (intravenous or subcutaneous)

Must be humanized or fully human antibodies

Long-term consequences of injecting antibodies is unknown

Question 22

what are current preventative (not cure) Prophylactic Treatments for Episodic and chronic migraine?

Answer 22

Erenumab (Aimovig): CGRP Receptor

Galcanezumab (Emgality): CGRP ligand

Fremanezumab (Ajovy): CGRP Ligand

Eptinezumab (Vyepti): FDA approved February 2020-CGRP ligand.

Question 23

what are current acute Treatments for migraine?

Answer 23

Gepants (CGRP receptor antagonists)

• Ubrogepant (Ubrelvy): The first-in-class oral CGRP antagonist
• Rimegepant (Nurtec ODT)
• Atogepant: currently being studied

Ditans (5-HT1F receptor antagonists)

• Only affects nerves, not blood vessels.
• Lasmiditan (Reyvow)