Migraine Flashcards
types of headaches
- Primary headaches
- Secondary headaches
A migraine is a primary headache – because it isn’t caused by a different medical condition, whereas seconday headaches are the symptom of another condition
What is aura
- Not everyone with migraine has an aura.
- Aura is a group of sensory motor and speech symtpoms – that are like warning signals that a migraine headache is about to begin.
- It can last 10 to 60 minutes typically before the headache pain – btu can appear during/even after.
- About 15 to 20% of people who experienced migraines have auras.
The four phases of mirgaine
- Prodrome
- Aura
- Headache
- Postdrome
prodrome phase:
The first stage lasts a few hours or even days.
Involves: problems concentrating, irritability, difficulty speaking, trouble sleeping etc.
Aura phase
The aura phase can last as long as 60 mins or as little as 5.
usually occurs before pain onset
headache phase
About four to 72 hours long.
postdrome
The postdrome stage goes on for a day or two – often called a migraine ‘hangover’ and 80% of those who have migraine experience it.
- Involves: being unable to concentrate, feeling depression, fatigue, difficulty undertsanding things, feeling euphoric
types of migraine: (6)
- Migraine without aura (common migraine)
- Migraine with aura (complicated migraine): 15-20%
- Migraine with brainstem aura
- Hemiplegic neuron - genetic with aura.
- chronic migraine (at least 15 days per month)
- status migrainosus (lasts over 72 hours)
risk factors for miragine (4)
- Genetics: up to 80% of people who get migraine headaches have a first-degree relative with the disease
- Gender: migraine headaches happen to women more than men – especially woman aged 15 and 55. Likely related to hormones
- Stress level: you get migraine with stress
- Smoking / caffeine
Genetics of migraine - named
Familial hemiplegic migraine (FHM1-4).
genes on GWAS identified in migraine:
TRPM8,
TASK2 channels,
glial Cx43
(NMDA and P2X7)
Familial hemiplegic migraine - TYPE 1
GoF mutation that’s found in a voltage-gated calcium channel – P/Q type calcium channel, which plays a large part of NT release. Expressed in excitatory neurons.
Familial hemiplegic migraine - TYPE 2
Mutation in Sodium-potassium ATPase, very important for keeping ionic gradient across neuronal membrane. If this fails – you end up initiating spreading depolarisation, which are fundamental to migraine with aura (and other diseases)
Familial hemiplegic migraine - TYPE 3
Mutation in voltage gated sodium channel – SCN1A. predominantly expressed in interneurons (inhibitory system in the brain). If you have a reduction/LoF you end up with DS. if you have too much (GoF) you end up with migraine.
Familial hemiplegic migraine - TYPE 4
Mutation in gene encoding PRRT2 (associated with poly-cystic kidney disease and infantile seizures.
cortical spreading depolarisation
CSD of spreading depolarisation is a wave of electrophysiological hyperactivity followed by a wave of inhibition.
CSD results in a profound vasodilation (in non-metabolically compromised tissue)
What does CSD induce
- CSD induces oedema, reflex middle meningeal vasodilation and increases neural activity in trigeminal ganglion and trigeminal nucleus (areas involved in pain processing).
CSD results in neuroinflammation of the meninges.
spreading depolairsation vs spreading depression
Depression: the suppression of neuronal activity recorded in ECoG signal. Reduction in brain activity as a consequence of depolarisation.
If you are recording depolarisation: cortical spreading depolarisation.
If you are looking at suppression of activity as a consequence of this depolarisation, this is cortical spreading depression.
How does CSD cause migraine pain:
CSD-activating pain receptors that are in the dura
- nociceptive neurons that innervate the dura mater are simulated
- release vasoactive neuropeptides such as calcitonin gene-related peptide (CGRP) and pituitary adenylate cyclase-activating polypeptide-38,
- causes activatity in trigeminovascular pathway and vasodilation
- also mast cell degranulation and plasma extravasation
underlied by ACTIVATION and SENSITISATION of the trigeminovascular network
where does the trigemino-cervical complex project to
multiple brainstem, thalamic, hypothalamic, and BG nuclei
how do triptans work
Triptans are effective abortive drugs. These work by a variety of mechanisms including:
- Vasoconstriction
- And target hypothalamus
- Have a multitude of sites of actions.
Calcitonin gene-related approach (CGRP) in migraine
very potent vasodilator which plays a major role in migraine pathophysiology. When released around the brain, dilates blood vessels and cause severe inflammation in the coverings of the brain (the meninges)
- CGRP-targeted drugs prevent/stop migraine entirely in 25% and an improvement is seen in a further 50%.
Pituitary adenylate cyclase-activating peptide (PACAP) in migraine
, PACAP is a vasodilator found in the trigeminal nerve, with levels rising during migraines.
- PACAP injections can induce migraine-like attacks in people who have previous experience with migraine.
- Severe PACAP ABs in CTs.
botox in migraine
- Can reduce frequency and disability, mechanism thought to be due to reduced release of NTs incl. CGRP, substance P and glutamate form peripheral trigeminal nociceptive neurons and disruption of TRP channels.
o Therefore, reduces neuronal hyperexcitability and both peripheral and central sensitisation to pain.
Topiramate in migraine
- Thought to exert its effect in chronic migraine prevention – through reduction of nociceptive transmission via trigeminovascular modulation, which inhibits neuronal hyperexcitability and suppresses the initiation and development of cortical spreading depolarisation.
non-pharma emerging treatments in migraine
Neuromodulation: both invasive and non-invasive show promise for treatment of chronic migraine. DBS.
Thalamocortical dysthymias in migraine patients may be responsible for abnormal cortical hyperexcitability – so focal cortical stimulation can suppress activation of ascending trigemino-thalamic pathway
gene therapy in migraine - chemogenetics
Potential role of chemogenetics: as migraines are paroxysmal – idea of chemogenetic approach is quite appealing (on-and-off switch effectively). – brief change in neuronal activity. Wouldn’t have to take drug every day – no adverse effects.
gene therapy in migraine - manipulating ion channels
reduce hyperexcitability of ‘pain pathway’ in neurons:
Increase potassium channels / decrease sodium channels to reduce the intrinsic excitability of pain pathway neurons.
gene therapy - prime editing
Maybe CRIPSR/Cas9 – can be good for enhancing or suppressing activity – RATHER then base editing. regulation of gene activation.
what is allodynia
- This refers to the experience of pain from stimuli that isn’t normally painful.
- Allodynia is the result of pain processing dysfunction in the nervous system called central sensitisation, nerve that carry pain signals react to sending pain signals in response to touch, movement, or temperature that wouldn’t normally cause pain.
- Many people with migraine report of allodynia – brushing hair is painful.
- Most common in those with migraine with aura, increases risk of episodic migraine processing to chronic migraine.
