migraine

see also:

• Mx of acute migraine
• acute unilateral headache
• headache
• neurology
• cervicogenic headache
• http://www.sciencemag.org/news/2016/01/feature-will-antibodies-finally-put-end-migraines

• the third most common medical condition worldwide
• ranks as the seventh most disabling condition in terms of years of life lost to disability
• of the general population:
  • 24% of females aged 40yrs have migraine
  • 10% are active migraineurs (6% of males, 15% of females)
  • 5% have at least 18 migraine days per year
  • 1% have at least 1 migraine day per week
• migraine patients:
  • anyone can have an attack occasionally without necessarily being a migraine patient, it is not the attack but the repeated occurrence that is abnormal, thus:
    • definition:
      • at least 2 attacks with aura, or,
      • at least 5 attacks without aura
    • onset < age 50yrs in 90%
    • peak incidence:
      • age 10-12yrs males
      • age 14-16yrs females
    • from age 16yrs, F:M ratio = 2-3:1
    • among active migraineurs:
      • median attack frequency 1.5 per month
      • >10% have weekly attacks
      • median attack duration is 1 day, but 20% have attacks lasting 2-3 days
• associated co-morbidities:
  • epilepsy
  • major affective & anxiety disorders
  • ischaemic stroke (only in young females)
  • endolymphatic hydrops including Meniere's disease - migraine may have a role in causing deafness

• genes possibly involving ion-channel function appear to set the individual threshold
• 44 independent DNA variants have been robustly associated with migraine risk, these map to 38 genes
• may be related to methyltetrahydrofolate reductase gene (MTHFR gene) variants C677T (esp. migraine with aura) and A1298C
  • hence folate metabolism could play a role in the pathophysiology of migraine
• familial hemiplegic migraine (FHM):
  • in half of reported families, FHM has been assigned to chromosome 19p13 (involving the Cav2.1 (P/Q) type voltage-gated calcium channel CACNA1A gene) and this group are more likely to have cerebellar ataxia and attacks triggered by minor head trauma
  • those families without the chromosome 19 link do not get cerebellar ataxia
  • 20% of the families have mutations in the ATP1A2 gene ( Na+/K+ ATPase gene)

• see also:
  • Ann Indian Acad Neurol. 2012 Aug; 15(Suppl 1): S15–S22. Pathophysiology of migraine
• it seems likely that the trigeminovascular system and its cranial autonomic reflex connections, the trigeminal–autonomic reflex, act as a feed-forward system to facilitate the acute attack, the fundamental problem in migraine is in the brain due to inherited channelopathies and is no longer considered to be caused by cerebral vasodilatation.
• the group of neurons from the superficial laminae of trigeminal nucleus caudalis and C1/2 dorsal horns can be regarded functionally as the “trigeminocervical” complex and can explain the occipital headache component of migraine
• the large cerebral vessels, pial vessels, large venous sinuses and dura mater is surrounded by a plexus of largely unmyelinated fibers that arise from the ophthalmic division of the trigeminal ganglion and in the posterior fossa from the upper cervical dorsal roots
  • stimulation of the trigeminal ganglion has been shown to cause increases in extracerebral blood flow and local release of both CGRP and SP, and neurogenic plasma extravasation around the dura as well as structural changes of the dura including mast cell degranulation
  • plasma extravasation can be blocked by ergot alkaloids, indomethacin, acetylsalicylic acid and the serotonin-5HT1B/1D agonist, sumatriptan
• following transmission in the caudal brain stem and high cervical spinal cord, information is relayed rostrally such that vascular nociceptive signals processing then occurs in the ventroposteromedial (VPM) thalamus, medial nucleus of the posterior complex and in the intralaminar thalamus
• in addition, recent studies have suggested that uncorrected ocular refractive errors such as astigmatism, spherical equivalent (SE), and anisometropia are more likely to be present in migraine sufferers than in those without migraines.¹⁾
• aura
  • 30% have aura and this appears to have a neurogenic origin
  • the aura appears to be the human equivalent of the cortical spreading depression (CSD) of Leao in animals
  • visual aura has been described as affecting the visual field, suggesting the visual cortex, and it starts at the center of the visual field, propagating across the visual cortex to the periphery at a speed of 3 mm/min
  • focal hyperemia tends to precede the spreading oligemia
    • after oligaemia, the cerebrovascular response to hypercapnia in patients is blunted while autoregulation remains intact
    • CSD induces nitric oxide release and cerebral vasodilatation
    • ketamine is well known to block CSD in animals can ameliorate prolonged aura in patients

• cervicogenic triggers
  • perhaps mediated by the greater occipital nerve at level of C1 facet joints
• insulin metabolic theory
  • most, if not all of the common migraine triggers (sucrose, red wine, peanuts, menstrual cycle, oral contraceptives, bananas, aspartame, glucosamine, monosodium glutamate, caffeine, citrus and emotional stress) can potentially reduce insulin sensitivity raising the possibility that insulin may have a common role in triggering attacks via a cascade of metabolic events²⁾
• subtle increases in intracranial pressure theory
  • GLP-1 agonists appear to reduce frequency of migraine attacks apparently by modulating cerebrospinal fluid pressure and reducing intracranial venous sinuses compression, resulting in a decrease in the release of calcitonin gene-related peptide (CGRP), a key migraine-promoting peptide ³⁾
• modulators of genetic threshold:
  • hormonal fluctuations (eg. oestrogen OCP, progesterone)
    • combined oral contraceptive pill (OCP) or progesterone-only contraceptive regimes may alter frequency of migraines
    • migraines are often related to the menstrual cycle
    • migraines usually improve in the 2nd and 3rd trimesters of pregnancy as hormonal levels stabilise but then recommence or may start for the first time in the 1st week post partum (DDx includes post LP headache)
  • fatigue
  • relaxation after stress eg. after a strenuous day, on vacations or weekends
  • meteorological changes eg. hot, humid weather or changes in weather
  • air pollution
  • substance misuse
  • sleep deprivation
  • excessive sleep
  • fasting
  • food (precipitates attacks in 15-20% of sufferers):
    • tyramine-containing (eg. red wine, hard cheeses, herring)
    • phenylethylamine-containing (eg. chocolate)
    • 1-octopamine (eg. citrus)
    • nitrites (eg. processed meats)
    • caffeine withdrawal or XS
    • monosodium glutamate
  • vasodilators (eg. alcohol, nitrogylcerin, some anti-hypertensives)
  • exercise
  • orgasm
• inter-ictal cortical hyperexcitability:
  • excitability level is proportional to attack frequency
  • ? due to:
    • defective mitochondrial oxidative phosphorylation
    • low intracellular magnesium
    • increased levels of neurotoxic amino acids
    • inherited dysfunction of calcium channels
• migraine generator:
  • PET scans have revealed an area of increased cerebral blood flow in contraleteral upper brainstem which may be important in initiating attack & unlike the secondary activation of cortical pain areas, persists despite pain relief with sumatriptan
  • role of blue and grey light:
    • it appears that even low levels of blue or grey light triggers a neural pathway via melanopsin retinal cells which causes persistence of activity in certain neurons for up to 20-30min following the exposure⁴⁾

• nitric oxide:
  • IV infusion of NO resulted in greater dilatation of middle cerebral artery and were more likely to develop migraine headache (without aura) cf with placebo or non-migraineurs
  • thus ? role for NO in initiation & maintenance of migraine headache
• migraine aura:
  • traditional view that aura is due to vasoconstriction whilst headache due to vasodilatation - is too simplistic
  • current view:
    • aura is caused by “cortical spreading depression” (CSD), a depolarisation wave that propagates across the brain cortex at 2-3mm/min & is assoc. with transient depression of spontaneous & evoked neuronal activity. This wave lasts several minutes, preceded by a front of brief neuronal excitation & intense spike activity.
    • CSD has yet to be unequivocally demonstrated in man.
• headache & associated symptoms:
  • activation of trigeminovascular system is pivotal
  • afferent fibres, arising from ophth. division of CV & the upper Cx spinal cord segments, innervate the proximal parts of the large cerebral vessels, pial vessels, large venous sinuses, & dura mater
  • these sensory fibres carry nociceptive information & project centrally, terminating within the trigeminal nucleus caudalis in the lower brainstem & upper Cx cord.
  • the information is relayed further via the quintothalamic tract to the thalamus & cortical pain areas
  • depolarisation of trigeminal ganglion or its perivascular nerve terminals activates the trigeminovascular system (this can also be activated by exptal CSD ⇒ link headache to aura)
    • ⇒ central transmission of nociceptive information & retrograde perivascular release of powerful vasoactive neuropeptides, which in animal expts promote a neurogenic inflammation response (yet to be demonstrated in migraine) consisting of 2 componenets:
      • dural vasodilatation mediated via release of calcitonin-gene-related peptide (CGRP) from trigeminal Adelta-fibres
      • dural plasma extravasation mediated via release of neurokinin A & substance P from trigeminal C-fibres.
• serotonin:
  • migraineurs have a systemic disturbance of 5HT metabolism assoc with low 5HT plasma levels b/n attacks & increased levels & release of platelet 5HT during attacks.
  • contrary to earlier belief, the ictal rise of plasma 5HT is not the cause of migraine but probably represents a self-defence mechanism
  • selective stimulation of 5HT1 receptors may safely abort attacks

• if 3 of the following criteria are met, then a LR+ = 3.5x, if 4 are met then LR+ is 24x⁵⁾:
  • Pulsating
  • duration of 4-72 hOurs
  • Unilateral
  • Nausea
  • Disabling

• premonitory phase
  • begins 24 to 48 hours before a migraine attack fully sets in
  • associated with over activity of the hypothalamus
  • symptoms include poor concentration, food cravings esp. chocolate, irritability and insomnia
  • Rx with rest, anti-migraine meds or NSAIDs in this phase may avoid or minimise the headache phase
• aura phase
  • occurs in 30% of those with migraine
  • thought to be due to cortical spreading depression in which a slowly spreading wave of electrical activity occurs
  • may have:
    • visual auras - flashing lights, swirling shapes, moving wavy lines, blind spots
    • sensory auras - numbness or tingling of face or limb
    • some have dysphasia
  • Rx with rest, anti-migraine meds or NSAIDs in this phase may avoid or minimise the headache phase
• headache phase
  • usually throbbing unilateral headache associated with nausea and light/sound sensitivity
  • may also cause facial pain if trigeminal nerve is activated
  • partly mediated by calcitonin gene-related peptide (CGRP)
  • lasts 4-72hrs if untreated
• post-drome
  • “hangover” phase often with even more fatigue, poor cognition
  • not managing this phase well by rest may lead to more difficult to treat “overlapping migraines”

• attacks lasting 4-72h untreated
• at least 2 of the following headache characteristics:
  • unilateral
  • pulsating
  • moderate to severe (disturbing or precluding daily activities)
  • aggravated by movement
• at least one associated symptom:
  • nausea or vomiting
  • photophobia
  • phonophobia

• NB. 33% migraineurs experience both types during their life
• criteria for typical aura:
  • 1 or more transient focal neurological aura symptoms ⇒ focal cortical or brainstem dysfunction
    • 99% have visual, together with sensory (31%) or aphasic (18%) symptoms & rarely, motor ones (6%)
  • gradual development of aura symptom over > 4min, or several symptoms in succession
  • aura symptoms last 4-60min
  • headache follows or accompanies aura within 60min
    • up to 42% pts have attacks of aura without headache
• 5 stages of an attack:
  • prodrome
    • food craving, yawning, heightened perception, fluid retention
    • may start 50hrs before the headache
  • aura
    • visual field changes
  • headache
    • anorexia, nausea, +/- vomiting
    • malaise, lethargy
    • photophobia
    • heightened sense of smell
    • difficulty focusing
    • poor concentration
    • usually lasts 4-72hrs
  • resolution phase
    • vomiting
    • deep sleep
    • medications
    • usually lasts 2-12hrs
  • recovery phase
    • limited food tolerance
    • tired
    • hungover
    • diuresis
    • usually lasts 2-24hrs

• a subtype of migraine with aura
• at least 2 aura symptoms originating in brainstem or both occipital lobes

• rare autosomal dominant
• discovery of genetic basis has revolutionised our understanding of various disorders, now episodic (migraine, hemiparesis, epilepsy, ataxia) and chronic (ataxia, cerebellar atrophy) neurological syndromes in man and mouse can be regarded as “cerebral calcium channelopathies”. P/Q type Ca channels are involved in CSD & release of neurotransmitters including 5-HT.

• see acute unilateral headache and headache

• sub-arachnoid haemorrhage - sudden onset “new” headache
• AV malformations, internal carotid dissections, epilepsy
• mitochondrial DNA disorders (eg. mitochondrial encephalopathy with lactic acidosis & stroke-like episodes [MELAS])
• cerebral autosomal dominant arteriopathy with subcortical infarction & leucoencephalopathy (CADASIL)
• hemicrania continua
  • chronic mainly unilateral headache for over 3 months without painfree intervals which resolves completely with indomethacin Rx (which must be used long term in doses 25-300mg/d) but not with triptans
  • easily misdiagnosed as migraine or cluster hedaches as other features may include brief stabbing retro-orbital pains, throbbing nature, nausea, phonophobia, photophobia, conjunctival injection, nasal congestion, rhinorrhoea, ptosis or miosis

• may also occur in migraineurs & needs to be Rx on its merits
• diagnostic criteria (opposite to those in migraine headache):
  • at least 2 headache characteristics:
    • bilateral
    • non-pulsating
    • mild-moderate
    • no aggravation by movement
    • no or only mild nausea or photophobia or phonophobia

• gradual increase in headache frequency & drug consumption & a change in headache characteristics
• pts ultimately use “painkillers” and large quantities of caffeine-containing drinks to Rx daily atypical headaches, alternating with migraine-like aggravations
• daily use of a low dose is much riskier than large amount on one day of the week
• frequent headache sufferers who use painkillers or anti-migraine drugs more often than 1-2 days/wk should withdraw abruptly from all analgesics and caffeine
• after a few weeks of withdrawal symptoms, the severity & frequency of headaches usually decreases & the original headache characteristics return, permitting correct Dx & Rx

• sinusitis
• CNS infections
• head Injury

• simple pain, analgesia and analgesics
• non-steroidal anti-inflammatory drugs (NSAIDs)
• anti-emetics

• ergot alkaloids
• triptans
• calcitonin gene-related peptide (CGRP) receptor antagonists
  • atogepant appears to be effective

• see Mx of acute migraine

• avoid over-stimulation - prolonged computer use, etc
• avoid sleep deprivation
• get adequate exercise
• avoid excessive caffeine - consider weaning off caffeine totally (sudden caffeine withdrawal causes headaches)
• avoid hormonal therapies which exacerbate migraine
• manage stress

• only help ~50% of patients and even then tend to reduce attacks by ~50%.
• individual response is unpredictable
• high risk of adverse effects
• beta adrenergic blockers
  • usual adverse effects of beta blockers
  • propranolol
  • metoprolol
  • and probably atenolol, timolol & nadolol but efficacy not shown for other beta blockers
• 5HT receptor antagonists:
  • pizotifen
    • tends to cause weight gain
  • methysergide
• anticonvulsants
  • topirimate
    • NPS RADAR Dec 2008 - topirimate for migraine prevention
    • PBS approval only if cannot tolerate beta blockers or pizotifen
    • usual dose 50mg bd
    • 50% develop paraesthesiae
    • 6-7% develop cognitive effects including cognitive slowing, language difficulties and difficulties with memory and concentration.
    • tends to produce weight loss rather than weight gain
    • no evidence that topiramate is more effective than other migraine-prevention drugs
  • sodium valproate
• recent trial showed promising results with high dose riboflavine (vit. B2) which increases mitochondrial energy efficiency
• evidence is lacking for efficacy of:
  • amitryptiline
  • calcium channel blockers
  • clonidine
  • NSAIDs
  • herbal drug feverfew
  • hormonal manipulations
• verapamil (Isoptin) is highly effective in preventing cluster headaches
• folic acid, vitamin B6/12 supplements
  • appear to halve migraine episodes in a pilot study - see here
• botox injections
  • now available on PBS for those who suffer migraine on 15 or more days each month
  • injections are given by a neurologist into 31 spots, including the forehead, temples and back of the head
• calcitonin gene-related peptide (CGRP) blockers
  • erenumab (Aimovig):
    • approved by FDA in 2018; monthly injections appear to halve the rate of attacks but it is expensive at around $AU800 for each monthly injection