Migraine:

PATHOPHYSIOLOGY:

Cortical spreading depression – wave of neuronal excitation in the cortical grey matter, that
spreads from the site of origin at rate 2-6 mm/min;

- This cellular depolarization causes primary cortical phenomenon = aura phase, that
activates trigeminal fibers, causing headache phase

- Neurochemical base of CSP: the release of K+ or/ the excitatory amino acid glutamate
from neural tissue  this release depolarizes the adjacent tissue  which releases more
neurotransmitters  depression propagation.

 spreading depression reduces metabolism  oligemia (which does not correspond to

vascular territories)
 Oligemia can be clinically silent (migraine without aura);
 Threshold required (?) to produce symptoms in pts with aura but NOT in pts
without aura.

 CSD can induce acute hypoxia accompanied by dramatic failure of brain ion homeostasis
and prolonged impairment of neurovascular and neurometabolic coupling

 CSD activates trigeminovascular system (trigeminal ganglion, trigeminocervical complex,

thalamus and dura mater)  this stimulates nociceptive neurons on dural blood vessels to
release plasma proteins and pain-generating substances  this results in sterile
inflammation + further vasodilation = pain

Pain-generating substances:
 Calcitonin gene-related peptide (CGRP): is a member of Calcitonin receptor
family: CGRP + Calcitonin Receptor + Amylin Receptor + Adrenomedullin receptor
 Substance P
 Vasoactive intestinal peptide
 Neurokinin A
 Nitric oxide (?)

ANATOMY OF TRIGEMINOVASCULAR PAIN PATHWAYS:

Anatomy of the trigeminovascular system–ascending projections. The trigeminal ganglion (TG)

gives rise to pseudo-unipolar trigeminal primary afferents which synapse on intra- and
extracranial structures (blood vessels) as well as the spinal cord trigeminocervical complex
(TCC). Second-order neurons from the TCC ascend in the quintothalamic (trigeminothalamic)
tract synapsing on third-order thalamocortical neurons. Direct and indirect ascending projections
also exist to the locus coeruleus (LC), periaqueductal grey (PAG), and hypothalamus. The third-
order thalamocortical neurons in turn synapse on a diffuse network of cortical regions including
the primary and secondary motor (M1/M2), somatosensory (S1/S2), and visual (V1/V2) cortices.
A reflex connection from the TCC to the superior salivatory nucleus (SuS) exists, which projects
via the sphenopalantine ganglion (SPG) providing parasympathetic innervation to the extra- and
intracranial structures. Ins, insula; PtA, parietal association; RS, retrosplenial; Au, auditory; Ect,
ectorhinal; RVM, rostral ventromedial medulla.
 CSD is also partially mediated by release of trigeminal and parasympathetic
neurotransmitters from perivascular nerve fibers

 Perivascular nerve activity results in release of substances, such as pain-generating

substances, which interact with the blood vessel wall to produce dilation, protein
extravasation and sterile inflammation.
 This stimulates trigeminocervical complex (shown by induction of c-fos AG by PET
scan)  info then relayed to thalamus and cortex for pain registration. Other centers
involvement may explain the associated autonomic symptoms and affective aspects
of pain.
 Plasma extravasation may play role in pain expression, but it may be not sufficient by
itself to cause pain. Other stimulators’ presence may be required.

Although some drugs that are effective for migraine inhibit plasma extravasation,
substance P antagonist and the endothelin antagonist Bosentan inhibit plasma
extravasation but not effective as antimigraine drugs.

 Pain process requires: activation of nociceptors of pain-producing intracranial

structures + reduction in N functioning of endogenous pain-control pathways to gate
the pain.

 delayed meningeal blood flow increase is mediated by trigeminal-parasympathetic

brainstem connection

 altered descending modulation (regulation) in the brainstem contributes (?) to the

headache phase of migraine  this leads to loss of inhibition / enhanced facilitation (relief),
resulting in trigeminovascular neuron hyperexcitability.
  CSD upregulates genes: genes encoding for COX-2, TNF – alpha, IL – 1 beta, galanin and
metalloproteinases. Metalloproteinases’ activation  leads to leakage of blood-brain
barrier (BBB)  K+, nitric oxide (NO), adenosine and other products released by CSD to
reach and sensitize the dural perivascular trigeminal afferent endings.

Increased net activity of matrix metalloproteinase -2 (MMP-2) was demonstrated:

- Pts with migraine without aura have  (matrix metalloproteinase-9 / tissue inhibitors
of metalloproteinase-1) =  MMP-9/TIMP-1 ratio;
- Pts with migraine with aura have  MMP-9/TIMP-1 ratio

 Brainstem activation: once CSD occurs on the surface of the brain, H+ and K+ ions diffuse
to the pia mater and activate C-fiber meningeal nociceptors, releasing a proinflammatory
soup of neurochemicals (eg. CGRP) and causing plasma extravasation to occur => sterile
neurogenic inflammation of trigeminovascular complex; once trigeminal system is
activated, it stimulates the cranial vessels to dilate = the common pathway to the throbbing
headache

NEUROIMAGING:

FDG-PET: (interictal state in migraineurs): hypometabolism of central pain processing areas

including bilateral insula, bilateral anterior and posterior cingulate cortex, left premotor and
prefrontal cortex, and left primary somatosensory cortex.

fMRI: stimulated blood flow changes: upon heat stimuli  reduced response in nucleus
cuneiformis (=component of brain stem pain modulating circuits). During migraine attacks, this
dysfunction might lead to hyperexcitability of trigeminovascular neurons and thus to the
perception of headache.
 Anterior temporal pole of migraineurs being more active after painful heat stimulation
(then controls). The temporal pole further depicted increased functional connectivity to
various brain regions that might be involved in migrainous symptoms, such as the
anterior cingulate cortex, the somatosensory cortex, amygdala, and others.
 During odor stimulation, migraineurs had increased rCBF in the left temporal pole and
lower values in the frontal and temporo-parietal regions, posterior cingulate gyrus, and
right locus coeruleus. 

Migraineurs have stronger connectivity between the PAG (periaqueductal grey) and several brain
areas that are relevant for nociceptive and somatosensory processing. Cutaneous allodynia is
thought to be the manifestation of central sensitization during migraine attacks. Comparing the
“resting state” connectivity of migraineurs with and without cutaneous allodynia, differences in
the connectivity of the PAG/nucleus cuneiformis to various discriminative pain processing
centers (brain stem, thalamus, insula, cerebellum) and higher order pain modulating areas
(frontal and temporal regions) were identified. With the use of a seed-based approach, resting
functional connectivity of the right middle temporal, posterior insula, middle cingulate, left
ventromedial prefrontal, and bilateral amygdala regions best discriminates migraine and
control brains. 

In summary, being a migraineur means having subtle differences in brain structure and function
even outside of attacks. Importantly, most areas are part of the unspecific pain processing areas
or of the trigeminal system. A major challenge is to understand how these differences predispose
to migraine attacks, or in other words, which structures drive the “migraine cycle” from interictal
via premonitory phase to the headache phase and, finally, the postdrome period that then runs
over back to the interictal phase.

Premonitory phase:
Premonitory symptoms: are likely related to the hypothalamus and include concentration
problems, tiredness, irritability, or depression. 

One of the most important fMRI studies in this respect assessed the (de-)activation pattern
elicited by trigemino-nociceptive stimulation of the nasal mucosa as the headache day
approached. Compared with control subjects, interictal migraineurs have reduced activation of
the spinal trigeminal nuclei. This deactivation had a cyclic behavior over the course of a
migraine interval: there was normalization prior to the next attack and a significant reduction of
deactivation during the attack. This cyclic behavior might thus reflect the increased susceptibility
of the brain to generate the next attack, and the identification of its pacemaker would be crucial
for our understanding of the start of a migraine attack.

See image below:

The migrainous migraine during the premonitory phase. In nitroglycerin-induced migraine
attacks, H215O-PET demonstrated increased rCBF in the posterior hypothalamic region
(A and B), the periaqueductal grey region (C and D), and dorsal pons (E and F), which are
highlighted by circles. The color bar indicates the color coding of the Z scores. From a clinical
perspective, the hypothalamus might be involved in the premonitory symptoms prior to the
experience of head pain. Such symptoms involve tiredness, concentration problems, yawning,
appetite alterations, and frequent urination. Activation in the midbrain and PAG likely
reflects a mechanism through which nociceptive head pain symptoms may be generated. 
Migraine attacks, MRI:
The migrainous brain during migraine head pain. Many studies have demonstrated that migraine
attacks are associated with an increase of rCBF in mesencephalon and pons, which cannot be
found in experimental head pain, indicating specificity for migraine attacks. After termination of
the migraine attack with sumatriptan, these changes persisted, suggesting involvement in
migraine generation or sustentation, rather than specifically trigeminally mediated pain.

Brain stem nuclei, such as PAG and raphe nuclei, have great influence on trigeminovascular
processing in experimental migraine models

Migraine center:
 there is a probability of dysfunction in the regulation involved in antinociception and
vascular control of the centers (periaqueductal gray, midbrain reticular formation and
locus ceruleus)
 Thalamic processing of pain is gated by ascending serotonergic fibers from dorsal raphe
nucleus and from aminergic nuclei in the pontine tegmentum and locus ceruleus (LC) (LC
can alter brain flow and BBB permeability)
 Due to periodicity of migraine, there may be a link to suprachiasmatic nucleus of the
hypothalamus that governs circadian rhythm.

Cutaneous allodynia:
Secondary pain pathways of the trigeminothalamic system (= central pathway) become
sensitized during a migrainous episode => mediation of migrainous pain.

Dopamine pathway:
 Dopaminergic hypersensitivity is present in pts with migraine
 Symptoms such as: n/v, yawning, irritability,  BP and hyperactivity can be attributed
to relative dopaminergic stimulation
 Dopamine receptor hypersensitivity has been shown experimentally with dopamine
agonists (e.g. Apomorphine)
 Dopamine antagonists (e.g. Prochlorperazine) completely relieve almost 75% of
acute migraine attacks.

Magnesium deficiency:
 Magnesium deficiency in brain  triggers platelets aggregation and glutamate release
 resulting in 5-hydroxytryptamine release (vasoconstrictor)
 Oral magnesium shows benefit for preventative treatment
 IV magnesium may be effective for acute Tx

Endothelial dysfunction:
 Vascular smooth muscle cell dysfunction may involve impaired cyclic guanosine
monophosphate and hemodynamic response to nitric oxide (NOx)
  NOx released by microglia is potentially a cytotoxic proinflammatory mediator
 NOx initiates and maintains brain inflammation via trigeminal neuron system activation
 NOx levels continue to be  even in the headache-free period
 In premenopausal women with migraine (especially those with aura),  endothelial
activation (component of endothelial dysfunction) is evident

Serotonin and migraine:

 5-hydroxytryptamine (5-HT) = serotonin receptor, is the most important receptor in the
headache pathway
 Immunohistochemical studies detected 5-HT1D receptors in trigeminal sensory
neurons, including peripheral projections to the dura and within trigeminal nucleus
caudalis (TNC) and solitary tract
 5-HT1B receptors are present on smooth muscle cells in meningeal vessels
 All available triptans are selective 5-HT1B/D full agonists; they may  headache by
abolishing neuropeptide release in the periphery and blocking neurotransmission by
acting on 2-nd order neurons in the trigeminocervical complex.

Lasmiditan is 5-HT1F receptor agonist only (selective) (5-HT1F is only present in CNS, unlike 5-
HT1B/D receptors, which are also present in CVS); no vasoconstrictive action.
Peripheral Afferent Projections:
The brain is known to be largely insensate, but a rich plexus of nociceptive nerve fibers that
originate in the trigeminal ganglion innervate the pial, arachnoid, and dural blood vessels,
including the superior sagittal sinus and middle meningeal artery, as well as large cerebral
arteries. Activation of these structures, particularly the dura mater, with mechanical, chemical,
or electrical stimulation results in headache pain very similar to the pain in migraine, as well as
other symptoms associated with migraine, including nausea and photophobia. The nociceptive
innervation of the intracranial vasculature and meninges includes nonmyelinated (C-fibers) and
thinly myelinated (Aδ-fibers) axonal projections, mainly through the ophthalmic (V1) division of
the trigeminal nerve, but also to a lesser extent, through the maxillary (V2) and mandibular
divisions (V3). There is also neuronal innervation of the dura mater from the cervical dorsal root
ganglia. The axon terminals of nociceptive nerve fibers that innervate the dura mater contain
vasoactive neuropeptides CGRP, substance P, neurokinin A, and pituitary adenylate cyclase-
activating peptide (PACAP), which are thought to be released upon stimulation causing
vasodilation of dural and pial vessels.

Central Afferent Projections:

There is also a central afferent projection from the trigeminal ganglion that enters the caudal
medulla of the brain stem, via the trigeminal tract, which terminates in the spinal trigeminal
nucleus caudalis (Sp5C; TNC), as well as the upper cervical spinal cord (C1–C2). Nociceptive
Aδ- and C-fibers predominantly terminate in the superficial laminae, I and IIo, as well as deeper
laminae V–VI of the TNC and cervical extension. Stimulation of the dural vasculature in animal
models, including the superior sagittal and transverse sinuses, and middle meningeal artery,
results in activation of neurons in the TNC, C1 and C2 regions of the cervical spinal cord, together
known as the trigeminocervical complex (TCC). Furthermore, stimulation of the greater
occipital nerve also causes neuronal activation in the same regions and enhances convergent
inputs from the dural vasculature. These data suggest that the trigeminal nucleus extends
beyond its caudalis boundary to the dorsal horn of the higher cervical region in a functional
continuum that includes the cervical extension. This convergence of neuronal inputs into the
TCC and the convergence of inputs from intracranial and extracranial structures probably
accounts for the distribution of pain perception in migraine over the frontal and temporal regions,
plus the involvement of parietal, occipital, and higher cervical regions. Therefore, the severe and
throbbing nature of pain in migraine is thought to result from activation, or the perception of
activation, of these nociceptive inputs from intracranial and extracranial structures, that converge
and are relayed through the TCC.

Ascending Projections from the TCC

All nociceptive information from craniovascular structures is relayed through the TCC, and via
ascending connections to other areas of the brain stem and diencephalon, involved in the
processing of pain and other sensory information.
There is a reflex connection from the trigeminal nucleus to the parasympathetic outflow to the
cranial vasculature via the superior salivatory nucleus (SuS). The SuS is activated by dural
electrical stimulation, or directly from the brain stem, and this traverses back to the TCC via the
parasympathetic outflow to the craniovasculature. There are also direct ascending connections
with other medullary pontine nuclei including the rostral ventromedial medulla (RVM),
nucleus raphe magnus (NRM), parabrachial nucleus and locus coeruleus, and midbrain
nuclei, the ventrolateral periaqueductal gray (vlPAG) and cuneiform nucleus, with
demonstrated functional nociceptive inputs from the dura mater. Somatosensory and visceral
nociceptive information from the head and orofacial structures, via the TCC, is also conveyed
directly to hypothalamic nuclei, along the trigeminohypothalamic tract, including the anterior,
lateral, posterior, ventromedial, perifornical, and supraoptic hypothalamic nuclei and activated
by dural nociceptive stimulation. Likewise, functional dural inputs are relayed through the caudal
medullary TCC, via the quintothalamic (trigeminothalamic) tract, to the thalamus. Specifically
dural nociceptive inputs are processed in the ventroposteromedial (VPM) thalamus and its
ventral periphery, the medial nucleus of the posterior complex, including posterior thalamic
nucleus and the intralaminar thalamus.

Migraine Risk Factors:

  C-reactive protein levels
  ILs levels
  TNF-alpha and adhesion molecules (markers of systemic inflammation) levels
 Oxidative stress and thrombosis
  body weight
  BP
 Hypercholesterolemia
 Impaired insulin sensitivity
  homocysteine levels
 Stroke
 CAD (CHD)

Medication overuse headache / transformed migraine:

o Opiates: critical exposure dose is around 8 days/month (more pronounced in men)
o Barbiturates: critical exposure dose is around 5 days/month (more pronounce in
women)
o Triptans: migraine progression is only in pts with  frequency of migraine at baseline
(10-14 days/month)
ETIOLOGY:

- Migraine has strong genetic component: 70% of migraine pts have a 1st-degree
relative w migraine
- Non-syndromic migraine headache w or w/o aura shows multifactorial inheritance
pattern
- Rare syndromes w migraine as symptom show autosomal dominant pattern
- 4 regions in which single-nucleotide polymorphisms influence the risk of developing
migraine

1. Familial hemiplegic migraine (FHM)

 Is a rare type of migraine w aura that is preceded or followed by hemiplegia
(typically resolves)
 May be associated w cerebellar ataxia (is also linked to 19p locus)
 3 genes have been identified as causative for FHM:
 FHM type 1:
 Characterized clinically by nystagmus & cerebellar signs
 Caused by mutations in the CACNA1A gene located on 19p13
(which codes for a brain-specific CA channel)
 Only 7% of pts with clinical Dx of FHM had mutations of that gene
 FHM type 2:
 Occurs in pts who also have a seizure dis-r
 Attributed by mutations in the ATP1A2 gene located on 1q21q23
(which encodes a Na+/K+ pump)
 Only 7% of pts with a clinical Dx of FHM had mutations in ATP1A2
 FHM type 3:
 Caused by mutations in the SCN1A gene located on 2q24
 These mutations are also known to cause familial febrile seizure
dis-rs and infantile epileptic encephalopathy
 Rare cause of FHM

2. Migraine in other inherited disorders

 MELAS (Mitochondrial Myopathy, Encephalopathy, Lactic Acidosis and Stroke-
like episodes). Migraine occurs w  frequency in pts w mitochondrial disorders,
such as MELAS
 CADASIL (Cerebral Autosomal Dominant Arteriopathy with Subcortical Infarcts
and Leukoencephalopathy)
 Genetic dis-r that causes:
  migraine w aura
 strokes before age of 60
 progressive cognitive dysf-n
 behavioral changes
 autosomal dominant, 90% of cases due to mutations of INOTCH3 I gene
located on chromosome 19
 pts have significant morbidity, but life expectancy =68 years
 RVCL (Retinal Vasculopathy w Cerebral Leukodystrophy)
 genetic vasculopathy
 Autosomal dominant, caused by mutations in the TREX1 gene
 HIHRATL (Hereditary Infantile Hemiparesis, Retinal Arteriolar Tortuosity and
Leukoencephalopathy)
 Genetic vasculopathy
 Caused by mutations in the COL4A1 gene

3. Migraine and other vascular disease

 Pts w migraines are more likely to have cardiovascular or cerebrovascular
disease: stroke (particularly infarct in cerebellum), MI, etc.
 Migraine w aura  the risk of MI by 91% and ischemic stroke by 108%
 Migraine w/o aura  both risks by 25%
 Migraine in pregnancy: is linked to strokes and vascular diseases;
 Migraine w aura -  risk for HTN by 9%
 Migraine w/o aura -  risk for HTN by 21%

4. Migraine and Iron and sensory perception

 Pts w migraines have  local Iron deposits in putamen, globus pallidus and red
nucleus
 This is a result of physiologic response to repeated activation of nuclei involved
in central pain processing OR by damage to these structures due to the
formation of free radicals in oxidative stress (=is a cause becoming chronic
condition)
 Sensory perception (vibrotactile stimulation), including stimulus amplitude
discrimination, temporal order judgement and duration discrimination, was .

Migraine PRECIPITANTS:
 Hormonal changes: menstrual,  Fasting/skipping meals
pregnancy, ovulation  Smoking
 Excessive/insufficient sleep  Red wine
 Strong odors: perfumes, colognes,  Stress
petroleum distillates  Lack of exercise
 Exposure to bright/fluorescent  Head trauma
lighting  Weather changes
  Motion sickness

Caffeine, artificial sweeteners (aspartame, saccharin), monosodium glutamate (MSG), citrus

fruit, tyramine-containing foods, meat w nitrites = are potential precipitants

CLINICAL PRESENTATION:

o Throbbing or pulsatile headache

o Unilateral and localized in frontotemporal and ocular area
o Builds up in 1-2 hrs, progressing posteriorly -> diffuse
(also can be felt anywhere around head and neck)
o Lasts 4-72 hrs; 1/3 of F report >24 hours

Other symptoms:
o N & V (in 80% & 50%) along w anorexia and food intolerance
o Photophonia and phonophobia
o Lightheadedness
o Migraine-associated vertigo /vestibulopathy
o Hemiparesis (defines hemiplegic migraine)
o Aphasia
o Confusion
o Paresthesias or numbness

Prodrome:
o Sensitivity to light, sight, odors
o Lethargy/yawning
o Food cravings
o Mental & mood changes (depression, anger, euphoria)
o Thirst and polyuria and fluid retention
o Anorexia
o Constipation/diarrhea

Aura:
o Develops over 5-20 min and lasts <60 min
o Visual, sensory or motor (or combination of these)
o Visual:
 Negative symptoms: scotomata, central scotomas, homonymous
hemianopic /quadrantic field defects, tunnel vision, altitudinal visual
defects, complete blindness
 Positive symptoms: scintillating scotoma (is diagnostic!)
o Sensory:
  Paresthesias (in 40%): cheiro-oral, w numbness starting in the hand ->
arm -> face, lips and tongue
 Usually occurs not in isolation but follows visual aura (diff Dx from
TIA/sensory seizure)
o Motor:
 Are associated w sensory symptoms and occur in 18% of pts
 Sense of heaviness of the limbs before headache w/o true weakness
 Speech and language disturbance – in 17-20% of pts
 Migraine triggers:
- Hormonal changes
- Head trauma
- Lack of exercise
- Sleep changes
- Medications: nitroglycerine, reserpine, hydralazine, ranitidine,
estrogen

Migraine variants (based on focal neurological findings):

 Hemiplegic migraine: unilateral paralysis or weakness
 Basilar-type migraines: aphasia, syncope and balance problems
 Ophthalmoplegic migraine: 3rd nerve palsy, w ocular muscle paralysis and ptosis,
including or sparing pupillary response

Dx CRITERIA:

International Headache Society

Criteria for Migraine w/o Aura
5 or more episodic headaches lasting 4-72 hrs with:
Any 2 of the following: Any 1 of the following:
 - n/v
- Unilateral location - photophobia/phonophobi
- Throbbing/pulsating a
- Worsened by movement
- Moderate or severe in intensity
MIGRAINE VARIANTS:
1. Childhood periodic syndromes
 Periodic syndromes evolve into migraine in adulthood
 Include:
- cyclic vomiting: child has at least 5 attacks of intense n & v, from 1 hr to 5
days
- abdominal migraine: episodic midline abd pain lasting 1-72 hrs w at least
2-4 other symptoms: n, v, anorexia and/or pallor
- benign paroxysmal vertigo of childhood: recurrent attacks of vertigo,
often associated w v or nystagmus
2. Late-life migrainous accompaniments
 in elderly persons, a stereotypical prodrome-like symptoms may entirely replace
the migrainous episode
 if always on 1 side  exclude a structural lesion by imaging
 keep in mind a possibility of secondary/new headache
3. Migraine with brainstem aura
 Pts may present w/o headaches but w basilar-type symptoms:
 Vertigo  Dysarthria
 Dizziness  Tingling of extremities
 Confusion  Incoordination
 4. Hemiplegic migraine
 Very rare migraine
 Headaches are associated w temporary, unilateral hemiparesis /hemiplegia, at
times accompanied by ipsilateral numbness/ tingling, w or w/o a speech
disturbance
 Focal neuro deficit may precede or accompany headache (usually less dramatic
than the motor deficit)
 Pts may experience disturbance of consciousness and (rarely) coma

5. Ophthalmoplegic migraine
 Transient palsies of the extraocular muscle w dilated pupils and eye pain
 This variant has been reclassified by Intern-l Headache Society as a neuralgia and
is thought to be caused by idiopathic inflammatory neuritis
 There is enhancement of the cisternal segment if the 3rd cranial nerve in acute
phase
6. Retinal (ocular) migraine
 Retinal & optic nerve involvement during or before a migraine headache
 Visual disturbance, papilledema & retinal hemorrhage affecting 1 eye
 International headache society criteria:
 Min 2 attacks of fully reversible, monocular phenomena, positive & /or
negative (scintillations, scotomata or blindness)
 These are to be confirmed by exam during an attack or by pt’s drawing of
a monocular field defect during an attack
 Migraine w/o aura must begin during the visual symptoms or follow them
within 60 min
 Pt must have N ophthalmologic exam between attacks

7. Status migrainosus: migraine attack persists for more than 72 hours, may result in
complications such as dehydration

8. Chronic migraine: migraine that occurs for more than 15 days/month for more than 3
months. Associated symptoms (n/v, photo-/phonophobia) may be less frequent

MIGRAINE COMORBIDITIES:
- Epilepsy ( the risk of migraine by 2.4): benign Rolandic epilepsy, benign childhood
epilepsy
- Familial dislipoproteinemias
- Hereditary hemorrhagic telangiectasia
- Tourette syndrome
- Hereditary essential tremor
 - Hereditary cerebral amyloid angiopathy
- Ischemic stroke (migraine w aura is a RF; odds ratio: 1:6)
- Depression and anxiety
- Asthma
- Patent foramen ovale
- Obesity
- PTSD

MIGRAINE’S COMPLICATIONS:
 Chronic migraine
 Migraine-triggered seizures
 Migrainous infarction (stroke w migraine); RFs for stroke:
- Migraine w aura - Cigarette smoking
- F sex - Estrogen use
 Persistent aura (30-60 min) w/o infarction

DIFFERENTIAL DX:

 Cerebral aneurysms  ICH

 Chronic paroxysmal hemicrania  Muscle contraction tension headache
 Cluster headache  Temporal/giant cell arteritis
 Dissection syndromes  Tolosa-Hunt syndrome
 HSV encephalitis  Viral meningitis

1. Headache as a primary disorder/headache: cluster headaches, muscle contraction

tension headache
Crash Migraine: abrupt onset, “crash” headaches, are similar to “thunderclap”
headache VS cluster headache (lasts only 15-180 min and easily recognized if were
present in the past).
Exertional headache: precipitated by strenuous activity (running, coughing, Valsalva)
and build in intensity over minutes; common in pts with inherited susceptibility to
migraine.

2. Migraine may be simulated/may simulate a secondary headache disorder or coexist w a

secondary headache disorder:
- Worst or 1st headache of pt’s life, rapid in onset
- A change in frequency, severity or clinical features of attack
- New progressive headache that persists for days
- Precipitation of headache w Valsalva maneuvers
- Associated neuro signs: diplopia, loss of sensation, weakness, ataxia
- Headache’s onset after 55 years
- Headache after head injury/trauma
- Persistent, 1-sided throbbing headaches
 - Headache w stiff neck or fever
- Atypical Hx or unusual character
- Inadequate response to optimal Tx

Intracranial aneurysm (aneurysmal subarachnoid hemorrhage):

 Severe headache and sudden in onset, reaches max intensity in minutes
 stiff neck
 photophobia
 n&v
 possibly alterations in consciousness
 Dx: CT w/o contrast  LP (if CT scan is “-“), (?)angiogram if N: CSF, CT & MRI

Space-occupying lesion:
 In pts w chronic, subacute or acute subdural hematoma, headaches is present
in 81% , 53% and 11 % respectively
 Intermittent headache (in 62%), lasting few hours
 More similar to tension-type headache (in 77%)
 Classic early morning brain tumor headache was only in 17% of pts
 Other neuro signs/symptoms: seizures, confusion, prolonged nausea and
hemiparesis

Cerebral venous thrombosis:

 Involves sagittal sinus in 70%
 Symptoms of  ICP (intracranial pressure): headache and papilledema
 If thrombus to superficial cortical veins = focal findings
 Dx: MRI, MRA or MR venography

Spontaneous internal CA dissection:

 Uncommon cause of headache and acute neuro deficit
 In younger pts w unilateral, severe, persistent head pain of sudden onset
 Precedes neuro signs: Horner syndrome.

WORK UP:
 Exclude structural, metabolic and other causes that mimic or coexist w migraine
 Rule out comorbid dis-s, that could complicate h/a and its Tx
 Establish a baseline for Tx and exclude contraindications to drug administration
 Measure drug levels to determine compliance, absorption or med overdose

The choice of lab/imaging studies:

  ESR and CRP  if considering temporal/giant cell arteritis
 Visual field testing for pts w persistent visual phenomena
  CGRP (neurotransmitter that causes vasodilation) levels in blood = biomarker for
permanent trigeminovascular activation  Dx of chronic migraine

MIGRAINE TREATMENT:
1. Acute (abortive): aims to reverse (or at least stop) the progression of migraine that has
started
2. Preventive (prophylactic): given in the absence of a h/a, aims to reduce frequency &
severity of migraine attack, make acute attacks more responsive to abortive Tx and
improve pt’s quality of life

Non-pharmacologic Tx:
- Biofeedback
- CBT
- Relaxation Tx
- Occipital nerve stimulation
- Cerena Transcranial Magnetic Stimulator (Cerena TMS)
- Vagus nerve stimulator (nVS)

1. Acute Tx:

Table 1. Abortive Medication Stratification by Headache Severity

Moderate Severe Extremely severe

NSAIDs Naratriptan DHE (IV)
Isometheptene Rizatriptan Opioids
Ergotamine Sumatriptan (SC, NS) Dopamine antagonists
Naratriptan (long-acting) for menstrual Zolmitriptan
migraine
Rizatriptan Almotriptan
Sumatriptan: Frovatriptan
 Transdermal: (Zecuity, NuPathe Inc)
 Intranasal powder 22 mg

Zolmitriptan Eletriptan
Almotriptan DHE (NS, IM)
Frovatriptan (long-acting) for menstrual Ergotamine
 migraine
Eletriptan Dopamine antagonists
Dopamine antagonists (Prochlorperazine)
DHE = Dihydroergotamine

TRIPTANS:
 Selective serotonin agonists, acting at 5-hydroxytryptamine -1: B/D/F (5-HT1B/1D/1F)
receptors on intracranial blood vessels and sensory nerve endings
 May be repeated in 2 hrs, with max 2 doses daily, no more than 3 d/weekly
 Contraindications: known CAD ( risk of MI, ischemia or other cardiac or CV risks),
uncontrolled HTN, hemiplegic migraine and PVD
 If pt takes propranolol -> max Rizatriptan = 5 mg
 Sumatriptan, Zolmitriptan and Rizatriptan are metabolized by MAO (avoid if pt takes
MAO-inhibitors)

 Treximet = Sumatriptan (85 mg) + Naproxen Sodium (NSAID, 500 mg)

ERGOT ALKALOIDS:
 Non-selective 5-HT1 agonists that have a wider spectrum of receptor affinities outside of
the 5-HT1 system, including Dopamine receptors
 Ergotamine:
- counteracts episodic dilation of extracranial arteries and arterioles
- has partial agonist and/or antagonist activity against tryptaminergic,
dopaminergic and alpha-adrenergic receptors
- causes constriction of peripheral and cranial blood vessels
 Dihydroergotamine (DHE)
- Alpha-adrenergic blocking agent with a direct stimulating effect on
smooth muscle of peripheral and cranial blood vessels
- Depresses central vasomotor centers
- Is non-selective 5-HT1 agonist with a wide spectrum of receptor affinities
outside of the 5-HT1 system, also binds to Dopamine
-  alpha-adrenergic antagonist and serotonin antagonist effect

ANTIEMETICS:
 Chlorperazine
 Promethazine
 Prochlorperazine (Dopamine antagonist)
 Metoclopramide (antiemetic, dopamine D2 receptor antagonist, 5-HT3 receptor
antagonist and 5-HT4 receptor agonist)
 Ketorolac

CGRP RECEPTOR ANTAGONISTS: (small-molecule)

 Ubrogepant
 Rimegepant

CGRP = 37 amino acid neuropeptide, belonging to calcitonin family; vasoactive peptide released
from meningeal vessels, initiates nociceptive perception (pain). CGRP either block receptor or
peptide
3 large molecule CGRP (mABs) antagonists (bind to CGRP directly?)– for preventive therapy;
6 Small molecule CGRP receptors antagonists = Gepants for acute therapy;
 2. Preventive Tx:

Indications for prophylactic migraine Tx:

- Frequency of migraine attacks: >2/month;
- Duration of attacks: >24 hrs;
- H/a causes disruption in pt’s life = disability >3 days;
- Abortive Tx fails or overused;
- Abortive medications used > 2/week
 - Symptomatic Tx contraindicated or ineffective;
- Migraine variants (hemiplegic or migraine producing profound disruption or risk of
permanent neuro injury)

Episodic migraine: <15 monthly h/a days (MHDs) or monthly migraine days (MMDs)
Chronic migraine: min 15 MHDs w min 8 of MMDs.

Mechanism of Action of prophylactic med-ns:

 5-HT2 antagonism (Methysergide)
 Regulation of voltage-gated ion channels (Ca channel blockers)
 Modulation of neurotransmitters (Beta-blockers, TCA)
 Enhancing Gamma-aminobutyric acid-ergic (GABAergic) inhibition (Valproic acid,
Gabapentin)
 Prevention of acetylcholine from presynaptic membrane (botulinum toxin)
 Calcitonin gene-related peptide (CGRP) inhibitors (Erenumab, Fremanezumab,
Galcanezumab)
 Alteration of neuronal oxidative metabolism (riboflavin) and reduction of neuronal
hyperexcitability (magnesium replacement)
 Classes of Prophylactic drugs:

 Antiepileptic
 Topiramate
- blocks voltage dependant Na and Ca channels
- enhancing the inhibitory effect of GABA (Gamma Amino-Butyrate =
neurotransmitter that transmits communication between neuro cells;
GABA  the action of nerve cells to help control anxiety and fear; GABA
plays role in behavior, cognition and body’s stress response)
- inhibits carbonic anhydrase activity (transports CO2 in blood)
- inhibits excitatory glutamate pathway :  the action of excitatory
neurotransmitters through kainate and AMPA receptors (kainate and
AMPA = ionotropic glutamate receptors that produce excitatory
responses by allowing passage of Na and K)   risk of seizures
- S/E: weight loss and dysesthesia
 Valproic acid (Depakote)
- Good mood stabilizer
- S/E: weight gain, hair loss and PCOD
 Gabapentin, Lamotrigine, Oxcarbazepine – limited data for migraine use

 Antidepressants
 TCA: Amitriptyline and Nortriptyline – commonly used
 SSRIs, SNRI: Duloxetine (Cymbalta) and Venlafaxine (Effexor)
 Antihypertensive
 Beta-blockers: for young and anxious pts
 Ca-channels blockers
 ACE (Angiotensin-converting enzyme) inhibitors: Lisinopril
 Angiotensin receptor blockers: Candesartan

 Botulinum toxin A – Onabotulinumtoxin A; Botox (Allergan)

- For pts w chronic intractable migraine that has failed to respond to 3
conventional preventative meds, attacks > 4 hrs on min 15 days/month for 3
months
- Not recommended for episodic migraine
- Injections are to scalp and temple q 2-3 months

 Calcitonin gene related peptide inhibitors (CGRP – potent vasodilator; concentrations 

after triptans Tx)
Anti-CGRP monoclonal Abs (large molecules, target CGRP):
  MONOCLONAL ABs (CGRP ligand – targeting):
- Freamanezumab (Ajovy, Teva Pharmaceuticals)
- Galcanezumab (Emgality, Eli Lilly & Co)
- Eptinezumab

 MONOCLONAL AB (targets CGRP receptor):

- Erenumab (Aimovig, Amgen)

Table 2. Preventive Drugs for Migraine

Frist line Second line

High efficacy B-blockers Methysergide
TCA Flunarizine
Divalproex MAOIs
Topiramate CGRP inhibitors
Botulinum toxin

Low efficacy Verapamil

Cyproheptadine
Unproven efficacy Gabapentin

Alternative Tx:
- Biofeedback
- CBT
- Butterbur (Petasites Hybridus): reduces frequency and severity of M
attacks (monitoring Liver enzymes is required)
 - Riboflavin (B2) 400 mg
- Magnesium
- Feverfew
- Coenzyme Q10
- Melatonin: 2 mg 1 hr before bedtime

Table 3. Preventive Medication for Comorbid Conditions

Comorbid Condition Medication

HTN B-blockers
Angina B-blockers
Stress B-blockers
Depression TCA, SSRIs
Overweight Topiramate, Protriptyline
Underweight TCA (Nortriptyline, Protriptyline)
Epilepsy Valproic acid, topiramate
Mania Valproic acid

Diet:
- Alcohol
- Chocolate
- Caffeine withdrawal &/or overuse
- Avocado, citrus, dried fruit, bananas
- Nuts: peanuts, soy, nuts
- Aspartame
- Monosodium glutamate (MSG)
- Tyramine: aged cheese, smoked/cured meats, pickles, heavily yeasted breads, vinegars
New Tx:
 Tonabersat:
- benzopyran compound
-  cortical spreading depression and CSD-associated events by inhibiting
gap-junctions communication between neurons and satellite glial cells in
the trigeminal ganglion
-  frequency of aura attacks w or w/o headache but no efficacy on non-
aura attacks

 Transient receptor potential vanilloid type 1 antagonists

 Prostaglandin E receptor 4 receptor antagonists
 Serotonin 5HT1(F) receptor agonists
 Nitric Oxide synthase inhibitor
Table 4.
Current developmental pipeline in migraine

Mechanism/Indication Treatment

Calcitonin gene-related peptide (CGRP) mechanism antagonist

CGRP receptor antagonist (gepant) Olcegepant (638)

Telcagepant-acute (396)

Telcagepant-preventive (394)

Rimagepant (561)

BI44370TA (216)

MK-3207 (391)
 Ubrogepant (828)

Atogepant (AGN-241689) (preventive)+

CGRP antibody (nezumab) Eptinezumab (224)

Galcanezumab (225)

Fremanezumab (96, 97)

CGRP receptor antibody (numab) Erenumab (770)

Serotonin related

Serotonin 5-HT1F receptor agonist (ditan) Lasmiditan (260, 267)

Nitric oxide synthase (NOS) inhibition

Pan NOS 546C88 (507)

Inducible NOS

GW274150 acute (649)

GW274150 preventive (403)

Neuronal NOS plus triptan NXN-188 (428, 595)

Glutamatergic targets

NMDA receptor migraine with prolonged aura Ketamine (10)

Prevention of aura not headache Tonabersat (326, 381)

AMPA/kainate Tezampanel/LY293558 (704)

iGluR5 (kainate) receptor LY466195 (448)

mGluR5 (glurants) ADX10059 (839)

AMPA receptor antagonist BGG492 (353)

Neuroinflammatory targets

TRPV1 SB-705498 (165)

Substance P/neurokinin-1 Dapitant (218)

Lanepitant (351)

GR205171 (176)

Fosaprepitant (629)

Lanepitant (349) Prevention

Neurogenic plasma protein extravasation (PPE) CP-122,288 (691)

4991W93 (233)

Other targets

Orexin 1 and 2 receptors (rexants) Fliorexant (150)

Angiotensin receptor (?) Candesartan (765, 800)

Telmisartan (219)

Emerging targets

Acid sensing ion channel (ASICs) Amiloride (406)

Pituitary adenylate cyclase activating peptide (PACAP) PACAP receptor antagonists (17, 41,
874)

Neuronal NOS Neuronal NOS inhibition (310)

Phosphodiesterase inhibition Ibudilast (514)

Neuromodulation strategies

Transcranial magnetic stimulation (TMS) Single-pulse TMS (94, 537)

Occipital nerve stimulation (ONS) Chronic migraine (538, 705, 735)

Transcutaneous vagal nerve stimulation Gammacore device (327, 736)

Supraorbital nerve stimulation Cefaly (711)

Sphenopalatine ganglion stimulation ATI device (NCT01540799)