this presentation containsrecent advances in the field of migraine including classification,pathophysiology and management of migraine.

1. Dr.Asha Valiyaveettil
Khoula Hospital

2.  Introduction
 Classification
 Pathophysiology
 Management of acute attack
 Prophylactic treatment
 Neuromodulation
 Conclusion

3.  Complex neurobiological disorder recognized since antiquity
 Leading cause of neurological disability from 15 to 49 years of
age
 Affects women more than men (3:1) with a 1yr of prevalence
of 16 %
 Only one‐third of patients diagnosed, two‐thirds never
prescribed specific medication
 Understanding of pathophysiology progressed along with new
advances in biomarkers and genetics
 New discoveries led to new treatment options, specifically
targeted against molecules implicated in migraine pathogenesis
 Nonpharmacological options (non-invasive brain stimulation)
provided new therapies for migraine.

4. IHS Classification System: Primary Headache
Cephalalgia 2004;24,S(1)

5. IHS Classification System: Secondary Disorders
Cephalalgia 2004;24,S(1)

6. CHARACTERIST
IC
MIGRAINE TENSION CLUSTER
Age of onset 25 to 55 years 30 to 50 years 20 to 40 years
Location
Unilateral (but may
be bilateral)
Bilateral
Unilateral, orbital,
supraorbital,
Duration of
episode
4 to 72 hrs 30 min to 7 days 15 to 180 min
Severity Moderate to severe Mild to moderate Extremely severe
Type Pulsating, throbbing Pressing, tightening but
not pulsating
Boring, searing
Pattern 1 to 2 attacks per
month
<180 attacks per year
(or <15 attacks per
month)
1 to 8 attacks per day
separated by pain-
free periods
Associated
symptoms
Nausea, vomiting,
photophobia,
phonophobia (2 of
these)
Either photophobia or
phonophobia, but not
both, no nausea or
vomiting
Conjunctival injection
Lacrimation
Forehead/facial
swelling Nasal
congestion Rhinorrhea
Ptosis Miosis Eyelid
edema
Comparison of Most Common Primary Headaches

7. Diagnosis Algorithm
Patients presents with
complaint of a headache
Critical first steps :
• Detailed history
• Focused physical examination
• Focused neurological examination
• BP, Ocular/Fundus Examination
Detailed History
• Characteristics of the headache
• Assess functional impairment
• Past medical history
• Family history of migraines
• Current medications and previous
medications for headache (Rx and over-the-
counter)
• Social history
• Review of systems – to rule out systemic
illness
Causes for concern :
• Subacute and / or progressive headache over
months
• New or different headache
• “Worst headache ever”
• Any headache of maximum severity at onset
• Onset after the age of 50 years old
• Symptoms of systemic illness
• Seizures
• Any neurological signs
Causes for
concern?
no
Meets criteria for primary
headache disorder?
yes
Evaluate type of primary
headache
Initiate patient education
and lifestyle management
Consider secondary headache
disorder
no
Migraine
Cluster
Headache
Tension-type Headache
Other headaches

17. Vascular theory
Cortical spreading depression theory (CSD)
Neurovascular theory

18. MIGRAINE – A MULTISYMPTOM COMPLEX
Cortical
Activation
Brainstem
Activation

19. Neurovascular theory
 Cortical Excitation leading
to Cortical Spreading
depression
 Trigemino-vascular system.
 Calcitonin gene-related
peptide (CGRP)
 Neurokinin A
 Substance P
- Pain impulses travel to
Trigeminal nucleus
caudalis (TNC) in brain
stem and finally to
thalamus and cortex

20. AURA

21. Migraine triggers CSD
activates the trigeminal nerve
release of neurotransmitters like Substance P, Neurokinin A & CGRP*
(which is a calcium-dependent process)
cause vasodilatation of meningeal blood vessels
(and extravasation of plasma proteins & fluids)
A sterile inflammatory response called
neurogenic inflammation
HEADACHE
* Calcitonin Gene Related Peptide Contd….

22. Dilatation of meningeal blood vessel
causes
stretching of the nerve fibers around the vessel
On one hand,
it releases the chemicals On the other hand,
from the nerve fibers, impulses are relayed to
which further dilates Trigeminal Nucleus Caudalis
arteries and makes (in the brain stem)
the dilation painful
Thalamus
exposure to neurotransmitters
hypersensitization of trigeminal nerve ends Cortex
Throbbing Headache Cutaneous Allodynia
Peripheral Sensitization Central Sensitization
Contd….

23.  Dysfunction of Ca++ or K+ or Na+ channels
may lead to susceptibility to CSD (This is
probably genetic)
 CSD is a short lasting wave of depolarization
(excitation) followed by prolonged
depression
 CSD starts from behind and travels forward
at 2-3 mm/min
Pink area is normal functioning area
Red area is wave of depolarization
Blue area is area of depression
Note the progression of wave from behind to front

24. 1. Cortical Excitation leads to increased
extracellular K+
2. Activates the voltage-gated calcium
channel in pre-synaptic neuron
(channel opens)
3. Allows entry of excess calcium ions
into the pre-synaptic neuron
4. Causes release of the excitatory
neurotransmitters like GLUTAMATE
5. GLUTAMATE binds to the Glutamate
receptor on the post-synaptic neuron
and leads to further depolarization
(excitation)
CSD: Cortical Spreading Depression
Glutamate
receptor
Cortical
Neurons
Voltage-gated Calcium channel
N-type, P/Q- type
of
1
2
3
4
5
2
Postsynaptic
neuron
Glutamate
K+
Excitation
Triggers

25. Cortical hyperexcitability has been considered typical of
migraine
 Glutamate, through activation of its receptors, has been
implicated in the triggering & propagation of cortical spreading
depression
 Higher glutamate levels have been found in plasma, saliva
and cerebrospinal fluid of migraine patients (than in normal
people)
 High plasma glutamate levels seen in migraine patients could
reflect cortical neuronal hyperexcitability.
 Plasma glutamate level monitoring in migraine patients might
serve as a biomarker:
 as an objective measure of disease status
 of response to treatment
Ferrari A et al. Cephalalgia 2009; 29:423–29.

26. 10
0
30
40
50
60
70
80
90
100
Glutamate
plasma
levels
(micromol
/
L)
20
Migraine
patients
Controls
9.36
61.79
* P < 0.05
Migraine patients vs Controls
*
Ferrari A et al. Cephalalgia 2009; 29:423–29.

27. 1. Action Potential (electrical
impulse) in the trigeminal nerve
fibre
2. Activates the N-type voltage-
gated calcium channel (channel
opens)
3. Allows entry of excess calcium
ions
4. Causes release of
neurotransmitters like Substance
P, CGRP*, Neurokinin A
(onto the surface of meningeal blood
vessel)
5. Released neurotransmitters
interact with meningeal blood
vessel leading to vasodilation,
platelet activation and plasma
protein extravasation
(neurogenic inflammation)
Meningeal
blood vessel
Trigeminal
nerve fibre
N-type voltage-gated Calcium channel
of
1
2
3
4
5
2
* Calcitonin Gene Related Peptide

28. Neurogenic inflammation
When activated, the trigeminal nerve ends
release neurotransmitters
Vasodilatation
Plasma protein
extravasation
Platelet activation
Meningeal blood vessel
Responsible for the throbbing headache seen in patients with migrain

29.  Neurokinins facilitate the production of cyclooxygenases
 Cyclooxygenases convert arachidonic acid to prostaglandins
1 2 3

30. Neurogenic inflammation may be
involved in generating and sustaining the
migraine pain
Fusco M et al. Neurol Sci 2003;24: S61–S64.

31. Trigemino-Vascular System (TGVS)
CSD
meningeal
blood
vessel
Neuropeptid
e release
Peripheral Sensitization
Central Sensitization
Trigeminal
Nucleus Caudalis
Brain stem
Trigeminal
nerve
Neurogenic
inflammatio
n
TG – Trigeminal
ganglion
TG
VASODILATATION
Sustained Neurogenic Inflammation leads to
Peripheral Sensitization

32.  The inflammation and edema activate peripheral
meningeal pain receptors called nociceptors
Nociceptors transmit signals to the trigeminal ganglion and the TNC

34. Cutaneous allodynia is a marker for central sensitization,
which may make the migraine episode more difficult to treat

35. TNC
Pai
n
TNC: Trigeminal Nucleus
Caudalis
Brain stem
Meningeal blood
vessel

36. Burstein R et al. Ann Neurol. 2000;47:614-624.
Burstein R et al. Brain. 2000;123:1703-1709.
• Combing hair
• Shaving
• Wearing eyeglasses
• Wearing contact lenses
• Wearing jewellery
Patients often avoid one or more of the following activities
because of cutaneous allodynia

37. Pain can be referred to any of three branches of the trigeminal
and/or cervical nerves & thus pain can be perceived on one or both
sides of the head,
around the eyes or sinuses, and in the posterior area of the head and
neck

39. Acute Therapy
IHS Guidelines make the following recommendations
for acute therapy:
• Educate migraine sufferers and encourage them to participate in
management
• After a course of NSAIDs, use triptans, DHE (Dihydroergotamine) or
ergotamine in patients with more severe migraine or in poor NSAID
responders
• Select non-oral administration in patients with nausea & vomiting
• Consider a self-administered rescue medication
• Guard against medication-overuse headache (“rebound”)
• Clinical evidence does not support a specific algorithm

40. Acute Therapy: Pros and Cons
 PROS:
– Rapid onset of action
– Relatively inexpensive
– Ideal for occasional migraine
 CONS:
– Doesn’t address frequency of attacks or impact on quality of life
– If not taken at onset, less effective
– Acute therapies not always effective
– Undesirable side effects
– Frequent use can cause medication overuse headache
(“rebound” headache)

45. MIGRAINE PROPHYLAXIS
Aim of pharmacologic prophylaxis in migraine:
1. reducing the number of migraine days per month,
2. reducing severity of headache pain and associated
symptoms,
3. shortening individual attacks,
4. improving the effect of acute medication,
5. preventing medication-overuse headache

46. MIGRAINE PROPHYLAXIS INDICATIONS
 Recurring migraine that significantly interferes with the patient’s daily
routine despite acute treatment (e.g., two or more attacks a month
that produce disability that lasts at least 3 days or headache attacks
that are infrequent but produce profound disability);
 Failure, contraindication to, or troublesome side-effects from acute
medications;
 Overuse of acute medications;
 Special circumstances, such as hemiplegic migraine or attacks with a
risk of permanent neurological injury;
 Very frequent headaches (more than two a week), or a pattern of
increasing attacks over time, with the risk of developing medication
overuse headache or rebound with acute attack medicines;
 Patient preference (i.e., the desire to have as few acute attacks as
possible).

47. MIGRAINE PROPHYLAXIS
Migraine drug prophylaxis is considered efficacious if the
frequency of attacks is decreased by atleast 50% within 3
months
- Efficacy can be evaluated after 3 months, and not earlier
- Duration of effective migraine prophylaxis should be for at least 6
months
Choice of migraine prophylactic drug should follow the possible
side effects, contraindications and co-morbidities of patients
besides efficacy.

48. Prophylactic Treatment Of Migraine
Assess factors that may trigger migraine
First-line treatment:
l Medication
- Calcium channel blockers (flunarizine)
- Tricyclic antidepressants
- Beta-blockers
l Antiepileptic drugs
- Divalproex
- Topiramate
- Gabapentin
Successful ?*
Try combination
no
yes
Continue treatment for
6-12 months, then
reassess
Successful ?*
Refer to Neurologist or Headache
Specialist
no
yes Continue treatment for
6-12 months, then
reassess
* A migraine prophylaxis is considered successful if the frequency of migraine attacks per month is decreased
atleast by 50% within 3 months.
Reinforce education and lifestyle
management
Consider other therapies (biofeedback,
relaxation)
Screen for depression and generalized
anxiety

52.  Magnesium (300-500 mg per day)
 Riboflavin (400 mg per day)
 CoQ10 (300 -1200 mg per day)
 Melatonin (3 mg qhs)

58. MODULATORS OF CERVICAL INPUT
TO HEADACHE
Occipital Nerve Stimulation
INHIBITORS OF CORTICAL SPREADING DEPRESSION
Memantine, Tonabersat, Transcranial Magnestic Stimulation
Adapted from Jones HR. Netter’s Neurology, St. Louis, MO; Saunders; 2005.
INHIBITORS OF CGRP RECEPTOR
Telcagepant
CIRCULATORY TRIGGERS TO
BRAIN EXCITABILITY?
PFO Closure
PFO - Patent foramen ovale

59.  ACUTE THERAPIES
 CGRP Antagonist – Initial placebo controlled trials look
promising
 Transcranial magnetic stimulation
 Inhaled ergotamines
 PREVENTIVE THERAPIES
 PFO Closure – Multiple closure devices in clinical trials
 Memantine – Initial uncontrolled results are promising
 Occipital nerve stimulation
 Tonabersat :The drug is the first in a brand new
selective class of drugs called neuronal gap junction
blockers
PFO - Patent foramen ovale

60.  Monoclonal antibodies
 Aimovig (erenumab)
 Ajovy(fremanezumab)
 Emagality(galcanezum
ab)
 Eptinezumab
 Cgrp receptor
antagonists (gepants)
 Olcegepant
 Telcagepant
 Ubrogepant
 Atogepant
 rimegepant

61. CHRONIFICATION OF MIGRAINE
C/C migraine: Headache days 15/> /month for 3
months ,at least 8 migrainous attacks
Risk factors
 Attack frequency
 Acute medication overuse
 Snoring
 Stressful life events
Granella F et al. Cephalalgia. 1998;18(suppl 2):30-33; Scher AI et al. Curr Pain Headache Rep. 2002;6:486-491.

62.  The midbrain PAG controls
major brain functions,
such as pain and
analgesia, fear and
anxiety.
 Periaqueductal Grey (PAG)
area is closely related to
trigeminal nucleus
caudalis.
Migraine Progression – Anatomical

63. PAG is also a major
component of a
descending pain inhibitory
system and is important in
controlling pain.
Progressive and permanent
neuronal damage to areas
related to pain modulation
(at the level of PAG)
Migraine Progression – Anatomical

64.  Progression from Peripheral to Central
Sensitization
 Cutaneous Allodynia (pain induced by an innocuous
stimulus)
 Repeated Central Sensitization
 Treatment refractoriness esp. to triptans &
preventive treatment
Migraine Progression – Physiological/ Functional
Bigal ME et al. Headache 2008;48:7-15

65.  Strategies for attack modification in
migraine
 Early acute treatment
 Prevent overuse of acute medication
 Early preventive treatment
 Life style modification
 Avoid triggers
 Relaxation techniques
 Treat depression and anxiety

66.  Early treatment during an attack and early
preventive treatment in individuals with migraine
along with modification of risk factors for
progression may yield better outcomes