Cephalgia recent updates in migraine Hedache classification migraine management

1. Classification of Headache &
management of Migraine
Dr VAIBHAV KUMAR SOMVANSHI
2nd YEAR DM NEUROLOGY RESIDENT
GMC KOTA

2. Outline
• Classification ICHD-3
• Diagnostic criteria
• Pathophysiology
• Management
• Neuromodulation Devices
• Recent Updates
Non Pharmacological
Acute management
Emergency management
Refractory migraine management
Pregnancy and lactation
Childhood migraine
Preventive therapy
Chronic Migraine therapy

3. Classification of Headache

4.  The term migraine derives from the ancient Greek word, hemikranios, which means “half head,”
underscoring the unilateral distribution of head pain that is present in about 60%–75% of people
with migraine.

5. MIGRAINE
ICHD-3 Classification
1.1 Migraine without aura
1.2 Migraine with aura
1.2.1 Migraine with typical aura
1.2.1.1 Typical aura with headache
1.2.1.2 Typical aura without headache
1.2.2 Migraine with brainstem aura
1.2.3 Hemiplegic migraine
1.2.3.1 Familial hemiplegic migraine
1.2.3.1.1 Familial hemiplegic migraine type 1
1.2.3.1.2 Familial hemiplegic migraine type 2
1.2.3.1.3 Familial hemiplegic migraine type 3
1.2.3.1.4 Familial hemiplegic migraine, other
loci
1.2.3.2 Sporadic hemiplegic migraine
1.2.4 Retinal migraine
1.3 Chronic migraine
1.4 Complications of migraine
1.4.1 Status migrainosus
1.4.2 Persistent aura without infarction
1.4.3 Migrainous infarction
1.4.4 Migraine aura-triggered seizure
1.5 Probable migraine
1.5.1 Probable migraine without aura
1.5.2 Probable migraine with aura
1.6 Episodic syndromes that may be associated
with migraine
1.6.1 Recurrent gastrointestinal disturbance
1.6.1.1 Cyclical vomiting syndrome
1.6.1.2 Abdominal migraine
1.6.2 Benign paroxysmal vertigo
1.6.3 Benign paroxysmal torticollis

6. EPIDEMIOLOGY
• Migraine  one-year prevalence 12% in the general population, 18% women, 6% men.
• Migraine afflicts prepubescent boys and girls with a similar frequency.
• Peak migraine prevalence for both sexes occurs in fourth decade approximately 24% of women and
7% of men have migraine
Lipton, RB, Bigal, ME, Diamond, M, et al. Migraine prevalence, disease burden, and the need for preventative therapy. Neurology
2007; 68:343

7. MIGRAINE WITHOUT AURA
Previously used terms:
•Common migraine; hemicrania simplex.
Description:
• Recurrent headache disorder manifesting in attacks
• Lasting 4-72 hours.
• Typical characteristics of the headache are unilateral location, pulsating quality, moderate or
severe intensity, aggravation by routine physical activity and association with nausea and/or
photophobia and phonophobia

8. DIAGNOSTIC CRITERIA
• A. At least five attacks fulfilling criteria B–D
• B. Headache attacks lasting 4-72 hours (untreated or unsuccessfully treated)
• C. Headache has at least two of the following four characteristics:
1. unilateral location
2. pulsating quality
3. moderate or severe pain intensity
4. aggravation by or causing avoidance of routine physical activity (e.g. walking or climbing stairs)
• D. During headache at least one of the following:
1. nausea and/or vomiting
2. photophobia and phonophobia
• E. Not better accounted for by another ICHD-3 diagnosis.

9. MIGRAINE WITH AURA
Previously used terms:
•Classic or classical migraine; complicated migraine.
Description:
• Recurrent attacks, lasting minutes, of unilateral fully reversible visual, sensory or other
central nervous system symptoms that usually develop gradually and are usually followed by
headache and associated migraine symptoms.

10. DIAGNOSTIC CRITERIA
• A. At least two attacks fulfilling criteria B and C
• B. One or more of the following fully reversible aura symptoms:
1. visual
2. sensory
3. speech and/or language
4. motor
5. brainstem
6. retinal
• C. At least two of the following four characteristics:
1. at least one aura symptom spreads gradually over 5 minutes, and/or two or more symptoms occur in
succession
2. each individual aura symptom lasts 5-60minutes
3. at least one aura symptom is unilateral
4. aura is accompanied, or followed within 60 minutes, by headache
• D. Not better accounted for by another ICHD-3 diagnosis, and transient ischemic attack has been
excluded.

11. Migraine with brainstem aura
Diagnostic criteria:
• A. At least two attacks fulfilling criteria B-D
• B. Aura consisting of visual, sensory and/or speech/ language symptoms, each fully reversible, but
no motor or retinal symptoms
• C. At least two of the following brainstem symptoms:
1. dysarthria
2. vertigo
3. tinnitus
4. hypacusis
5. diplopia
6. ataxia
7. decreased level of consciousness

12. • D. At least two of the following four characteristics:
1. at least one aura symptom spreads gradually over 5 minutes, and/or two or more symptoms occur in
succession
2. each individual aura symptom lasts 5-60 minutes
3. at least one aura symptom is unilateral
4. aura is accompanied, or followed within 60 minutes, by headache
• E. Not better accounted for by another ICHD-3 diagnosis, and transient ischaemic attack has been excluded.

13. Hemiplegic migraine
Diagnostic criteria:
• A. At least two attacks fulfilling criteria B and C
• B. Aura consisting of both of the following:
1. fully reversible motor weakness
2.fully reversible visual, sensory and/or speech/ language symptoms
• C. At least two of the following four characteristics:
1. at least one aura symptom spreads gradually over 5 minutes, and/or two or more symptoms occur in
succession
2.each individual non-motor aura symptom lasts 5–60 minutes, and motor symptoms last <72 hours
3.at least one aura symptom is unilateral
4. the aura is accompanied, or followed within 60 minutes, by headache
• D. Not better accounted for by another ICHD-3 diagnosis, and transient ischaemic attack and stroke
have been excluded.

14. Neurology clinic nov 2019

15. Genetics
• Neurology clinic November 2019

16. A dysfunction of
neuromodulatory
structures locus
coeruleus or
periaqueductal grey
matter and hypothalamus
CGRP
5-HT1B/1D
receptors,
Prostaglandins
Leukotrienes
Integrated Neurovascular Hypothesis

18. CGRP
5-HT1B/1D
receptors,
Prostaglandins
Leukotrienes
Therapeutic targets
Paracetamol and
NSAIDS
Triptans
CGRP antagonists

19. The Migraine Attack

20. Migraine diary

21. Indications for imaging headache
• Acute headache
• Worst headache of life
• Thunderclap headache
• Chronic-progressive pattern (steadily worsening over time)
• Focal neurologic symptoms
• Abnormal neurologic examination
• Papilledema
• Abnormal eye movements
• Hemiparesis
• Ataxia
• Abnormal reflexes
• Presence of ventriculoperitoneal shunt
• Presence of neurocutaneous syndrome (neurofibromatosis or tuberous sclerosis)
• Age younger than three years

23. M Ashina. N Engl J Med 2020;383:1866-1876.
Proposed Treatment Algorithm for the Clinical Management of
Migraine.

24. Migraine Treatment Optimization Questionnaire (mTOQ-4) to
Assess TABLE 4-3
Response to Acute Treatment

25. Continuum 2018

26. Childhood migraine
• Headaches during childhood (7.7%), increase in frequency during adolescence
• Acetaminophen and NSAIDs, ibuprofen best.
• Three Triptans are approved (USFDA)for use in this population:
 almotriptan -12 to 17 yrs
 Rizatriptan - 6 to 17 yrs
 sumatriptan with naproxen -12 yrs and older
• Prohylactic  Topiramate Valproate and Cyprohepatidine are considered better than Amitryptiline and
Propranolol

27. Menstrual migraine
• Menstrual migraine  attack 2 day before and up to 3 days after the onset of menses, not at any
other time.
• Short term prophylaxis with Triptans (Sumatriptan 25 BD) or Naproxen 500 BD
• Hormonal therapy (OCPs without missing)
– Transdermal estradiol (1 x 100 ug days -3--+2)
– Combined oral contraceptive or transdermal patch
– Percutaneous estradiol (1.5 mg daily days -3 to +6)

28. Hormone and Migraine
• Systemic Review and meta-analysis done by
Noori-Zadeh et al suggest hyperprolectinemia in
Migraineurs as compare to control group
• Testosterone and androgen levels found to be low in male migraineurs with low Tr/Estradiol level
• Estrogen withdrawal and low progesterone, FSH and LH, B-hcG level associated with migraine
• TSH levels has no implications on migraine attack frequency.
Neurological Sciences; Ali Noori-Zadeh1 & Morvarid Karamkhani2 & Ali Seidkhani-Nahal3 & Afra Khosravi4 & Shahram Darabi5 https://doi.org/10.1007/s10072-019-04035-7

29. PREGNANCY AND LACTATION
• Acetaminophen (650 -1000mg) and metoclopramide(10mg) are the only treatments for migraine
that are considered safe in pregnancy.
• 2nd line options are safest in the second trimester before 20 weeks – NSAIDS, after that concerns
about prenatal constriction of the ductus arteriosus, persistent pulmonary hypertension of the
newborn, oligohydramnios
• Triptan  2nd & 3rd trimesters  increased risk of uterine atony, blood loss during labor.
However sumatriptan came out to be reassuring in pregnancy registry
• Medication safe during lactation  acetaminophen,ibuprofen, metoclopramide, prochlorperazine,
diphenhydramine, and sumatriptan.

30. Emergency setting - Migraine
Reasonable options –
• Sumatriptan 6 mg subcutaneous injection
• Antiemetics/Dopamine receptor blockers
Metoclopramide 10 mg intravenous (IV)
Prochlorperazine 10 mg IV or intramuscular (IM)
Chlorpromazine 0.1 mg/kg IV
• Dihydroergotamine (DHE 45) 1 mg IV combined with metoclopramide 10 mg IV
• Ketorolac 30 mg IV or 60 mg IM
Headache. 2012 Jan;52(1):114-28. Epub 2011 Dec 28.
adjunct use
of diphenhydrami
ne (12.5 to 25 mg
IV every hour up
to two doses) to
prevent akathisia
and other dystonic
reactions

31. Treatment of Status migraine
 Defined as headache that last for more than 72 hours whether it has been treated or not
 Combination of I.V. fluids and ketorolac or DHE or valproiate and metocloperamide
 Single dose of parenteral dexamethasone (10 to 24 mg)  reduce risk of early headache recurrence in the
emergency department.
 Intravenous methylprednisolone in a single dose can be utilized to break long-lasting migraine attacks.
Gallagher RM. Emergency treatment of intractable migraine. Headache 1986;26:74–75

32. Refractory Migraine
• Parenteral ergotamine  refractory migraine. should be avoided for 24 hours after administration of
a triptan.
• I.V. MgSO4 (1 to 2 g)  effective alternative treatment for migraine with aura.
• I.V. valproate is commonly used, but the evidence  contradictory
• iv metoclopramide, Prochlorperazine(level b)
• Corticosteroids-dexamethasone- should be offered to these patients to prevent recurrence of
headache (Should offer—Level B)

33. COVID 19 and Migraine
• Headache  one of the symptoms of COVID-19 infection(8%)
• Migraine patients see a spike in their attacks, reason abundance of migraine triggers.
• Current guidelines  uses of nonsteroidal anti-inflammatory drugs (NSAIDs), triptans and
narcoleptics are safe for the acute treatment of migraine attacks. Stop ACEI, ARB weighing risk
benefit.
• Doctors, nurses and other health care professionals  higher migraine risks than the general
population Working for grueling shifts of 6–8 h wearing personal protective equipment (PPE), it was
found that 81% of HCW developed de novo PPE associated headaches
• Sanitizers and soaps with strong odors should be avoided

34. When to start Preventive treatment
1. Recurring migraine that significantly interferes with the patient’s daily routine despite
acute treatment.
2. Failure of, contraindication to, or intolerable side effects to acute medications.
3. Acute medication overuse or the risk of developing acute medication overuse.
4. Special circumstances, such as hemiplegic migraine or migraine attacks with a risk of
permanent neurologic injury.
5. High-frequency episodic migraine or a pattern of increasing migraine attacks over time.
6. Patient preference, or patient desire to have as few acute attacks as possible.

35. Preventive medications for treatment of migraine
Loder E, Burch R, Rizzoli P. The 2012 AHS/AAN guidelines for prevention of episodic migraine: a summary and comparison with
other recent clinical practice guidelines. Headache 2012; 52:930

37. Botulinum Toxin for the Treatment of Chronic
Migraine
• Botulinum toxin type A inhibit the release of glutamate and calcitonin gene-related peptide ,
• Reduce the activity of central nociceptive neurons.
• FDA approved dosage is 155 Units distributed in 31 sites as in the PREEMPT trials
• Onabotulinumtoxin type A reaches its clinical effect at 7–10 days and plateaus at 3 weeks

40. Adherence, persistence to medications,Duration of
treatment
• Low adherence and persistence due to side effects and poor efficacy.(29% at 6 months and 20% at 12
months).
• Educate patient on long duration of treatment, need for adherence and persistence and expected
outcomes.
• Outcome: might not be complete cessation of headaches. >50%reduction can be reasonable.
• Lowering of dose be individualized to minimize side effects.
• Effective preventive therapy: 3-6 months before taper/stop.
• Don't discontinue any medication before trial with desired dose is given for at least 2-3 months.

41. MAbs Phase 3 Trials for Episodic(EM) and
Chronic(CM) Prophylaxis

42. M Ashina. N Engl J Med 2020;383:1866-1876.
Response Rates in Phase 3 Randomized Trials of
Monoclonal Antibodies against CGRP or Its Receptor for
Prevention of Episodic Migraine.

43. Triptans: : Level A; AHS
• More effective for moderate/severe HA than NSAIDs.
• Oral dose: almo 12.5, ele 20, nara 2.5,riza 5,suma 50, zolmi 2.5
• 2 hr relief: 42-76% (placebo 27%), half even had relief at 24 hr.
• Triptan combination even better (sumatriptan 85 and acetaminophen/napro 500 (80%,62%).
• C/I: history of stroke, MI, CAD, HM, migraine with BA, uncontrolled HTN, PAD.
• Avoid riza, zolmi, suma in 2wks of MAOI use (serotonin syndrome) New formulations: intranasal
suma , zolmitriptan spray.

44.  Two randomized, double-blind, single-attack, parallel-group studies conducted at 118 clinical centers
in the US.
 The studies included 1,461 (study 1) and 1,495 (study 2) individuals with migraine.
 Sumatriptan (85 mg) and naproxen (500 mg) fixed-dose tablet for  acute migraine attack superior
to monotherapy with either sumatriptan or naproxen, and was well tolerated

45. M Ashina. N Engl J Med 2020;383:1866-1876.
Freedom from Pain at 2 Hours in Randomized Clinical Trials of Treatments for
Migraine.

46. Nasal and Parentral route
• The nasal sprays result in substantial blood levels within 30–60 min.
• Their reported efficacy is only approximately 50–60%.
• Sumatriptan, 6 mg subcutaneously, is effective in ~70–80% of patients

47. Ditans, New 5-HT1F Agonist Acute Migraine
Medication
• Why new serotonin agonist?•
 Limitations of triptans:
 not all patients respond, not all patients tolerate
 contraindicated in cardiovascular or cerebrovascular disease (5HT1B receptor stimulation).
• Ditans: Most specific- on 5-HT1F receptor (Lasmiditan- 200 and 100 mg).
• SAMURAI, SPARTAN trials- finished. GLADIATOR- ongoing- interim analyses- effective.
• US FDA approved: Oct 2019
• 2 hour pain freedom is about 30%.
• Adverse effects: moderate dizziness and somnolence at 10-15%, less than triptans.  Adverse events
drug may cause driving impairment, and patients should not drive a motor vehicle, operate
machinery, or engage in potentially hazardous activities for at least eight hours after each dose of
lasmiditan
• Do not cause vasoconstriction (caused by 5-HT1B agonists), so safe in vascular disease.
Kuca B, Silberstein SD, Wietecha L, et al. Las miditan is an effective acute treatment for migraine: a phase 3 randomized study. Neurology 2018;91:e2222-e2232.Goadsby
PJ, Wietecha LA, Dennehy EB, et al. Phase 3 randomized, placebo controlled, double-blind study of lasmiditan for acute treatment of migraine. Brain (in press 2019).

48. CGRP antagonist
https://www.accessdata.fda.gov/drugsatfda_docs/appletter/2020/212728Orig1s000ltr.pdf

49. Neuromodulatlion Strategies

50. Greater occipital nerve block
Friedman BW, West J, Vinson DR, et al. Current management of migraine in US emergency departments: an analysis of the
National Hospital Ambulatory Medical Care Survey. Cephalalgia 2015;35(4):301–9

51. Neuromodulation Devices
• The Transcutaneous Supraorbital Neurostimulator :
• This FDA-approved (Cefaly Device)
• Preventative and acute treatment of migraine.
• Preventative treatment with for 20 minutes daily.
• Acute treatment, with a different setting of the device, lasts one hour.
• Device cost - $540.
• Electrodes needs to be replaced about every 3 months for $25.

52. • Non-Invasive Vagus Nerve Stimulator:
• GammaCore
• Used for acute attacks
• the cost of one month of use of gammaCore is currently $575.

53. • Transcranial Magnetic Stimulator:
• acute and preventative treatment of migraine.
• The preventive dose is 4 pulses of the magnet twice daily, with as needed extra pulses for acute
treatment to a maximum of 17 pulses per day

54. Non-Pharmacological
• Behavioural therapies
• Aim to reduce headache-related disability, quality of life, and psychological comorbidity.
• Indicated in patients with significantly impact of migraine
 if non pharmacologic therapy preferred due to side effects
 if patient behaviours and stress triggers for migraine attacks
Types: relaxation training, thermal/EMG biofeedback, cognitive-behavioral therapy. mindfulness
Level A recommendations by AAN.

55. Acute non pharmacological treatment
• Nerve blocks: No high evidence: supraorbital/troch/occipital nerve block but many experts use in
severe cases.
• Neurostimulation: Supraorbital nerve TENS: open-label trial: 2 hr pain relief 52.8%.However 1/3
required rescue medication.
• Non invasive VNS had 2 hr pain relief was 47%
• Single-pulse TMS: migraine with aura. 24hr relief 30% vs 15 placebo.

56. Role of spectacles in
migraine prevention.
• MigraLens are spectacle lenses with a pleasant green hue.
• Specifically absorb the wavelengths that cause migraine symptoms and migraine sensitivity.
• A clinical study shows participants who wore average of 6.2 to 1.6 migraine attacks per month—
that’s a 74% reduction in attacks!

57. Ongoing research
Spiegelmers
What is Spiegelmer?- a chemically synthesized mirrorimage oligonucleotide that can bind its target
with high specificity, comparable to antibodies.
CGRP-targeted Spiegelmers using CGRP-neutralizing L-aptamers- have been tested.
NOX-C89 and NOX-L41 can both bind CGRP.
NOX-C89- studies in rats:- Binds also to amylin- development halted.
NOX-L41- In vivo (rats)- inhibit plasma protein extravasation in the rat dura mater for 18hrs.
• Anti-pituitary adenylate cyclase-activating polypeptide (PACAP) mAbs
AMD-301- targets the PAC1 receptor.
undergone a phase II clinical trial.
Hoehlig K, Johnson KW, Pryazhnikov E, et al. A novel CGRP-neutralizing Spiegelmer attenuates neurogenic plasma protein extravasation. Br, Pharmacol. 2015;172(12):3086-3098. Do, T.P., Guo, S.
& Ashina, M. Therapeutic novelties in migraine: new drugs, new hope?. J Headache Pain 20, 37 (2019).

58. Points to ponder
• Our understanding of the mechanisms underlying migraine has evolved during the past decade, with
pathogenesis of migraine and the development of mechanism-based therapies.
• But uncertainties exact origin of migraine pain, mechanism underlying the paroxysmal nature and
features of migraine, exact site and mode of action of migraine-specific medications.
• An effort is needed to find new drug targets and develop biomarkers that can predict which patients
will have a response to each targeted therapy

59. Original
Dr Vaibhav Somvanshi

60. References
• Continuum headache november 2018.
• American Academy of Family Physicians 2018 guideline
• The American Headache Society 2016 guideline.
• Neurology clinic 2019
• NEJM December 2020 Migraine review
• Seminars in neurology February 2021
• Annals of India supplement April 2020
• www.uptodate.com