Sarkis M. Nazarian, M.D.Professor of Neurology and Ophthalmology, UAMS

Internal Medicine Neurology LecturesLittle Rock, Arkansas, July 9, 2014.

Headache and Migraine

Treatment 2014

1. Identify and define major primary benign headache syndromes.

2. Differentiate primary benign headaches from secondary, potentially life-threatening headaches. 

3. Utilize appropriate medical management and refer patient for non-medical treatments.

Objectives

This patient was referred for spells of “feeling tired” for up to 24 hours, followed by severe right parietal throbbing headache, associated with “tingling” sensation inside her head, lasting days to weeks. Severe spells once a week. The headaches are preceded by “colors” and “halos” in both visual hemifields, are associated with nausea (occasional emesis), photophobia, phonophobia, and osmophobia. She takes Fioricet, Ketorolac, and Stadol spray 2-3 times a day for 3-4 days a week.

She also has frequent “staring spells”, lasting 10 to 60 seconds, from which she can self-arouse; these can occur many times a day, and are preceded by fatigue and right throbbing headache. She has no had no convulsions, tongue biting, or incontinence. She was started on levetiracetam (Keppra) 500 mg bid at her local hospital, where workup with EEG and brain MRI was normal.

A 48-year old woman with headaches since age 10

At times, her headaches are also preceded by numbness and weakness, which starts in the left face, and spreads to her upper and lower extremities. These symptoms resolve over several weeks.

Verapamil 180 mg ER bid has improved frequency of severe headaches. Depakote and Topamax used to help, but have lost efficacy. Inderal was not helpful. Imitrex did not help.

PMH is significant for depression (on bupropion 100 mg tid), hypothyroidism (on replacement) and chronic insomnia.

Her mother, grandmother, and one daughter have or had similar severe headaches with lateralized weakness.

She is a high school graduate, smokes ½ ppd for close to 30 years. No coffee, alcohol, or drugs.

General and neurologic exams are unremarkable.

A 48-year old woman with headaches since age 10

1) Chronic daily headaches2) Medication overuse headaches3) Atypical partial complex epilepsy4) Conversion disorder5) Migraine with aura6) Rasmussen syndrome7) Hemiplegic migraine8) Petit mal epilepsy9) Trigeminal autonomic cephalalgia

What is your diagnosis?(choose as many as you need)

1 year prevalence of 90%Lifetime prevalence of 99%28 million in US have migraines each year

HA is the CC of 20% of patients seen in neurology

9% of adults in US see PCP for HA each year

40 million in US suffer from chronic HAs

Headaches

…a familial disorder, characterized by recurrent attacks of headache, widely variable in intensity, frequency, and duration. Attacks are commonly unilateral and usually associated with anorexia, nausea, and vomiting. In some cases, they are preceded by, or associated with, neurological or mood disturbances. All of the above characteristics are not necessarily present in each attack or in each patient.

World Federation of Neurology Research Group on Migraine and Headache

WFN Migraine Definition 1969

Migraine ProdromeIrritabilityExcessive fatigueDepressionMania, euphoriaYawningSalt cravingSugar craving

Migraine AuraPrevalence of migraine with aura reported in

4% of populations in the West, compared to 8% with migraine without aura. Estimated 12M affected in USA.

Peak prevalence is at age 5 in boys and 11-2 in girls, preceding the peak prevalence of migraine without aura.

Four types identified:Visual, in up to 99%Sensory, in 30% - 54%.Language, in 9% - 31%Motor: This is now considered to be part of

Familial Hemiplegic Migraine (FHM) exclusively.

Migraine AuraClassic visual aura is migratory and

expanding, with positive symptoms (fortification spectrum) preceding negative ones (scotoma). In sensory aura, paresthesias precede numbness. In language aura, patients describe both positive (paraphasias) and negative (anomia) symptoms.

Auras occur sequentially, usually starting with visual, then progressing to sensory, etc. It is almost unheard of for patients to have simultaneous different aura types.

Women are more likely to have hemianopia rather than fortification spectra than men (Alvarez, AJO 1960).

Visual Aura Lashley in 1941 gave the most detailed analysis of his

own scotomas, and mapped them to progress at a rate of 3-4 mm/min across the visual cortex, postulated it was due to a spreading cortical abnormality.

Aura usually starts near fixation and spreads peripherally, gaining velocity as it expands.

Always hemianopic; usually not confined to a quadrant. Very rarely complete hemianopia.

Zig-zag lines at periphery; may be in color or mono-chromatic. Center has scotoma, which gradually recovers vision as outer edge of aura continues to expand.

Leao first described in 1944 the phenomenon of spreading depression (SD) at 3-4 mm/min in lab animals whose cortex was subjected to mechanical or chemical trauma.

Migraine Pathophysiology

The Trigeminothalamic System

Sensory Aura

Arm affected 96% of the time, face 67%, leg 24%, and torso 18%.

Usual progression is from fingers up to arm, then jumping to face before the shoulder, eventually affecting the lips, mouth, and tongue.

Language aura is more common in hemiplegic migraine (47% compared to 20% in classic). About 80% have paraphasias or expressive loss, compared to 40% with loss of comprehension.

Acephalgic migraine: CM Fisher’s criteria

Scintillations or other visual, later other symptoms.

Build-up of scintillations“March” of paresthesiasTwo or more similar spellsHeadache (present in 50%)15-25 minute spells (95% of TIAs last <15 mins)“Flurry” of spells around age 50Benign courseNormal cerebral angiographyExclusion of cerebral thrombosis, embolism,

dissection, epilepsy, thrombocythemia, polycythemia, TTP.

Sinus Features at Onset of Headache Hide the Presence of Migraine

Cady et al. Poster presented at: 10th IHC; June 29-July 2, 2001; New York, NY.

66%

40%20%

63%63%63%

53%57%

67%

0% 33% 67% 100%

Vomiting

Phonophobia

Pulsating

Nausea

Unilateral

Worsened by Activity

Photophobia

Moderate-Severe Pain

Drainage

Stuffiness

99%

Weather Associated

n=30 (subjects may report more than one symptom)

Headache Symptoms at Screen

Common symptoms associated with sinus

73%

Cutaneous allodynia in migraine

Allodynia is the phenomenon of normally non-painful cutaneous stimuli being perceived as painful.

Present in 60-75% of migraine Usually in ipsilateral trigeminal

distribution (scalp, head, neck), but often spreads to the ipsilateral upper extremity.

Typically develops within an hour of headache onset, and can persist for hours after headache resolution.

Data from the Centers for Disease Control and Prevention, US Census Bureau, and the Arthritis Foundation.

Disease Prevalence in the US Population

Migraine is More Common than Asthma & Diabetes Combined

1%

5%6%

7%

12%

Rheumatoidarthritis

Asthma Diabetes Osteoarthritis Migraine

Migraine hypotheses

Vascular (Graham & Wolff, 1938-1963)

Neural (Moskowitz, 1984)Unified, or neurovascular5-HT or serotonin (Anthony & Lance, 1969)

Channelopathy

What is migraine? – Current Concepts

Migraine is a disturbance of subcortical sensory modulation systems.

“Normal light is unpleasant, normal sounds uncomfortable and, probably, normal pulsing of vessels felt as pain” (Goadsby, 2003).

Throbbing pain is mediated by sensitization of peripheral trigeminovascular neurons, cutaneous allodynia by central sensitization (Burstein, 2003).

Triptans are successful in preventing induction of sensitization in central, but not peripheral, trigeminovascular neurons.

The Migraine Process: Activation of Nerves and Blood Vessels

Serotonin Receptors

5-HT receptors have been classified into seven different families. The 5-HT3

receptor is a ligand-gated ion channel; all other 5-HT receptors belong to a superfamily of G-protein-coupled receptors with seven transmembrane domains.

5-HT1B/1D, 5-HT1F, 5-HT2B, 5-HT7 subtypes have been implicated in migraine.

Familial Hemiplegic Migraine Autosomal dominant disorder, mutation in a

P/Q calcium channel (CACNL1A4) gene on Chromosome 19p. Same gene defect causes episodic ataxia type 2.

Close to 19p locus for CADASIL (cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy), which often includes migraine.

MELAS (mitochondrial encephalomyopathy, lactic acidosis and stroke-like episodes) also in the differential diagnosis of FHM, presents with episodic sudden headache and convulsions.

Physical Factors That May Precipitate Migraine

Menses, ovulation, pregnancyBirth control/hormone replacement (estrogen)

IllnessIntense or strenuous activity/exercise

Sleep deprivation/excess, jet lag

Fasting, missing meals

Physical Factors That May Precipitate Migraine - II

Bright or flickering lightsExcessive or repetitive noisesOdors/fragrances/tobacco smoke

Weather/seasonal changesHigh altitudesMedications

Dietary Factors That May Precipitate Migraine

ChocolateSour creamRipened cheeses (Cheddar, Brie, etc)

Cured meats (sausage, hot dogs, etc)

Chicken livers, pateHerring, pickled or dried

Dietary Factors That May Precipitate Migraine - II

Pickled, fermented, or marinated foods

MSGFreshly baked yeast products, bread

Nuts or nut buttersBeans: broad, lima, fava, snow peasOnions

Dietary Factors That May Precipitate Migraine - III

Figs, raisins, papayas, avocados, red plums

Citrus foodsBananasCaffeinated beverages (withdrawal)

Alcoholic beveragesAspartame/phenylalanine cont. foods

Food Additives that may precipitate Migraine

Aspartame/phenylalanineMSGSulfitesNitritesTartrazine (FD&C yellow dye)

Benzoic acid

Medications that may precipitate Migraine

Birth control/hormone replacement drugs (estrogen)

Vasodilators - e.g. trinitroglycerine, persantine

PDE-5 inhibitors – e.g. sildenafilCatecholamine depleters - e.g.

reserpine

Disorders Associated with Migraine

Stroke (esp. with smoking and OCPs)Patent Foramen OvaleObesity & metabolic syndromeEssential tremorSleep disorders, Obstructive Sleep ApneaCollagen-vascular disordersAntiphospholipid syndromeEhlers-Danlos SyndromeAnxiety, depression, bipolar disorderPreeclampsia, orthostatic hypotension

PFO and stroke in migraine with aura

Migraineurs are 2-2.5 times as likely to have stroke as non-migraineurs.

PFO (patent foramen ovale) has been found in 48% of patients with migraine aura, 23% in non-aura migraineurs, and 25% in controls (Anzola et al, Neurology 1999).

Divers with PFO are more likely to develop headaches after a dive, suggesting gas bubbles can ppt. migraine (Wilmhurst et al, Lancet 2000).

Is it microemboli in the brain vasculature or vasoactive substances in blood unfiltered by the lungs that causes the migraine? Does closure of the PFO reduce the incidence of migraine aura and headache? Do anticoagulants decrease the incidence of aura and migraine?

Claviceps purpurea

Migraine therapy - Ergot alkaloids

Used since the 1940s; inexpensiveAvailable as po (w/ caffeine), pr forms Powerful vasoconstrictors (veno>arterial)

Retro-pleural, -peritoneal, endocardial fibrosis

Painful dysesthesias (St. Anthony’s fire)Raynaud’s phenomenonPsychoactive properties: Salem witch trials

MIGRAINE ABORTIVE RX

Sumatriptan 6 mg sqDHE 1 mg IMDHE nasal spray 2 mgSumatriptan nasal spray 20 mgErgotamine suppository 2 mgTriptan tablets (various), spraysMidrin (isometheptene,

dichloralphenazone, APAP); Sansert (methysergide), had been taken off the market, recently re-introduced.

AVOID butalbital (Fiorinal) and opioids.

Dihydroergotamine (DHE-45)

Less arterial constriction compared to ergots.Very effective: 70-75% pain-free at 1 hour.Available as IV, IM, sq injection or nasal spray. Peak levels in 2-11 mins (IV), 15-45 mins (sq), 30

mins (IM), 30-60 mins (nasal).Lower headache recurrence compared to Imitrex.Lower cost than triptans.Side effects: N/V, diarrhea, leg cramps, abdominal

discomfort; effect on dopamine receptors.

IV DHE-45 Protocol (Raskin 1990)

Metoclopramide (MC) 10 mg IV over 30’;DHE test dose 0.5 mg over 2-3’

NauseaNo DHE x 8°, then repeat DHE 0.3-0.4 mg q 8° prn w/ MC, for up to 3 days

Headache persists, no nausea

DHE 0.5 mg w/o MC in 1°

Headache resolved, no nausea

DHE 0.5 mg q 8° for 2 days, with MC prn

NauseaDHE 0.75 mg q q 8° for 2-5 days, with MC

No NauseaDHE 1 mg q q 8° for 2-5 days, with MC

SUMATRIPTAN

Poorly absorbed orally, 14% bioavailable; Tmax: 2-2.5 hours. Plasma half-life 2 hours only. Receptor binding is reversible. Metabolized by MAO; possible “serotonin

syndrome”. In meta-analysis, response 56% for 50 mg, 58%

for 100 mg; recurrence in 30-35%. Side effects: “Chest-related symptoms”,

tingling, paresthesias, warm feeling, dizziness, flushing.

5-HT1B/1D RECEPTOR AGONISTS

Sumatriptan (Imitrex, Glaxo Wellcome)

Naratriptan (Amerge, Glaxo Wellcome)

Zolmitriptan (Zomig, Glaxo Wellcome)

Rizatriptan (Maxalt, Merck) Eletriptan (Relpax, Pfizer)Almotriptan (Axert, Pharmacia)Frovatriptan (Frova, Elan)

Triptan chemical formulas

Second-generation Triptans

Better oral pharmacokinetics:Higher bioavailability (45-75%)More rapid therapetic plasma levels: 30-60 minutes.

Longer half-lives (esp. frova & nara)Greater potency at 5-HT1B/1D receptorIncreased lipophilicity and brain entry

Triptan therapeutic gains

Serotonin Syndrome May rarely occur when triptans are used with

serotonergic drugs (SSRIs, MAOIs, TCAs, Li+, LSD, tramadol, L-DOPA, St. John’s wort, L-tryptophan, Buspar, cocaine, Demerol, Talwin, trazodone, fenfluramine, MDMA “ecstasy”)

Neuromuscular (myoclonus, hyperreflexia, shivering, rigidity, tremor, incoordination), autonomic (tachycardia, diaphoresis, fever, GI hyperactivity, pupils), neuropsychiatric (anxiety, delirium, lethargy, seizures, coma)

Combination TherapyNew combination medication

TreximetFixed combination sumatriptan (85

mg) and naproxen sodium (500 mg)Relief was superior to either individual

medication used as monotherapy in trials

Decreased use of using rescue medication compared to monotherapy

Need to remind patients not to take Naprosyn or other NSAIDS with this medication

Combination TherapyTriptans plus Prokinetics

During a migraine there is impaired gastric motility and delayed gastric emptying.

This can lead to nausea and impaired absorption of medications.

Prokinetics such as Reglan not only increase gastric emptying, but also reduce nausea.

Prokinetics may speed up absorption of triptans and therefore alleviate headache faster and prevent central sensitization.

MIGRAINE PROPHYLAXIS

Tricyclic antidepressantsBeta-blockers: Proporanolol, atenolol, etc.

Flunarizine (not locally available)Divalproex, topiramate, other AEDsTizanidineNSAID’s (Naproxen, indomethacin)Riboflavin 400 mg/dMagnesium 400 mg/d, fish oil (??)

Advice for migraine sufferers

Keep daily headache log or diaryAvoid daily pain medications; DO take the daily

meds for headache prevention.Avoid undue stress reduction – read “Don’t Sweat

the Small Stuff – and It’s All Small Stuff”, by Richard Carlson.

Exercise several times a weekKeep regular sleep and meal schedulesAvoid caffeine, alcohol, and tobaccoAvoid foods such as chocolate, cheese, and nuts if

they cause headachesAvoid NutraSweet, MSG (Accent), nitrites (hot

dogs), sulfites (wine), food dyes (FD&C Yellow 5).

Chronic Daily Headaches (CDH)

Headache occurring >15 days/month is usually due to affective and somatoform disorders. These headaches are refractory to most migraine and tension headache therapies.

Topiramate and Botox A injections have been shown to be of benefit in prophylaxis and approved for this indication.

Fibromyalgia, Myofascial Pain, Chronic Fatigue Syndrome, etc., also have headache as major components of their symptomatology.

TENSION-TYPE PROPHYLAXIS

Tricyclic Antidepressants

Other migraine prophylaxis agents

Combinations of the above

Posttraumatic HeadacheWrenching and

displacement of pain structures during head trauma

Example is postconcussion

Chronic HANeck painNervousnessEmotional labilityCrying spellsInability to concentrate

Medication Overuse Headache

“Drug rebound headache”, “transformed migraine”

Diffuse, bilateral headache; daily, constant, present on awakening

Aggravated by mild mental or physical exertionAssociated with neurovegetative symptoms of

depression: asthenia, anxiety, insomnia, poor memory

Associated with overuse of NSAIDs, triptans, ergots, benzos, barbiturates, opioids

Tolerance to acute migraine agentsNo response to preventive migraine meds

Guidelines for Limiting Use of Abortive Therapies

Caffeine: Limit coffee to one cup/dayNSAIDs: 10-15 treatment days/month;

5 treatment days/month is protective.Combinations: 10 treatment days/monthErgots, triptans: 10 treatment days/month;

use ergots with caution. Opioids: 8 treatment

days/monthButalbital: 5 treatment days/month

Bigal M et al. Headache 2008;48:1157

Cluster Treatment & Prophylaxis

Cluster headache: 7:1 men:women; associated with smoking. Non-pulsating, “boring” pain. Often wakes patient from sleep. Unable to sit still, agitated, restless. Activation in ipsilateral hypothalamus, rather than contralateral midbrain. High suicide risk.

Acute treatment: Ergots, DHE, triptans, intranasal lidocaine; may respond to high-flow (7-15 L/min) oxygen for 10-20 minutes.

Prophylactic treatments: Verapamil, divalproex, lithium carbonate, corticosteroids, indomethacin.

Cluster Treatment & Prophylaxis

Cluster headache: 7:1 men:women; associated with smoking. Non-pulsating, “boring” pain. Often wakes patient from sleep. Unable to sit still, agitated, restless. Activation in ipsilateral hypothalamus, rather than contralateral midbrain. High suicide risk.

Acute treatment: Ergots, DHE, triptans, intranasal lidocaine; may respond to high-flow (7-15 L/min) oxygen for 10-20 minutes.

Prophylactic treatments: Verapamil, divalproex, lithium carbonate, corticosteroids, indomethacin.

Trigeminal Autonomic CephalalgiasChronic Paroxysmal Hemicrania: More frequent

(>5/d) and of shorter duration (2-30 mins.) than cluster. 3:1 women. Responds to indomethacin.

SUNCT: Short-lasting, unilateral, neuralgiform headaches with conjunctival injection and tearing. At least 20 attacks a day, each lasting 10-60 seconds; refractory to treatment. Lamotrigine may be useful in prevention.

Hemicrania Continua: Continuous cluster-like headache, more common in women; responds to indomethacin.

Hypnic headache: Short (~30 minutes) attacks of bilateral pain that awaken patient, usually same time every night. Common in older patients.

Non-pharmacologic treatmentsBiofeedback: Thermal technique (warming

or cooling hands), found to reduce headache frequency by 35%.

Relaxation Therapy: Four types - with tension, using imagery, by breathing exercises, by hypnosis. Overall 35% reduction in headache frequency. Relaxation & thermal feedback together - 56% reduction.

Acupuncture. Botulinum A toxin: Has been found

effective in chronic migraine.

Benign headaches

Exertional headacheCough headacheCoital headacheCold stimulus headache: “ice cream”

Idiopathic stabbing headache: “ice-pick”

External compression headache: “swim goggle”

Toxic Vascular Headaches

Infection, feverHypoxia, anemia, dehydrationHypoglycemiaHangoverCaffeine and CNS stimulant withdrawal

Opioid withdrawalDecompression

Aneurysmal Subarachnoid hemorrhage

“Thunderclap headache”: Severe, maximal at onset

Neck and intrascapular pain, photophobia

20% have minimal or mild headache, gradually worsening

Headache worsened by movement75% have meningismus

Subarachnoid Hemorrhage

Spontaneous Int. Carotid A. DissectionPain in face, head, or neck, followed by

retinal or brain stroke within hours to days. Pain is most commonly in anterior neck, frontal or parietal area, present in 80-85%. Headache may be insidious, or “thunderclap”. It resolves within a week in 90%, but it can last for several years.

Horner’s syndrome develops in about half the patients. Baumgartner et al found it in 28% of patients with stroke, but in 53% of those without.

Cranial nerve palsies (IX-XII) develop in about 12%. Pulsatile tinnitus is present in 10%.

TIAs or strokes of retina and brain develop in 50-95% of patients; TIA often precedes stroke.

Reversible Cerebral Vasoconstriction Syndrome (RCVS)

Presents with thunderclap headacheFirst described in a 1988 by Call, Fleming, et al.Mostly in women, 20-50 year-old range; resolves in 3

months, and 89% of patients have excellent prognosis.

Angiography reveals segmental intracranial stenoses.Mostly benign, but focal deficits in 43%, strokes in

39%, SAH in 34%, bleeds in 20%, seizures in 17% in a recent review of 193 patients. [Singhal AB et al, Arch Neurol 2011;68:2005]

Ppt. by vasoactive drugs (cocaine, amphetamines, etc.); also common in peripartum period.

Guidelines for Use of CT/MRI1. Decreased alertness or cognition 2. Onset of pain with exertion, coitus,

coughing or sneezing3. Worsening under observation4. Nuchal rigidity5. Focal neurological signs6. First headache in patient over 507. Worst headache ever experienced8. Headache not fitting a defined pattern

Idiopathic Intracranial Hypertension

“Pseudotumor cerebri”Young, obese women predominateHeadache, papilledema, visual loss; few

cases without papilledemaCSF pressure >15 cm H2ONormal cerebrospinal fluid formulaMay be due to intracranial sinus

thrombosis, especially in post-partum women

Rarely, due to hypervitaminosis AVisual outcome worse if patient anemic

Giant Cell ArteritisESR>55 mm/hr, age>55 years; elevated C-

RPTemporal headache, jaw claudicationAssoc w/ polymyalgia rheumaticaAnorexia, anemia, weight lossBlindness due to optic nerve infarct from

posterior ciliary artery involvementBiopsy: Multinucleated giant cells, internal

elastic membrane lossHigh-dose corticosteroids to keep ESR nl

Trigeminal Neuralgia Brief, lancinating pain in trigeminal nerve

distribution (usually V2 or V3) Trigger zones, often inside mouth Avoidance behavior Onset in middle age, except younger in MS Treatment: Carbamazepine, other AEDs,

baclofen, tizanidine Surgery: Radiofrequency lesion of

Gasserian ganglion, Jannetta procedure

Occipital Neuralgia

Lancinating pain on background of dull, steady occipital pain

Paresthesias and hyperalgesia of occiput Radiating pain with pressure over occipital

nerve Usu. in setting of cervical spine disease Treatment: Local anesthetic & steroid

block, TCAs, AEDs

Occipital Nerve Block 26-gauge, 1/2” needle introduced medial to

the external occipital protuberance. Needle advanced to periosteum, then

withdrawn 1-2 mm. Mixture of bupivacaine (Marcaine) 0.5%, 1-2

ml, and triamcinolone (Kenalog) 40 mg/ml, 0.5 ml, injected slowly in 0.5 cc aliquots, with aspiration prior to each injection.

Nerve blocks for headache relief

The Migraine “Tiara”

Botulinum toxin for chronic migraine

Botulinum toxin for chronic migraine

Two randomized, placebo-controlled studies of onabotulinumtoxinA injections (12 weeks apart) for the prevention of chronic migraine headaches, with follow-up for 24 weeks (679 and 705 subjects),

revealed no change in frequency, but fewer headache days and migraine days com pared to placebo, and HIT-6 scores were lower in treated patients.Most common adverse effects with Botox injections were neck pain, muscle weakness, eyelid ptosis, myalgia, and muscle stiffness, as well as, paradoxically, worsening migraine.

The MIDAS headache score

The HeadacheImpactTest (HIT-6)

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Neurother 2007;7(12):1785-1789. Ho TW et al. Randomized controlled trial of an oral CGRP receptor

antagonist, MK-0974, in acute treatment of migraine. Neurology 2008;70:1304-1312.

Bigal ME, Lipton RB: The differential diagnosis of chronic daily headaches: an algorithm-based approach. J Headache Pain 2008;8:263-272.

Goadsby PJ: Advances in the understanding of headache. Brit Med Bull 2005;73 and 74:83-92.

Ferrari MD: Migraine. Lancet 1998; 351:1043-51. Russell MB: Epidemiology and genetics of cluster headaches. Lancet Neurol

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