Sarkis M. Nazarian, M.D.
Professor of Neurology and Ophthalmology, UAMS
Internal Medicine Neurology Lectures
Little Rock, Arkansas, July 9, 2014.
1. Identify and define major primary
benign headache syndromes.
2. Differentiate primary benign headaches
from secondary, potentially life-threatening
3. Utilize appropriate medical
management and refer patient for non-
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.
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.
1 year prevalence of 90%
Lifetime prevalence of 99%
28 million in US have migraines each
HA is the CC of 20% of patients seen in
9% of adults in US see PCP for HA each
40 million in US suffer from chronic
…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
Prevalence 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.
Classic 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
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.
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
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.
Scintillations or other visual, later other symptoms.
Build-up of scintillations
“March” of paresthesias
Two or more similar spells
Headache (present in 50%)
15-25 minute spells (95% of TIAs last <15 mins)
“Flurry” of spells around age 50
Normal cerebral angiography
Exclusion of cerebral thrombosis, embolism,
dissection, epilepsy, thrombocythemia,
Cady et al. Poster presented at: 10th IHC; June 29-July 2, 2001; New York, NY.
0% 33% 67% 100%
Worsened by Activity
n=30 (subjects may report more than one symptom)
Headache Symptoms at Screen
Allodynia is the phenomenon of normally non-
painful cutaneous stimuli being perceived as
Present in 60-75% of migraine
Usually in ipsilateral trigeminal distribution (scalp,
head, neck), but often spreads to the ipsilateral
Typically develops within an hour of headache
onset, and can persist for hours after headache
Data from the Centers for Disease Control and Prevention, US Census Bureau, and the
Disease Prevalence in the US Population
Asthma Diabetes Osteoarthritis Migraine
Vascular (Graham & Wolff, 1938-1963)
Neural (Moskowitz, 1984)
Unified, or neurovascular
5-HT or serotonin (Anthony & Lance,
Migraine is a disturbance of subcortical sensory
“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,
Triptans are successful in preventing induction of
sensitization in central, but not peripheral,
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
5-HT1B/1D, 5-HT1F, 5-HT2B, 5-HT7 subtypes
have been implicated in 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
MELAS (mitochondrial encephalomyopathy, lactic
acidosis and stroke-like episodes) also in the
differential diagnosis of FHM, presents with
episodic sudden headache and convulsions.
Menses, ovulation, pregnancy
Birth control/hormone replacement
Intense or strenuous activity/exercise
Sleep deprivation/excess, jet lag
Fasting, missing meals
Bright or flickering lights
Excessive or repetitive noises
Migraineurs are 2-2.5 times as likely to have stroke as non-
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?
Used since the 1940s; inexpensive
Available as po (w/ caffeine), pr forms
Powerful vasoconstrictors (veno>arterial)
Retro-pleural, -peritoneal, endocardial
Painful dysesthesias (St. Anthony’s fire)
Psychoactive properties: Salem witch
Sumatriptan 6 mg sq
DHE 1 mg IM
DHE nasal spray 2 mg
Sumatriptan nasal spray 20 mg
Ergotamine suppository 2 mg
Triptan tablets (various), sprays
dichloralphenazone, APAP); Sansert
(methysergide), had been taken off the
market, recently re-introduced.
AVOID butalbital (Fiorinal) and opioids.
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.
Metoclopramide (MC) 10 mg IV over 30’;
DHE test dose 0.5 mg over 2-3’
No DHE x 8°, then repeat
DHE 0.3-0.4 mg q 8° prn
w/ MC, for up to 3 days
Headache persists, no
DHE 0.5 mg
w/o MC in 1°
Headache resolved, no
DHE 0.5 mg q 8° for 2
days, with MC prn
DHE 0.75 mg q q 8° for
2-5 days, with MC
DHE 1 mg q q 8° for
2-5 days, with MC
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.
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,
New combination medication
Fixed 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
Triptans plus Prokinetics
During a migraine there is impaired gastric motility
and delayed gastric emptying.
This can lead to nausea and impaired absorption of
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
Beta-blockers: Proporanolol, atenolol,
Flunarizine (not locally available)
Divalproex, topiramate, other AEDs
NSAID’s (Naproxen, indomethacin)
Riboflavin 400 mg/d
Magnesium 400 mg/d, fish oil (??)
Keep daily headache log or diary
Avoid daily pain medications; DO take the daily meds for
Avoid undue stress reduction – read “Don’t Sweat the
Small Stuff – and It’s All Small Stuff”, by Richard
Exercise several times a week
Keep regular sleep and meal schedules
Avoid caffeine, alcohol, and tobacco
Avoid foods such as chocolate, cheese, and nuts if they
Avoid NutraSweet, MSG (Accent), nitrites (hot dogs),
sulfites (wine), food dyes (FD&C Yellow 5).
Headache occurring >15 days/month is usually due to
affective and somatoform disorders. These headaches
are refractory to most migraine and tension headache
Topiramate and Botox A injections have been shown to
be of benefit in prophylaxis and approved for this
Fibromyalgia, Myofascial Pain, Chronic Fatigue
Syndrome, etc., also have headache as major
components of their symptomatology.
Combinations of the above
displacement of pain
structures during head
Example is postconcussion
Inability to concentrate
“Drug rebound headache”, “transformed migraine”
Diffuse, bilateral headache; daily, constant,
present on awakening
Aggravated by mild mental or physical exertion
Associated with neurovegetative symptoms of
depression: asthenia, anxiety, insomnia, poor
Associated with overuse of NSAIDs, triptans,
ergots, benzos, barbiturates, opioids
Tolerance to acute migraine agents
No response to preventive migraine meds
Caffeine: Limit coffee to one cup/day
NSAIDs: 10-15 treatment days/month;
5 treatment days/month is protective.
Combinations: 10 treatment days/month
Ergots, triptans: 10 treatment days/month;
use ergots with caution.
Opioids: 8 treatment days/month
Butalbital: 5 treatment days/month
Bigal M et al. Headache 2008;48:1157
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 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
Acute treatment: Ergots, DHE, triptans, intranasal lidocaine;
may respond to high-flow (7-15 L/min) oxygen for 10-20
Prophylactic treatments: Verapamil, divalproex, lithium
carbonate, corticosteroids, indomethacin.
Chronic 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
Hemicrania Continua: Continuous cluster-like
headache, more common in women; responds to
Hypnic headache: Short (~30 minutes) attacks of
bilateral pain that awaken patient, usually same time
every night. Common in older patients.
Biofeedback: Thermal technique (warming or
cooling hands), found to reduce headache frequency
Relaxation Therapy: Four types - with tension, using
imagery, by breathing exercises, by hypnosis.
Overall 35% reduction in headache frequency.
Relaxation & thermal feedback together - 56%
Botulinum A toxin: Has been found effective in
“Thunderclap headache”: Severe,
maximal at onset
Neck and intrascapular pain,
20% have minimal or mild headache,
Headache worsened by movement
75% have meningismus
Pain 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.
Presents with thunderclap headache
First 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
Ppt. by vasoactive drugs (cocaine, amphetamines,
etc.); also common in peripartum period.
1. Decreased alertness or cognition
2. Onset of pain with exertion, coitus, coughing
3. Worsening under observation
4. Nuchal rigidity
5. Focal neurological signs
6. First headache in patient over 50
7. Worst headache ever experienced
8. Headache not fitting a defined pattern
Young, obese women predominate
Headache, papilledema, visual loss; few cases
CSF pressure >15 cm H2O
Normal cerebrospinal fluid formula
May be due to intracranial sinus thrombosis,
especially in post-partum women
Rarely, due to hypervitaminosis A
Visual outcome worse if patient anemic
ESR>55 mm/hr, age>55 years; elevated C-RP
Temporal headache, jaw claudication
Assoc w/ polymyalgia rheumatica
Anorexia, anemia, weight loss
Blindness due to optic nerve infarct from posterior
ciliary artery involvement
Biopsy: Multinucleated giant cells, internal elastic
High-dose corticosteroids to keep ESR nl
Brief, lancinating pain in trigeminal nerve
distribution (usually V2 or V3)
Trigger zones, often inside mouth
Onset in middle age, except younger in MS
Treatment: Carbamazepine, other AEDs, baclofen,
Surgery: Radiofrequency lesion of Gasserian
ganglion, Jannetta procedure
Lancinating pain on background of dull, steady
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,
26-gauge, 1/2” needle introduced medial to the
external occipital protuberance.
Needle advanced to periosteum, then withdrawn 1-2
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
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,
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Headache Classification Committee of the International Headache Society. The
International Classification of Headache Disorders, second edition. Cephalalgia