Headache is one of the top 10 reasons people in the U.S. go to the doctor. With a prevalence this high, it is no surprise that all neurology exams have multiple questions on headache. There are nuances to headache diagnoses that neurologists must understand, and that test writers love to bring up. In this chapter, you will review the most commonly tested headache types, imaging, and treatments.

Authors: Andrew Levin MD, Brian Hanrahan MD, Steven Gangloff MD

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Primary Headache Disorders

Migraine

  • Epidemiology:
    • Pediatric: Slightly more common in boys
    • After puberty: 3x more common in women (18% vs 6%)
    • No gender predilection after age 65
  • Diagnostic criteria:

A. At least 5 attacks 
B. Headaches lasting 4-72 hours
C. At least two of the following characteristics:
       1. Unilateral symptoms
       2. Pulsing/throbbing quality
       3. Moderate/severe pain intensity
       4. Worsened pain with activity.
D. At least one of the following:
       1. Nausea/vomiting
       2. photophobia/phonophobia. 

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 three of the following six characteristics:
     1. At least one aura symptom spreads gradually over ≥5 minutes
     2. Two or more aura symptoms occur in succession
     3. Each individual aura symptom lasts 5-60 minutes
     4. At least one aura symptom is unilateral
     5. At least one aura symptom is positive
     6. The aura is accompanied, or followed within 60 minutes, by headache

  • At least two auras, one of which is fully reversible motor weakness.
  • Can be sporadic or familial.
  • Familial Type 1: Caused by an autosomal dominant mutation to CACNA1a gene (P/Q calcium channel) on chromosome 19.
    • CACNA1a gene mutations can also cause episodic cerebellar ataxia.
  • Familial Type 2: Associated with ATP1A2 (Na-K ATPase channel) on chromosome 1. 
  • Familial Type 3: Mutation to SCN1a on chromosome 2.
      • SCN1a gene mutations can also cause genetic epilepsy with febrile seizures plus (GEFS+) and Dravet syndrome.
  • Formerly called “basilar” migraine
  • At least two brainstem symptoms for aura:
    1. dysarthria
    2. vertigo
    3. tinnitus
    4. hyperacusis
    5. diplopia
    6. ataxia
    7. decreased level of arousal
  • Migraine with ≥15 headache days a month, for >3 months.
  • The only FDA-approved medication for chronic migraine is botulinum injection (onabotulinumtoxinA).
  • Migraine with visual symptoms, such as flashing or shimmering lights.
  • It will sound very similar to migraine with aura, except the visual disturbance is monocular.
  • Pathophysiology:
      1. Activation of the trigeminovascular reflex, dorsolateral pons, hypothalamus, and periaqueductal grey.
      2. Release of vasoactive peptides (calcitonin gene-related peptide (CGRP), neurokinin A, substance P).
      3. Vasodilation and sterile inflammation in dural vessels, leading to activation of first-order trigeminal afferents which presents clinically by throbbing head pain.

Abortive Migraine Treatment

  • Abortive migraine therapy should be considered in patients with severe headache episodes regardless of frequency.

Triptans: 

  • First-line therapy with Level A evidence. 
  • Mechanism of action: Agonists at 5HT-1B (meningeal blood vessel constriction) and 5HT-1D (prevents nociceptive neuropeptide release).
  • Contraindicated in patients with a history of CAD, stroke, hemiplegic migraine and migraine with brainstem aura.
  • Common side effects: drowsiness, a sensation of warmth, paresthesias, dizziness, and nausea.
  • Sumatriptan
  • Zolmitriptan
  • Rizatriptan
  • Almotriptan
  • Eletriptan.
  • Naratriptan
  • Frovatriptan
    • Has the longest half-life (25h) and used often in patients for menstrual-related migraines.

Ditans (Lasmiditan):

    • Mechanism of action: 5HT-1F receptor agonism (receptors on trigeminal ganglion)
    • Lasmiditan (oral tablet) is the only drug currently on the market.
    • No contraindication for patients with coronary artery disease or stroke.

CGRP antagonists (Rimegepant, Ubrogepant):

  • Mechanism of action: Inhibition of CGRP receptors.
  • Side effects may include nausea, tiredness and dry mouth.
  • Avoid ubrogepant strong CYP3A4 inhibitors

NSAIDs: ibuprofen, ketorolac, naproxen, flurbiprofen, diclofenac

Anti-emetics: prochlorperazine, metoclopramide, promethazine

Prophylactic Migraine Treatment

  • Prophylactic migraine therapy is indicated when symptoms occur more than 4 headaches, or 8 headache days, a month.
  • Metoprolol (level A evidence)
  • Propranolol (level A evidence)
  • Timolol (level A evidence)
  • Nadolol (level B evidence)
  • Atenolol (level B evidence)

Should be avoided in patients with asthma and Raynaud’s phenomenon.

  • Topiramate (level A evidence): One of the most common first-line therapies. Side effect profile includes calcium phosphate stones, paresthesias, cognitive symptoms, fatigue, and weight loss. (Level A evidence)
    • Risk for cleft lip and low birth weight if used during pregnancy. 
  • Valproic acid (level A evidence): Adverse effects include ataxia, sedation, tremor, nausea/vomiting. Monitor liver enzymes.
    • Should be avoided during pregnancy.
  • Gabapentin (level U evidence): May be helpful for comorbid tremor, RLS, and neuropathy.
    • Side effects include dizziness and sedation.
  • Tricyclic antidepressants (TCAs):
    • Adverse effects may include anticholinergic side effects (dry mouth, constipation, weight gain, orthostatic hypotension, and sedation).
    • Amitriptyline (level B evidence)
    • Nortriptyline (metabolite of amitriptyline; less side effects)
    • Imipramine
    • Protriptyline (level U evidence; less sedation; may be activating)
  • SSRIs/SNRIs
    1. Venlafaxine (level B evidence)
    2. Duloxetine
    3. Fluoxetine (level U evidence)
  • CGRP antagonists:
    • Novel (approved 2018) class of monoclonal antibody medications for migraine prevention. 
      • The antibodies block CGRP, which is an important vasoactive peptide involved in the migraine cascade.
    • First drug developed specifically for migraine prevention.
    • Once monthly injections:
      • Fremanezumab (can also be given quarterly)
      • Erenumab (side effect of constipation)
      • Glacanezumab
    • Quarterly IV infusion
      • Eptinezumab
  • Butterbur
    • An herbal supplement from a shrub (level A evidence).
    • Side effects include upset stomach and diarrhea.
  • Magnesium (oxide, citrate, sulfate)
  • Coenzyme Q10
  • Riboflavin (Vitamin B2)
  • Supraorbital nerve stimulation
  • Percutaneous sphenopalatine ganglion stimulation
  • Transcranial magnetic stimulation

Status Migrainosus Treatment

  • If headache has persisted >72 hours, it is considered status migrainosus, and warrants aggressive treatment. 
  • Intravenous infusion of antiemetics, ketorolac, valproic acid, magnesium, and steroids can be tried. 

Dihydroergotamine (DHE): 

    • Multi-day in-hospital infusion to break status migrainosus. 
    • Contraindications: peripheral vascular disease, coronary artery disease, severe hypertension, angina, recent triptan use within 24 hours, pregnancy, severe liver disease. 
    • Obtain an EKG before administering. 
    • Some experts use a half-sized “test dose” as the first dose to monitor for potential cardiac side effects.

Migraine in women 

      • Women of child-bearing age who have migraine with aura have a two-fold increase in the relative risk of stroke.
        • Six-fold increase in risk if they also use estrogen-containing OCPs
        • Nine-fold increase risk of stroke if they use estrogen-containing OCPs and also smoke.
      • Most abortive and preventive treatments carry an increased risk of fetal harm. 
        • Butalbital, codeine, triptans, topiramate, and valproic acid should all be avoided
          due to risks to the fetus. 
      • Acetaminophen is the first-line headache medication in pregnancy.
        • Nonsteroidal anti-inflammatory drugs (NSAIDs) may be used only in the first or
          second trimester.
      • Other treatment options include metoclopramide, magnesium, and occipital nerve blocks.

Trigeminal Autonomic Cephalgias (TACs)

  • TACs is a group of disorders characterized distinguished from each other by attack frequency/duration, but share a number of features including:
    • Unilateral, side-locked location – typically V1 (peri-orbital, temporal)
    • Ipsilateral autonomic symptoms which may include:
      • conjunctival injection and/or lacrimation
      • nasal congestion and/or rhinorrhea
      • eyelid edema
      • forehead and facial sweating
      • miosis and/or ptosis

Short-lasting Unilateral Neuralgiform Headache attacks with Conjunctival Injection and Tearing (SUNCT) or autonomic symptoms (SUNA):

    • Presents as very brief (5 to 240 seconds) of stabbing pain in the orbital and temporal region with ipsilateral tearing, rhinorrhea, nasal congestion, and conjunctival injection.
    • Attacks can occur up to 100 times a day.
      • Lacrimation and tearing are due to parasympathetic activation of the trigeminal-autonomic reflex, involving the trigeminal nucleus caudalis (TNC) of CN V and the superior salivatory nucleus (SSN) of CN VII.
    • Treatment: Lamotrigine. Topiramate and gabapentin may work as well.

Paroxysmal Hemicrania:

    • Presents with severe, frequent (~15-40 daily), brief (<30 minutes), unilateral attacks (V1 distribution) with autonomic features.
    • The pain is usually localized around the eye, temple, and forehead and is often associated with autonomic symptoms including lacrimation, ptosis, rhinorrhea, and facial flushing.
    • It is more common in women.
    • Treatment: Indomethacin.
      • Response to indomethacin is so classic that it is part of the diagnostic criteria.

Hemicrania Continua:

    • Presents with a unilateral continuous headache with autonomic features.
    • Diagnostic criteria require symptoms to be present for more than three months.
    • Symptoms fluctuate but exacerbations can last minutes to days.
    • Treatment: Indomethacin

Cluster Headache:

    • Presents with recurrent, severe unilateral headaches around the eye with autonomic symptoms.
    • Episodes usually last 15-180 minutes and occur up to 8 times in a day.
    • Episodes often have circadian and/or circannual patterns.
    • Cluster headaches are seen more often in men and smokers.
    • Treatment:
      • Abortive therapy is high flow oxygen, injectable sumatriptan or nasal zolmitriptan.
      • Prophylactic therapy is usually Verapamil (calcium channel blocker). Lithium, valproic acid, melatonin and galcanezumab can also be used.

Tension Headache

  • Epidemiology
    • Most common primary headache disorder
    • Lifetime prevalence 78%
    • Annual prevalence up to 44%
  • Diagnostic criteria
    1. At least 10 episodes of headache occurring on <1 day/month on average (<12 days/year) and fulfilling criteria 2-4.
    2. Lasting from 30 minutes to 7 days
    3. At least two of the following four characteristics:
      1. bilateral location
      2. pressing or tightening (non-pulsating) quality
      3. mild or moderate intensity
      4. not aggravated by routine physical activity such as walking or climbing stairs
    4. Both of the following:
      1. no nausea or vomiting
      2. no more than one of photophobia or phonophobia
  • Treatment
    • Abortive: NSAIDs, Tylenol, caffeine
    • Preventive: amitriptyline, nortriptyline, venlafaxine, mirtazapine, biofeedback

Chronic Daily Headache

  • Non-migraine headache for ≥15 days/month for >3 months.

New Daily Persistent Headache (NDPH)

  • Presents with a daily continuous headache for >3 months.
    • Can have features of migraine or tension-type headaches
  • Patients typically remember the day of headache onset. 
  • Highly treatment-resistant.

Hypnic Headache

  • Headaches occur during sleep, typically between 2-4am; often called “alarm clock headache”
    • This occurs ≥10 days per month for >3 months and lasts between 15 minutes to 4 hours. 
  • More common in the elderly and women.
    • Mean age of onset is 60 years. 
  • Lithium, caffeine, and melatonin are classic treatments.
    • Indomethacin can also be tried.
 

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