Chapter 441_ Migraine and Other Primary Headache Disorders

The primary headache disorders discussed include:

1. Premonitory (prodrome): Symptoms that occur before the headache phase, which may include mood changes, food cravings, and fatigue.

2. Headache phase: The actual migraine headache, often accompanied by sensitivity to light, sound, or movement, and nausea.

3. Postdrome: Symptoms that occur after the headache phase, which may include fatigue, difficulty concentrating, and mood changes.

Approximately 15% of women and 6% of men are affected by migraine over a 1-year period.

Common symptoms associated with a migraine attack include:

• Sensitivity to light
• Sensitivity to sound
• Sensitivity to movement
• Nausea
• Vomiting

Migraine is described as a recurring syndrome of headache associated with other symptoms of neurologic dysfunction in varying admixtures.

The symptoms associated with the premonitory (prodromal) phase of a migraine attack include:

• Neck discomfort
• Cognitive impairment (brain 'fog')
• Mood change
• Fatigue
• Yawning/sleepiness
• Polyuria/polydipsia
• Food cravings

Triggers that can initiate or amplify a migraine headache include:

• Altered sleep patterns
• Hunger
• Let-down from stress
• Physical exertion
• Stormy weather or barometric pressure changes
• Hormonal fluctuations during menses
• Alcohol or other chemical stimulation, such as nitrates

Migraine patients exhibit heightened sensitivity to environmental and sensory stimuli, which is particularly amplified in women during the menstrual cycle. This sensitivity can lead to difficulty in habituating to sensory stimuli and may contribute to the initiation of headache attacks.

The trigeminovascular system plays a key role in migraine pathogenesis by modulating sensory input. The trigeminovascular input from the meningeal vessels passes through the trigeminal ganglion and synapses on second-order neurons in the trigeminocervical complex (TCC), which are crucial for pain processing in migraines.

The trigeminovascular system is involved in the modulation of nociceptive input related to migraine. Activation of cells in the trigeminal nucleus leads to the release of vasoactive neuropeptides such as CGRP and PACAP, which play a significant role in migraine attacks. The system also involves projections to various brain regions, including the thalamus and hypothalamus, which contribute to pain processing and modulation.

CGRP receptor antagonists, known as gepants, are effective in both acute and preventive treatment of migraine. Additionally, four monoclonal antibodies targeting CGRP or its receptor have shown efficacy in preventing migraines, while one PACAP monoclonal antibody has demonstrated effectiveness in a phase 2 study.

5-hydroxytryptamine (5-HT), or serotonin, is implicated in migraine pathophysiology. Triptans, which are designed to selectively stimulate certain 5-HT receptors (primarily 5-HT1B and 5-HT1D), are used to treat migraines by arresting nerve signaling in nociceptive pathways and promoting cranial vasoconstriction. Ditan drugs also target neural pathways but act differently than triptans.

Familial hemiplegic migraine (FHM) is associated with mutations in ion channel genes that affect membrane excitability. Notably, mutations in the CACNA1A gene, which encodes a P/Q-type voltage-gated calcium channel, are responsible for about 50% of FHM cases. Additionally, mutations in the ATP1A2 gene are also linked to FHM.

Dopamine is involved in the pathophysiology of migraine, as many premonitory symptoms can be induced by dopaminergic stimulation. Migraineurs exhibit dopamine receptor hypersensitivity, leading to symptoms such as yawning, nausea, and vomiting. Dopamine receptor antagonists are effective in treating migraines, particularly when administered parenterally or alongside other antimigraine agents.

Mutations in the neuronal voltage-gated sodium channel SCN1A are responsible for about 20% of familial hemiplegic migraines (FHM) and specifically cause FHM type 3.

Functional neuroimaging suggests that the brainstem regions and the posterior hypothalamic gray matter region, particularly near the suprachiasmatic nucleus, are involved in migraine and cluster headache, respectively.

In the premonitory phase of migraine attacks, activation is seen in the hypothalamic, dorsal midbrain, and dorsolateral pontine areas. During migraine attacks, dorsolateral pontine activation persists, indicating its fundamental role in migraine expression.

The lateralization of changes in the dorsolateral pontine area correlates with the lateralization of head pain in hemicranial migraine, meaning that activation on one side of the brainstem corresponds to pain on the same side of the head.

Positron emission tomography (PET) and high-resolution T1-weighted magnetic resonance imaging (MRI) using voxel-based morphometry were used to study brain activation in migraine and cluster headache.

The classic diagnostic criteria for migraine headache include:

• Migraine Aura: Visual disturbances (flashing lights, zigzag lines) or other neurologic symptoms, reported in 20-25% of patients.
• Premonitory Phase: Symptoms such as yawning, sleepiness, fatigue, cognitive dysfunction, mood change, neck discomfort, polyuria, and food cravings lasting from hours to days.
• Headache Phase: Associated features like nausea, photophobia, phonophobia, allodynia, or vertigo.
• Postdrome: Feelings of tiredness, concentration problems, and mild neck discomfort lasting for hours to a day.
• Chronic Migraine: Defined as having episodes of migraine on 8 or more days per month and at least 15 total days of headache per month.

A headache diary is significant in diagnosing migraine as it helps in:

• Tracking Symptoms: Documenting the frequency and characteristics of headaches.
• Assessing Disability: Evaluating how headaches impact daily activities.
• Identifying Patterns: Recognizing triggers and patterns in headache occurrences, aiding in the differentiation between migraine and other headache types.

Typical symptoms experienced during the premonitory phase of a migraine attack include:

• Yawning
• Sleepiness
• Fatigue
• Cognitive Dysfunction
• Mood Change
• Neck Discomfort
• Polyuria
• Food Cravings These symptoms can last from a few hours to days before the headache phase begins.

The criteria include:

Repeated attacks of headache lasting 4-72 hours in patients with a normal physical examination and no other reasonable cause for the headache, plus:

Acephalgic migraine, also known as typical aura without headache, involves recurrent neurologic symptoms, often accompanied by nausea or vomiting, but with little or no headache. It is noted that:

• Vertigo can be prominent in these patients.
• Approximately one-third of patients referred for vertigo or dizziness may have a primary diagnosis of migraine, often termed vestibular migraine.

The Migraine Disability Assessment Score (MIDAS) is a well-validated, easy-to-use tool designed to assess the extent of a patient's disease and disability related to migraine. It helps in evaluating the impact of migraines on a patient's daily life and functioning.

The MIDAS score is categorized into four grades based on the level of disability:

1. Grade I—Minimal or Infrequent Disability: 0-5
2. Grade II—Mild or Infrequent Disability: 6-10
3. Grade III—Moderate Disability: 11-20
4. Grade IV—Severe Disability: > 20

Nonpharmacologic management strategies for migraine include:

• Identifying and avoiding triggers
• Maintaining a regulated lifestyle with a healthy diet and regular exercise
• Establishing regular sleep patterns
• Avoiding excess caffeine and alcohol
• Managing stress through techniques like yoga, meditation, and biofeedback

The main pharmacologic classes used in acute attack therapies for migraine include:

1. Nonsteroidal anti-inflammatory drugs (NSAIDs)
2. 5-HT1B/1D receptor agonists (triptans)
3. CGRP receptor antagonists (gepants)
4. 5-HT1F receptor agonists (ditans)
5. Dopamine receptor antagonists

Understanding migraine as an inherited tendency helps patients recognize that while migraines can be managed and controlled through lifestyle adjustments and medications, they cannot be completely eradicated. This knowledge can reduce anxiety and improve management strategies.

Prior to nasal spray, the pump must be primed 4 times; 1 spray (0.5 mg) is administered, followed in 15 min by a second spray.

Savi Dual: Two pulses at onset followed by two further pulses.

The first tier treatment options include:

1. Sumatriptan 50 mg or 100 mg PO
2. Almotriptan 12.5 mg PO
3. Rizatriptan 10 mg PO
4. Eletriptan 40 mg PO
5. Zolmitriptan 2.5 mg PO
6. Rimegepant 75 mg
7. Ubrogepant 50 or 100 mg
8. Lasmiditan 50, 100, or 200 mg

For slower effect but better tolerability:

• Naratriptan 2.5 mg PO
• Frovatriptan 2.5 mg PO

For infrequent headache:

• Ergotamine/caffeine 1-2/100 mg PO

Migraine therapy must be individualized. A standard approach for all patients is not possible. The therapeutic regimen may need to be refined until one is identified that provides the patient with:

• Rapid relief
• Complete relief
• Consistent relief
• Minimal side effects

Repeat dosing of the same medicine at 2 hours is:

• Ineffective for triptans
• Effective for gepants

Adjunct medications that are sometimes useful include:

• Antiemetics (e.g., domperidone 10 mg or ondansetron 4 or 8 mg)
• Prokinetics (e.g., metoclopramide 10 mg)

If additional medication is required within 60 minutes because symptoms return or have not abated, the initial dose should be:

• Increased for subsequent attacks
• A different class of drug should be tried as first-line treatment

Dihydroergotamine nasal spray 2 mg, Zolmitriptan 5 mg nasal spray, Sumatriptan 20 mg nasal spray, Rizatriptan 10 mg MLT wafer, Zavegepant 10 mg nasal spray.

Ergotamine 2 mg is the most effective for headache recurrence, usually taken with caffeine.

Naratriptan 2.5 mg, Almotriptan 12.5 mg, Rimegepant 75 mg, Ubrogepant 50 or 100 mg, Single-pulse transcranial magnetic stimulation, Noninvasive vagus nerve stimulation, Remote electrical neuromodulation.

Zolmitriptan 5 mg nasal spray and Zavegepant 10 mg nasal spray are recommended for early vomiting.

Prevention: Ergotamine PO at night, Estrogen patches, Rimegepant 75 mg PO taken during menses. Treatment: Triptans, Dihydroergotamine nasal spray.

Zolmitriptan 5 mg nasal spray, Zavegepant 10 mg nasal spray, Sumatriptan 6 mg SC, Dihydroergotamine 1 mg IM.

NSAIDs are most effective when taken early in the migraine attack.

The combination of acetaminophen (paracetamol), aspirin, and caffeine has been approved for the treatment of mild to moderate migraine.

Triptans are selective 5-HT1B/1D receptor agonists, while ergotamine and dihydroergotamine are nonselective receptor agonists.

Rizatriptan and eletriptan are considered the most efficacious triptans based on population studies.

Triptans are generally not effective in migraine with aura unless given after the aura is completed and the headache has started.

The average oral dose of ergotamine for a migraine attack is 2 mg.

The reported pain relief rate for nasal formulations is only ~50-60%.

Peak plasma levels of dihydroergotamine are achieved 3 minutes after intravenous dosing.

Sumatriptan, at doses of 3, 4, or 6 mg subcutaneously, is effective in ~50-80% of patients.

Gepants are small-molecule CGRP receptor antagonists effective in the acute treatment of migraine. They are more likely to render patients pain-free at 2 hours and symptom-free compared to placebo, with minimal side effects such as mild nausea.

5-HT1F receptor agonists like lasmiditan have no vascular effects, making them suitable for patients with cardiovascular and cerebrovascular disease. They are effective in acute migraine treatment and have side effects like dizziness and somnolence.

Dopamine receptor antagonists can enhance gastric absorption of oral medications during a migraine, decrease nausea/vomiting, and restore normal gastric motility. They can be used as adjunctive therapy when other treatments fail.

Opioids are modestly effective for acute migraine treatment but are suboptimal for recurrent headaches. Their use should be limited to severe, infrequent headaches unresponsive to other treatments due to risks of habituation, addiction, and potential worsening of migraine symptoms.

Single-pulse transcranial magnetic stimulation (sTMS) is FDA cleared for the acute treatment of migraine.

The FDA cleared options for acute migraine attacks include:

• Single-pulse transcranial magnetic stimulation (sTMS)
• Noninvasive vagus nerve stimulator (nVNS)
• Remote electrical neuromodulation using a smartphone app
• Transcutaneous supraorbital nerve stimulation
• External concurrent occipital and trigeminal neurostimulation (eCOT-NS)

Medication-overuse headache is a condition that can occur due to the frequent use of acute attack medications, particularly those containing opioids or barbiturates. It is characterized by an increase in headache frequency and is likely a reaction of the patient's underlying migraine biology to the medication rather than a separate headache entity.

Preventive treatments for migraine should be considered in patients with:

1. Increasing frequency of migraine attacks
2. Attacks that are unresponsive or poorly responsive to abortive treatments
3. Four or more migraine days a month

Most preventive migraine treatments must be taken daily, and there is usually a lag of 2-12 weeks before an effect is seen.

FDA-approved drugs for the preventive treatment of migraine include:

• Propranolol
• Timolol
• Sodium valproate
• Topiramate
• Eptinezumab
• Erenumab
• Fremanezumab
• Galcanezumab
• Rimegepant
• Atogepant

Phenelzine is a monoamine oxidase inhibitor (MAOI) used for migraine treatment, but it is reserved for very recalcitrant cases due to contraindications with tyramine-containing foods, decongestants, and meperidine.

The recommended dosage range for Nortriptyline is 25-75 mg at night, with some patients only needing a total dose of 10 mg. Generally, 1-1.5 mg/kg body weight is required.

Eptinezumab is administered at a dose of 100 or 300 mg IV every 12 weeks.

Galcanezumab is given as a 240 mg loading dose, followed by 120 mg monthly.

Common side effects of Candesartan include dizziness.

The typical dosage for Memantine is 5-20 mg daily, with common side effects including dizziness and tiredness.

Neuromodulation approaches, such as single-pulse transcranial magnetic stimulation (sTMS) and noninvasive vagus nerve stimulation (nVNS), are used when traditional medications fail or produce unacceptable side effects.

The probability of success with any one of the antimigraine drugs is approximately 40-50%.

Tension-type headache is characterized by bilateral tight, bandlike discomfort that builds slowly, fluctuates in severity, and may persist continuously for many days.

TTH is characterized by headaches that are completely without accompanying features such as:

• Nausea
• Vomiting
• Photophobia
• Phonophobia
• Osmophobia
• Throbbing
• Aggravation with movement

In contrast, migraine typically presents with one or more of these features.

The pathophysiology of TTH is thought to be primarily due to a disorder of central nervous system pain modulation. Unlike migraine, which involves a more generalized disturbance of sensory modulation, TTH appears to be more localized in its mechanism.

The treatment options for chronic TTH include:

1. Amitriptyline - the only proven treatment for chronic TTH.
2. Simple analgesics - such as acetaminophen, aspirin, or NSAIDs for pain management.
3. Behavioral approaches - including relaxation techniques.

Note: Triptans are not effective in pure TTH, and there is no evidence supporting the efficacy of acupuncture or onabotulinum toxin type A for chronic TTH.

TACs are characterized by:

• Short-lasting attacks of head pain
• Lateralized cranial autonomic symptoms, such as:
  • Lacrimation
  • Conjunctival injection
  • Aural fullness
  • Nasal congestion
• Pain is usually severe and may occur more than once a day.

Patients may be misdiagnosed with 'sinus headache' due to associated nasal symptoms.

TACs are characterized by prominent cranial autonomic syndromes, such as conjunctival injection and tearing, which are not present in conditions like trigeminal neuralgia, primary stabbing headache, and hypnic headache. The cycling pattern, length, frequency, and timing of attacks are also crucial for classification.

Cluster headache attacks typically occur daily, with one to two attacks of unilateral pain lasting for a short duration, recurring at about the same hour each day during a cluster bout. Patients usually experience these bouts for 8-10 weeks a year, followed by a pain-free interval averaging less than 1 year.

Common symptoms of cluster headache include:

• Ipsilateral symptoms: conjunctival injection, lacrimation, aural fullness, rhinorrhea, or nasal congestion.
• Cranial sympathetic dysfunction: such as ptosis.
• Unilateral photophobia and phonophobia: typically on the same side as the pain, unlike in migraine.

The recommended acute treatments for cluster headache attacks include:

1. Oxygen inhalation: 100% oxygen at 10-12 L/min for 15-20 minutes.
2. Sumatriptan: 6 mg SC, effective in shortening attacks to 10-15 minutes.
3. Nasal sprays: Sumatriptan (20 mg) and zolmitriptan (5 mg) are effective options.
4. nVNS: FDA cleared for acute treatment using stimulation cycles at headache onset.

Preventive treatments for cluster headache include:

• Oral glucocorticoids: A 10-day course of prednisone starting at 60 mg daily can interrupt pain bouts.
• Greater occipital nerve injection: With lidocaine and corticosteroids, effective for up to 6-8 weeks.
• CGRP monoclonal antibody: Galcanezumab, approved for episodic cluster headache, reduces attack frequency and is well tolerated.

Verapamil is favored as the first-line preventive treatment for chronic cluster headache or prolonged bouts.

The short-term prevention options for episodic cluster headache include:

1. Prednisone 1 mg/kg up to 60 mg qd, tapering over 21 days
2. Greater occipital nerve injection (local anesthetic and corticosteroids)
3. Galcanezumab 300 mg SC
4. nVNS 6-24 stimulations/d

The long-term prevention options include:

1. Verapamil 160-960 mg/d
2. Melatonin 9-12 mg/d
3. Topiramate 100-400 mg/d
4. Lithium 400-800 mg/d
5. nVNS 6-24 stimulations/d

The treatment of choice for paroxysmal hemicrania (PH) is Indomethacin (25-75 mg tid), which can completely suppress attacks of PH.

The essential features of paroxysmal hemicrania (PH) include:

• Unilateral very severe pain
• Short-lasting attacks (2-45 min)
• Very frequent attacks (usually >5 a day)
• Marked autonomic features ipsilateral to the pain
• Rapid course (<72 h)
• Excellent response to indomethacin

Potential side effects of verapamil include:

• Constipation
• Leg swelling
• Gingival hyperplasia
• Cardiovascular concerns, such as heart block and ECG abnormalities

Neuromodulation therapy is used when medical therapies fail in chronic cluster headache. Options include:

• Sphenopalatine ganglion (SPG) stimulation
• nVNS (noninvasive vagus nerve stimulation)
• Occipital nerve stimulation
• Deep-brain stimulation of the posterior hypothalamic gray matter

SUNCT is characterized by severe, unilateral orbital or temporal pain that is stabbing or throbbing in quality. Diagnosis requires:

1. At least 20 attacks lasting 5-240 seconds.
2. Ipsilateral conjunctival injection and lacrimation (though these may be absent in SUNA).
3. Pain patterns can include single stabs, groups of stabs, or longer attacks with a 'saw-tooth' phenomenon.
4. Lack of a refractory period to triggering and no response to indomethacin.
5. Normal neurologic examination apart from trigeminal sensory disturbance.

The treatment for SUNCT/SUNA includes:

Abortive Therapy:

• IV lidocaine can be used in hospitalized patients to arrest symptoms.

Preventive Therapy:

• Lamotrigine: 200-400 mg/d is the most effective for long-term prevention.
• Topiramate and Gabapentin may also be effective.
• Carbamazepine: 400-500 mg/d may offer modest benefit.
• Surgical options like microvascular decompression are seldom useful and may lead to complications.
• Greater occipital nerve injection and nVNS may provide limited benefit, while occipital nerve stimulation may help in some cases.

The essential features of hemicrania continua include:

• Moderate and continuous unilateral pain with fluctuations of severe pain.
• Complete resolution of pain with indomethacin.
• Exacerbations may be associated with cranial autonomic features such as conjunctival injection, lacrimation, and photophobia on the affected side.
• Age of onset ranges from 10 to 70 years, with women affected twice as often as men.

Primary Cough Headache is a generalized headache that begins suddenly, lasts for seconds to several minutes, and is triggered by coughing or similar actions. It can be treated with indomethacin (25-50 mg two to three times daily). In some cases, lumbar puncture may provide complete cessation of attacks for about one-third of patients.

Primary Exercise Headache resembles both cough headache and migraine, often triggered by any form of exercise. It is bilateral, has a throbbing quality, and lasts less than 48 hours. Migrainous features may develop in susceptible individuals, and it can be prevented by avoiding excessive exertion, especially in hot weather or at high altitudes.

There are three types of sex headaches: 1. A dull bilateral ache that intensifies with sexual excitement. 2. A sudden, severe headache occurring at orgasm. 3. A postural headache developing after coitus, which is a form of low CSF pressure headache. Notably, headaches at orgasm can be serious, as they may indicate subarachnoid hemorrhage in 5-12% of cases.

Treatment for Primary Exercise Headache includes: 1. Gradually increasing exercise intensity. 2. Indomethacin (25-150 mg daily) is generally effective. 3. Other options include gepants (rimegepant 75 mg orally or ubrogepant 100 mg orally), ergotamine (1 mg orally), and dihydroergotamine (2 mg by nasal spray) for short-term prevention.

Benign sex headaches may subside within a period of 5 minutes to 2 hours after ceasing sexual activity.

Treatment options for recurrent primary sex headaches include:

1. Propranolol: 40-200 mg/d for prevention.
2. Diltiazem: 60 mg tid as an alternative.
3. Indomethacin: 25-50 mg.
4. Gepants: Rimegepant (75 mg orally) or ubrogepant (100 mg orally).
5. Frovatriptan: 2.5 mg taken 30-45 min prior to sexual activity.

The differential diagnosis for thunderclap headache includes:

• Sentinel bleed of an intracranial aneurysm
• Reversible cerebral vasoconstriction syndrome (RCVS)
• Cervicocephalic arterial dissection
• Cerebral venous thrombosis
• Ingestion of sympathomimetic drugs or tyramine-containing foods in patients on MAOIs
• Pheochromocytoma

For cold-stimulus headache, Naproxen 500 mg taken 30 minutes prior to exposure can be helpful.

The essential features of primary stabbing headache include:

• Stabbing pain confined to the head or face
• Lasting from 1 to many seconds
• Occurring as a single stab or a series of stabs
• Absence of associated cranial autonomic features
• Absence of cutaneous triggering of attacks
• Irregular intervals of recurrence (hours to days)

The response of primary stabbing headache to indomethacin (25-50 mg two to three times daily) is usually excellent. Symptoms may wax and wane, and after a period of control, treatment can be withdrawn to observe the outcome.

Nummular headache is characterized by:

• Round or elliptical discomfort, fixed in place
• Size ranges from 1-6 cm
• May be continuous or intermittent
• Accompanied by local sensory disturbances like allodynia or hypesthesia
• Can be episodic but often continuous during exacerbations
• Local dermatologic or bony lesions need to be excluded by examination and investigation.

Hypnic headache typically begins a few hours after sleep onset, lasting from 15-30 minutes. It is usually moderately severe and generalized, although it may be unilateral and can be throbbing.

Patients with hypnic headache generally respond to:

1. Bedtime dose of lithium carbonate (200-600 mg)
2. One to two cups of coffee or caffeine 60 mg orally at bedtime (effective in about one-third of patients)
3. Verapamil (160 mg), flunarizine (5 mg nightly), or indomethacin (25-75 mg nightly) may also be effective.

Primary new daily persistent headache (NDPH) can present as:

• Migrainous type with unilateral headache and throbbing pain (most common)
• Featureless type appearing as new-onset tension-type headache (TTH)
• Nausea, photophobia, and/or phonophobia occur in about half of patients.
• More common in adolescents, and some patients may have a previous history of migraine.

The treatment of migrainous-type primary NDPH consists of using preventive therapies that are effective in migraine. Featureless NDPH is often refractory to treatment, and standard preventive therapies may be offered but are often ineffective.