14.1 Introduction

Headaches are one of the most common patient complaints when presenting to physicians; migraine plagues approximately 15% of adults and is listed as the second largest cause of disability worldwide as of 2016 review. ¹ Migraine manifests as recurrent episodes of moderate to severe headache and can be accompanied by photophobia, phonophobia, and nausea. Additional symptoms include symptom waxing with physical exertion, unilateral localization, and pain of a throbbing character. The debilitating nature of these disorders can result in significant loss of productivity, reduced social engagement, and poorer quality of life. Other associated neuropsychiatric conditions such as depression and anxiety can complicate the morbidity of this disease. The socioeconomic burden can be measured in the billions of dollars incurred both direct (health care utilization) and indirect costs attributable to disability. Although the overwhelming majority of headache disorders are benign in nature, alternative organic etiologies (e.g., brain tumor or cerebral aneurysm) must be excluded.

14.2 Classification of Migraine

The International Headache Society (HIS) published a revised International Classification for Headache Disorders (ICHD-3) in 2018 which allows for a formal classification schema among practitioners. ² Headache is characterized as primary or secondary and is differentiated from cranial neuropathies and other facial pain disorders. Primary headache denotes a disorder for which no identifiable structural or organic cause is known (e.g., migraine and tension headaches). Secondary headache is characterized by a known structural or systemic etiology. Furthermore, migraine can be subdivided based on the presence or absence of aura. Migraine without aura is the most prevalent subtype and may involve a higher frequency of attacks and greater disability than for those patients with aura. Migraine is further subdivided into chronic or episodic subtypes based on headache frequency. Chronic migraine represents 15 or more days of headache a month with 8 or more of those days with migraine headaches (Table 14‑1).

14.3 Etiology of Migraine

The pathophysiology of migraine disease is only partially understood despite ongoing research efforts. Current thinking suggests at least three mechanisms: extracranial arterial vasodilation, neurogenic inflammation, and decreased inhibition of central pain transmission. Cortical spreading depression, a phenomenon involving a slowly progressive wave of depolarization followed by electrical silence and hypoperfusion to the cerebral cortex, is thought to produce migraine aura and some believe that it represents an additional etiology of migraine headache. ³ Novel research using transcranial stimulation and biochemical analysis have provided convincing evidence that no single theory alone can yet explain the commencement, continuation, and resolution of migraine headaches, although several theories predominant current thinking.

The vasospasm-dilation theory describes changes in intra- and extracranial arterial diameter that promote migraine symptoms. Extracranial oligemia occurs during the headache’s prodrome and continues into the early headache phase. Paradoxically, as the pain phase begins, vasodilation occurs with resultant persistent hyperemia. Directed efforts at promoting vasoconstriction resulted in trials with various antiplasma extravasation and vasoconstriction agents such as caffeine, serotonergic 5HT_1B/1D receptor agonists (triptans), and nonselective serotonergic agonists (ergot alkaloids) and met with variable success.

A dysfunction in the complex neurophysiologic system, the trigeminal neurovascular system, may also contribute to migraines. It is postulated that there are anatomic connections between the intracranial meninges and extracranial periosteum (and pericranial muscles). ⁴ This extracranial etiology for migraine headaches was initially proposed in the early 1950s and 1960s, ^{5 ,​ 6} but has recently gained considerable support. Experiments in a mouse model showed an interconnected network of pain and sensory fibers traversing the calvarial bones through suture lines in young mice. These connections degenerated as the mice aged except at suture lines, where such connections remained intact. ⁷ Such sensory/pain fibers trifurcated, connecting the dura, the pia (by traversing the subarachnoid space), and the extracranial periosteum. Human studies have likewise found the persistence of sensory/pain fibers that traverse and connect the pericranial muscles, extracranial periosteum, cranial sutures, and the intracranial dura. ^{7 ,​ 8 ,​ 9} The presence and identification of this sensory/pain fiber network allows the theoretical construct where external pericranial irritation can lead to migraine headaches.

The presence of inflammation may modulate migraine severity; in patients with chronic migraine with bilateral occipital imploding headaches and associated chronic muscle tenderness, there was upregulation of inflammatory genes in human calvarial periosteum. ¹⁰ Some postulated that migraine headaches can originate in extracranial tissues that are hypersensitive to painful stimuli due to an inflammatory process. Further support for the theory of an extracranial source for migraines is shown through successful migraine reduction following nerve decompression surgeries, ^{11 ,​ 12 ,​ 13} occipital nerve stimulation, ^{14 ,​ 15} and nerve blocks. ^{16 ,​ 17} The theorized extracranial source for migraine headache has profound implications for the treatment and prophylaxis of this disorder.

14.4 Treatment Targets

A multitude of treatments have evolved, as many of the classic therapeutics have failed to effectively eliminate this disorder. Therapeutics aim to be abortive (halting progression and enacting resolution) or prophylactic (decrease attack frequency), but compliance remains low mostly due to perceived inadequate efficacy and/or adverse systemic effects. Of all the currently available treatments, only botulinum neurotoxin type A (BoNT-A) and topiramate have demonstrated efficacy in treating chronic migraine and received regulatory approval and BoNT is the only prophylactic treatment that is globally approved for chronic migraine. ¹⁸ Recently, calcitonin gene-related peptide (CGRP) receptor antagonists and monoclonal antibodies against the CGRP receptor sites have shown to be effective as a prophylactic treatment in chronic migraine. The duration of action is, however, reportedly to be limited to a 1-month period. ¹⁹

Seminal reports on BoNT-A found that it was effective as a prophylactic medication but only for some patients. ^{20 ,​ 21 ,​ 22 ,​ 23 ,​ 24 ,​ 25} In 2006, Jakubowski et al identified that the distinguishing factor for BoNT-A responders (>80% decrease in migraine days) was those with imploding or ocular headaches and boasted a 94 and 100% response rate, respectively. This was in contrast to those with exploding headaches who experienced only a 19% response rate. ²⁶ Such a stratification could be explained if imploding and ocular headache development involved extracranial innervation which is suppressed by BoNT-A chemodenervation.

Although the exact mechanism of action of BoNT is much debated, one proposal includes inhibition of peripheral sensory neurons. BoNT inhibits the release of inflammatory mediators, specifically substance P, ²⁷ CGRP, ²⁸ and glutamate ²⁹ by affecting their SNARE docking proteins. It is important to understand that although BoNT plays an important role in pain processing, it does not mediate acute pain. This is because A-delta or A-beta fibers are not mediated by neuropeptide release and therefore they are unaffected. Hence, BoNT can modulate pain processing without affecting the sensation of acute pain or resulting in local anesthesia upon injection.

Due to mounting evidence, BoNT-A injection has gained popularity as an alternative therapy for the treatment of migraine headache and was approved by the Food and Drug Administration (FDA) in 2010 as a prophylactic medication of chronic migraine. A 2018 Cochrane review reported that BoNT-A may reduce the number of migraine days for chronic migraine patients by 2 days per month. The same review called for further research with utility for episodic migraine as current results are inconclusive. ³⁰