A 43-Year-Old Man With New Headaches

Correct Answer: D

Most of you will have recognized that this patient is manifesting the onset of migraines, one of the most common diagnoses in the field of neurology. A diagnosis this common will have broad overlaps in epidemiology but includes migraine’s high frequency of 15%, predominance in women, and onset typically in young and middle-aged adults (peak incidence, age 30-40 years).¹ The authority in classification of headache is currently the 3rd edition of the International Classification of Headache Disorders (ICHD-3), which contains the clinical criteria for a diagnosis of migraine.² A review of that reference demonstrated that it is a clinical diagnosis, without specific laboratory or imaging parameters required. Whenever making this clinical diagnosis, all findings must be “not better accounted for by another ICDH-3 diagnosis,”² such that I suspect essentially all migraine patients will have received, for example, a computed tomography (CT) scan of the brain can be used to exclude other diagnoses.

Nonetheless, the classification scheme divides migraine into 3 types. “Migraine without aura” comprises attacks of headache that is some combination of unilateral, pulsating, moderate to severe, and worsened by physical activity and is associated with nausea, emesis, and/or photophobia and phonophobia.

The second form of migraine is the classical “migraine with aura” during which the headache is accompanied by (and often preceded by) a fully reversible neurologic aura that can be visual, sensory, auditory, motor, or retinal in nature. These auras last 5 to 60 minutes with the headache itself following within 1 hour. The presented patient experienced typical visual and retinal auras with appropriate timing characteristics followed by migraine’s pulsating and throbbing (“vascular”) headache. Because of these typical symptoms, migraine is the most likely diagnosis, even this early in the discussion. Answer D is the best choice. There is not yet enough time and natural history evolved to call this chronic migraine, the third type categorized by ICHD-3, since that variant requires an extensive number of headache days per month for greater than 3 months to be confirmed.

Although essentially all initially evaluated patients will likely have retinal examination and a brain CT scan with contrast in their diagnostic journey, several syndromes have differentiating characteristics and can be excluded as most likely causes. Thus, retinal detachment (Answer C) would have more profound and nonreversible vision disturbance in one eye.

Cluster headaches (Answer A) might fit male patients but come in bursts or clusters and are accompanied by other symptoms such as nasal discharge, red and tearing eyes, absence of aura, ocular in focus of symptoms and location, and interrupted with pain in clusters. Another differentiating characteristic is cluster headache’s awakening patients from sleep. These stigmata were not present in the presented patient. Finally, thunderclap headache (Answer E) refers to sudden onset of headache pain reaching maximum intensity in minutes, which has its own differential including ruptured aneurysm and subarachnoid hemorrhage.³ Again the presented patient’s symptom complex fits best with migraine.

A recent What’s The Take Home? discussed tic douloureux and included a detailed discussion of causation, which has now been shown to involve anatomic pathology of encroachment of the trigeminal cranial nerve V by abnormal vascular anatomy at its exit from the brainstem.⁴ Unfortunately, the pathogenesis of migraine has not been as thoroughly studied. There is also significant involvement of the trigeminal nerve in migraine, even to the point of involving a variety of effector small molecules in the pathogenesis. The complexity is far above this article’s scope and remains an active area of research and therapeutic potential. Some of the newer therapeutics related to the molecules will be addressed below, but a further detailed discussion can be found in a recent complex review.²

This brings us to the current therapeutic regimens and their order of battle for use in migraine cases.

Migraine therapeutics involve a mixture of something old and something new. The therapies available are categorized as follows: (1) classic older simple analgesics or NSAIDs that address pain nonspecifically and newer agents that work at points in the abnormal pathophysiology and/or biochemical pathways mediating the migraine syndromes and (2) first-line treatments addressing today’s acute headache as well as providing prophylactic/preventive treatment to decrease frequency of attacks.^1,3

When a headache is present or preceded by aura, therapies will be more effective if started early. First-line therapy includes NSAIDs, which are inexpensive and have substantial data to support efficacy (eg, aspirin, ibuprofen).^2,3 When NSAIDs are not adequate, triptans should be prescribed next. They exist in a wide variety of preparations, which can be prescribed somewhat akin to hypertension therapeutics in which when one agent doesn’t work, try another. Finally, small molecule calcitonin gene-related peptide receptor (CGRP) antagonists (also known as gepants) and 5-hydroxytryptamine (5-HT) receptor agonists (also known as ditans) have recently been approved for use in patients with refractory migraine.⁵ As the stepwise progression through these therapeutics proceeds, both economic costs and toxicity and adverse effect costs increase. Once basic NSAID strategies are ineffective, the more complex pharmacology is best handled by a neurologist or other headache specialist. It needs to be noted that there is general agreement that medications at risk for addiction and dependency, such as opioids, should not be used for treating migraine, as toxicity and addiction risk can be high. This is addressed in Answer B, which is incorrect on 2 counts—the use of opioids at all, and their use early on.

Prevention is the goal of therapies that decrease the frequency, duration, and/or severity of migraines. Older medications used in trials of migraine count and severity with 3 months of treatment include anticonvulsants, antihypertensives (eg, β-blockers), and antidepressants.³ Newer agents include onabotulinumtoxinA, perhaps by effecting the smooth muscle in blood vessels innervated by the trigeminal nerve,⁶ and injectable monoclonal antibodies against the CGPP mediator molecule or its receptor. Sufficient literature has been published on the efficacy, safety, and duration of these agents.^7-9

Patient Follow-Up. The clinical diagnosis of migraine was made. As a precaution regarding the unlikely presence of another diagnosis, a CT scan with contrast of the brain was performed and did not show hemorrhage or masses. Professional fundoscopy was performed and similarly did not show bleeding, retinal detachment, or any other intraocular pathology. The patient’s initial therapeutic regimen has included ibuprofen and acetaminophen when these symptoms appear, with particular attention to recognizing the aura and initiating therapy quickly even before onset of the actual headache. He has had 2 episodes in the last month, very adequately controlled by ibuprofen. The working diagnosis currently is thus episodic migraine with aura.

What’s The Take Home?

Migraine is an extremely common disorder that is undergoing new study regarding pathophysiology, biochemistry, and methods of therapeutic intervention. There is now general agreement that the trigeminovascular system is the seat of migraine disorders with abnormalities in the trigeminal innervation of the meninges and its vessels. Further, vascular smooth muscle physiology data has shown that migraine can be mediated by abnormalities in these sites, such as CGRP and/or its receptors.

The diagnosis of migraine remains strictly clinical and is characterized by typical vascular throbbing headaches associated with nausea/emesis, worsened by loud sound or strong light, and the presence of aura. These are neurologic, optic, or visual symptoms fully reversible within an hour and followed by the typical headache. Although no specific diagnostic blood or imaging studies exist for migraine (thus, a clinical diagnosis), other headache causes such as mass lesions or vascular catastrophes are typically excluded by CT imaging.

Therapeutics have improved in conjunction with improving knowledge of pathogenesis. Treatment is graded and stepwise. For the acute headache, the progression of treatment includes NSAIDs to tripans to small-molecule CGRP antagonists or 5-HT receptor agonists. For prophylaxis/prevention, the progression begins with antihypertensive, antiseizure, and antidepressant medications to the newer monoclonal antibodies against CGRP and its receptor and the use of localized onabotulinumtoxinA injections. Once entry-level therapeutics for management of the acute headache or prevention/prophylaxis is not adequate, the complexity of the newer modalities is best handled by specialists in headache management.

References:

1. Ashina M. Migraine. N Eng J Med. 2020;383:1866-1876. doi:10.1056/NEJMra1915327
2. Headache Classification Committee of the International Headache Society (IHS). The International Classification of Headache Disorders, 3rd edition. Cephalgia. 2018;38:1-211. doi:10.1177/0333102417738202
3. Robbins MS. Diagnosis and management of Headache. JAMA. 2021;325(18):1874-1885. doi:10.1001/jama.2021.1640
4. Rubin RN. A 52-year-old woman with episodes of severe jaw and cheek pain. Consultant. 2021;61(4):e16-e18. doi:10.25270/con.2021.03.00021
5. Dodick DW, Lipton RB, Ailani J, et al. Ubrogepant for the treatment of migraine. N Eng J Med. 2019;381:2230-2241. doi:10.1056/NEJMoa1813049
6. Herd CP, Tomlinson CL, Rick C et al. Botulinum Toxin for the Prevention of Migraine in Adults. Cochrane Database Syst Rev. 2018;6(6):CD011616. doi:10.1002/14651858.CD011616.pub2
7. Dodick DW, Silberstein SD, Bigal ME, et al. Effect of fremanezumab compared with placebo for prevention of episodic migraine: a randomized clinical trial. JAMA. 2018;319:1999-2008. doi:10.1001/jama.2018.4853
8. Silberstein SD, Dodick DW, Bigal ME, et al. Fremanezumab for the preventative treatment of chronic migraine. N Eng J Med. 2017;377:2113-22. doi:10.1056/NEJMoa1709038
9. Goadsby PJ, Reuter U, Hallstrom Y, et al. A controlled trial of erenumab for episodic migraine. N Eng J Med. 2017; 377:2123-32. doi:10.1056/NEJMoa1705848