Two decades ago, I was leaving my morning clinic at the hospital where I work when I suddenly felt an excruciating pain in my head. It was as if my skull were exploding while simultaneously being gripped in a vise that was getting tighter and tighter. I became nauseated and dizzy, and made my way unsteadily to the emergency room. I was in my early fifties, and my first thought was that this could be a burst aneurysm, known to some physicians as “the worst headache of your life.” To my relief, a CAT scan showed no sign of bleeding in the brain; then came the bad news. A neurologist arrived, examined me, and said he thought that I was suffering from a migraine. I had never had one before, but his diagnosis turned out to be correct, and, since that time, migraines have been an indelible feature of my life. Their frequency and severity have varied over the years, but once you become a migraineur, as doctors sometimes call us, you are always wondering when your next attack will be, planning how you might strategize around it, scrutinizing your life for possible triggers, and looking for some new treatment that might curb the agony.
As Tom Zeller, Jr., writes in “The Headache” (Mariner), the unpredictability of chronic headache conditions is particularly unnerving for those who suffer from them: “You may be delivering a speech before a large crowd, cooking dinner for a friend, or simply lazing alone on a hammock staring at the sky. You may even be sound asleep when it happens. At any moment it can appear, creeping in like a shadow in some cases, ambushing like a predator in others.”
Zeller, a science journalist, does not get migraines. He suffers from something generally acknowledged to be even worse: cluster headaches. Often featuring in lists of the most painful conditions in medicine—along with trigeminal neuralgia, sciatica, and gout—cluster headaches are named for the way that they descend in clusters, several times a day. The intensity of the pain is reflected in another name for the condition: suicide headache. Zeller describes the pain as “white-hot, blinding but invisible, frantic but elephantine” and writes of “writhing on the bathroom floor; of spittle and drool; of fingertips ground furiously into the scalp in a futile attempt to soothe whatever shrieking complex of anatomy is tearing at the right side of my head.”
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Cluster headaches are relatively rare, affecting less than one per cent of the population, whereas migraine is among the most common serious maladies. Globally, some 1.2 billion people suffer from it, some forty million of them in the United States. Men are more likely to experience cluster headaches, whereas female migraine patients outnumber their male counterparts at a ratio of about three to one. The two conditions provide the focus of Zeller’s book, which weaves together history, biology, a survey of current research, testimony from patients, and an agonizing account of Zeller’s own suffering, which began when he was in his twenties. Readers with migraine or cluster headaches will find themselves, as I did, comparing their own experiences with the rich material in the book, which is both a survey of the field and a great cry of pain.
Migraines vary widely from person to person—in terms of how they are experienced, what seems to trigger them, and how responsive they are to various drugs. They may begin in adulthood, as they did in my case, but they can also afflict children. More than half of women with migraine suffer attacks during menstruation, suggesting hormonal fluctuation as a trigger. Migraines may be preceded by a variety of subtle symptoms; Zeller lists “constipation, food cravings, frequent yawning, stiffness in the neck, or increased thirst and urination.” There is also the phenomenon known as aura, an array of sensory or motor symptoms that often portend the onset of pain, nausea, and a heightened sensitivity to light.
Aura is one of the most striking features of a migraine, but only about a third of sufferers experience it. I am one of them, and my experience is intensely visual. Before my headache arrives, there’s a kind of flashing light in the shape of a crescent moon with sawlike teeth, and this apparition gradually expands until it blocks the vision in my right eye. Oliver Sacks, in his masterly first book, “Migraine,” from 1970, includes paintings by various migraine patients of their auras. One that looks very much like mine bears the caption “A classical zigzag fortification pattern—its brilliance, in life, is as dazzling as a white surface in the noonday sun, and the edge is in continual scintillation.” Some relatively lucky migraineurs get aura but no pain following it. But for most, both with and without aura, the attacks are debilitating. During and after, I need to rest in a dark room. Even a glimmer of light is painful, and I feel physically and mentally spent, unable to function for the rest of the day.
Migraines typically affect one side of the head. (Indeed, etymologically, the term comes, via Latin, from a Greek word referring to this, hēmikrania, which lost its initial syllable as it passed from language to language.) The condition has been recognized through most of recorded history. Hippocrates described what appears to be an aura. “He seemed to see something shining before him like a light, usually in part of the right eye,” he wrote of a patient. “A violent pain supervened in the right temple, then in all the head and neck.” Aretaeus of Cappadocia, thought to have lived in the second century C.E., possibly at the same time as Galen, described a headache disorder similar to my experience: “These were bouts of head pain involving much torpor, heaviness of the head, anxiety, and weariness. . . . Patients fled light because the darkness soothes their disease.” A remedy recommended by Galen involved applying a torpedo fish—a member of the ray family—to the heads of sufferers, a treatment that Zeller speculates may have served as a counter-irritant. Aretaeus favored bloodletting, cupping, blistering, and, if all else failed, a gruesome cauterization of the scalp.
The occurrence of chronic head pain doubtless goes back much further. Zeller observes that the “portion of the population experiencing migraine and other headache disorders appears to be remarkably stable, neither ebbing nor flowing very much over time, and with only small variations across ethnicities and geographies”; this suggests that the problem may be as old as our species. He spends several pages outlining the practice of trepanation—drilling a hole in the skull—evidence of which has been found in skeletons dating back to the late Paleolithic era, some twelve thousand years ago. He cites not only historians and medics who take this as confirmation of early headache treatments—among them the seventeenth-century doctor Thomas Willis, who coined the term “neurology”—but also those who persuasively argue against that assumption. Still, he admits that his sufferings predispose him to think there must be something in that idea. “Anyone who has experienced the pain of a cluster attack will have at least contemplated an act of self-violence commensurate with trepanation,” he writes. “When there is a terror unfolding inside the skull, how crazy is it to think that another terror might let it out?”
For most of history, there was little advance in the treatment of headaches and a corresponding curiosity about what might work. Charles Darwin, himself a sufferer, recorded in the journals documenting his time aboard H.M.S. Beagle a folk custom that had been shared with him during a bad bout in Argentina. “A common practice is, to bind an orange-leaf or a bit of black plaster to each temple: and a still more general plan is, to split a bean into halves, moisten them, and place one on each temple, where they will easily adhere,” he wrote. “If a man, with patches on his head, is asked, what is the matter? he will answer, ‘I had a headache the day before yesterday.’ ”
Medical science may have had little to offer headache sufferers, but, as Zeller notes, “prior to the twentieth century, unexplained head pain was considered a consequential matter—a mysterious and even baffling affliction that warranted serious medical consideration, accumulating documentation, and frequently dramatic interventions.” An important theme running through his book is the scant attention these conditions now receive, given how many people suffer from them, and the difficulty that patients have in being taken seriously. There are far fewer caregivers and researchers tackling the headache conundrum than there are working on movement disorders such as Parkinson’s, degenerative diseases such as Alzheimer’s, and vascular maladies such as stroke. Patients seeking solutions often experience frustration and desperation. They visit neurologists, anesthesiologists, pain-management specialists, alternative healers, and online chat groups, trying to find explanations and relief.
Sufferers have also long been stereotyped by doctors, a tendency exacerbated by the fact that migraine patients are predominantly female. Zeller quotes an interview from the nineteen-forties with Walter C. Alvarez, a prominent physician on the staff of the Mayo Clinic: “Women who are most easy on the eyes, charming, dazzlingly intelligent and highly sensitive, are the very ones who are particularly prone to attacks of migraine headache.” Joan Didion addressed this denigrating view in her essay “In Bed.” “All of us who have migraine suffer not only from the attacks themselves but from this common conviction that we are perversely refusing to cure ourselves by taking a couple of aspirin,” she wrote. “ ‘You don’t look like a migraine personality,’ a doctor once said to me. ‘Your hair’s messy. But I suppose you’re a compulsive housekeeper.’ Actually my house is kept even more negligently than my hair.”
The question of what causes migraine and other chronic headaches is controversial, with two schools of thought, both of which can be traced back to the nineteenth century. One school contends that migraine is primarily an abnormality of the blood vessels and targets treatment accordingly. That is what I was taught in medical school nearly fifty years ago, and one of the first neurologists I consulted, noting that I would get a migraine while resting on Shabbat after a stressful week, suggested that my blood vessels, which had been tight and constricted, were relaxing, causing excessive blood flow into the brain and, thus, the headache. (It occurred to me that one solution might be never to relax.) His advice for prevention was vigorous exercise to enhance vascular tone, a regimen that, in my case, didn’t work.
The other camp holds that migraine emanates not from blood vessels but from the brain itself, like epilepsy. In a phenomenon known as electrical depolarization, an abnormal flux of ions triggers neurons to fire, moving up from the brain stem and into regions including the cortex. This mechanism can account for such symptoms as aura, nausea, photophobia, and tingling, and the weight of brain-scan evidence favors this hypothesis. Those who subscribe to it see blood-vessel contraction and relaxation as mere epiphenomena. Zeller offers a useful synthesis of the two views: “If one were to boil down existing knowledge of primary headache mechanics, these three statements would more or less cover it: (1) key parts of the brain seem to be involved; (2) certain neurochemicals seem to be important; and (3) we still aren’t entirely sure about the role of blood vessels in the whole matter.”
Depending on the doctor, and on the theory that he or she held, I have been prescribed various medications, sometimes in sequence, sometimes in combination. I began with tricyclic antidepressants, which, years ago, were found to be helpful for some migraine patients. But they affected my blood pressure—if I got up quickly from bed, it dropped to the point that I’d almost faint—and also made it hard to urinate. I moved on to verapamil, a drug that blocks calcium’s entry into the smooth-muscle cells around blood vessels, causing the vessels to relax and widen. It made my vascular tone and blood pressure plummet. Next was Topamax, an antiepileptic medication, whose nickname in medical circles is Dope-a-max, because it makes you feel stupid. Indeed, I felt as if my head were filled with potatoes; I could barely think and could speak only slowly. I then added propranolol, a beta-blocker that reduces the effects of adrenaline on the heart and the blood vessels. It also brought on a degree of fatigue and gloom that became intolerable, a known side effect of the medication. During acute migraine attacks, I took triptans, targeting the neurotransmitter serotonin, which ameliorated the headache in the short term by blocking pain receptors in the head. But triptans can be taken only in limited doses because of their risk of inflicting rebound headaches and their side effects of nausea, vomiting, and chest pain.
One weekend, in the midst of this trial and error of remedies, after stopping propranolol, I had an explosive series of unrelenting migraines, each episode dovetailing into the next. There was a brief respite of an hour or two between waves of auras and pain. I couldn’t leave my darkened room and feared I would be consigned to a life of debility. A neurologist prescribed high doses of prednisone, a corticosteroid, which broke the vicious cycle but induced severe anxiety and insomnia, so much so that I had to take lorazepam, a Valium-like benzodiazepine. None of these numerous medications were consistently beneficial.
Zeller aptly captures my experience. “What works for one person today may not always work, which will force them to seek out a new remedy from a well of options that necessarily shrinks with every change,” he writes. His own pharmaceutical quest is nothing short of hair-raising. The book opens with him high on psilocybin from magic mushrooms; he writes of a time when, working on a big story for the Times, he was “ingesting high doses of magnesium; inhaling up my nose regular squirts of water and capsaicin; popping calcium-channel blockers like candy; and practically mainlining caffeine, which sometimes seemed to abort an individual headache if taken quickly, but also, probably, helped to make the headaches worse overall.” At one point, he blacks out from taking too much verapamil: “I registered an abiding sense of thanks—not because I’d survived a reckless overdose, but because I had finally slept through the night without a headache.”
Despite our limited understanding of the biology of chronic headaches, there have been recent advances in identifying molecules in the brain which mediate pain. The discovery of a neurotransmitter called calcitonin gene-related peptide (CGRP) has markedly advanced the understanding and the treatment of migraine. This discovery came about when researchers inserted cannulas around patients’ fifth cranial nerve to sample the release of proteins during migraine and found CGRP in abundance. It was released from trigeminal nerve endings surrounding cranial blood vessels. Subsequent experiments found that intravenous infusions of CGRP invariably produced migraines.
Drugs developed to block the effects of CGRP arrived for patients in 2018. I was initially prescribed Aimovig, an antibody that is self-administered by injection once a month. For eight months, I didn’t have a single migraine, having previously averaged one every few weeks. At first, I thought I might be among the lucky twenty per cent of patients whom Zeller describes as “super responders”—“their lifelong, personal narratives of disabling, unexplained, recurrent head pain being completely rewritten in ways that would have been wholly unheard of just a few short years ago.” Alas, for me, the effects of Aimovig gradually waned, and I became despondent. Fortunately, another CGRP-targeting drug came on the market: Emgality. This worked for me, too, but, again, the benefit wore off after about a year.
Both Aimovig and Emgality were prescribed for me by a pain specialist. When they stopped working, I saw a neurologist who is in the migraine-as-epilepsy camp. She recommended Lamictal, an antiepileptic medication that is also used for psychiatric conditions such as bipolar disorder. It suppresses electrical depolarization and has been shown to be highly effective in people who have migraine with aura but not in those who have migraine without aura, a fact that lends credence to the hypothesis that aura represents an epileptic-like event in the brain. The benefit for me was substantial and has been ongoing. Meanwhile, the pain specialist I was consulting encouraged me to add on a long-acting CGRP antibody called Vyepti, which is given every three months. Sometimes, during the week or two before my Vyepti infusion, I feel tingling in my neck, without the flashing light in my eye but with moderate one-sided head pain. I’ve come to think of this as a mini-migraine. Immediately, I take Nurtec, another CGRP blocker, which can abort a full-blown attack.
The use of multiple medications is common among headache sufferers. One study cited by Zeller found that the average patient was taking at least four medications and that forty per cent were taking five or more. Lamictal, Vyepti, and Nurtec are all preventative. During a full-blown attack, I take triptans.
Why are migraines such a common part of human experience? Zeller notes that animals do not seem to suffer chronic headaches. “I’ve never seen one of my pets lie in its bed with its paw over its head,” an Australian pharmacologist tells him. This may indicate that migraines are produced by the interaction of the most primitive parts of our brain and the cortical structures that have evolved more recently. Zeller suggests that evolutionary biology may hold an explanation for chronic headaches. “It’s not hard to imagine that an acutely sensitive nervous system, attuned and highly responsive to sounds, sights, smells, and threats, would be valuable to our primitive forebears on the predatory savannah,” he writes. “Maybe the desirability of these triggerable, keenly attentive senses meant that our internal wiring would evolve to a razor’s edge, forever spring-loaded, but prone, in some of us, to errant firing under the wrong conditions.”
This hypothesis sounds persuasive, albeit frustrating for me. We are no longer on the predatory savanna, and I, for one, would prefer to have a nervous system that was not on a razor’s edge requiring multiple medications to restrain it. Still, with the four drugs I now take, migraines have lost much of their power to dictate the shape of my days; I suffer the full force of one only a couple of times a year, with “mini-migraines” marking the waning of my quarterly infusions. For me, that’s a huge improvement, enough to move through the world without the old dread always trailing behind. Reading Zeller’s book, I was reminded that there is a kind of uneasy fellowship in this condition—a vast, involuntary community of people mapping out their lives between attacks, haunted by uncertainty but sustained in part by accounts like his. If there’s a lesson here, it’s that pain resists mastery, but understanding, however incomplete, can offer its own form of relief. ♦
