Cluster headaches can hide in plain sight

Episodic cluster headaches and migraines are often confused, and more often than not, migraine is misdiagnosed as cluster.

Patients who present to primary care physicians reporting a migraine may actually be suffering from a different type of headache altogether.

About 5% of the U.S. population has cluster headaches, which can include up to eight attacks daily or near daily, lasting anywhere from 15 minutes to three hours, according to headache specialist Timothy Smith, MD, RPh, FACP. “To put that in perspective, migraine is about 100 times more common. So, while cluster headache is not a rare disorder, it is not as clinically recognized as migraine.”

Causes, symptoms

No one is sure what causes cluster headaches, but imaging studies indicate they are linked to a malfunction in the hypothalamus. Attacks tend to occur in phases that may last several weeks to a few months before remitting for months or even years, according to Dr. Smith, who is the medical director of pharmacology and internal medicine at the Ryan Headache Center in St. Louis, Mo. Triggers include alcohol, histamine, nitroglycerin, and generally anything that excites the nervous system. By contrast, migraines are characterized by unremitting pain lasting between four and 72 hours, typically coinciding with nausea and sensitivity to light and sound.

A distinguishing factor of cluster headaches is that they occur in groups and can go dormant for weeks or months Image by fizkes
A distinguishing factor of cluster headaches is that they occur in groups and can go dormant for weeks or months. Image by fizkes

Episodic cluster headaches and migraines are often confused, according to Stephen Silberstein, MD, FACP, who directs the headache center at Thomas Jefferson University Hospital in Philadelphia.

“Clusters are very commonly misdiagnosed as migraine, but more often than that, migraine is misdiagnosed as cluster,” he said. “The easiest way to tell the difference is that if you have a headache and you want to lie down, it's probably migraine. If you are compelled to run around and you want to hit your head against the wall, the odds are it's cluster. That's the big distinction.”

Dr. Smith noted that migraines may wax and wane depending on risk factors but rarely occur in groups and rarely go dormant for weeks or months. “That pattern is distinctly more consistent with cluster headache,” he said.

Further, chronic cluster headaches are often confused with episodic ones, but “They are different animals,” according to Dr. Silberstein. “Chronic clusters are unremitting, every day. Episodic may not come back for months or a year or more.” Dr. Silberstein said cluster headaches, either chronic or episodic, occur more frequently in men than in women, most commonly between ages 20 and 40 years.

Other distinguishing signs and symptoms of cluster headaches are pain on only one side of the head, nasal congestion, tearing and red eyes, and sometimes swelling of the eyelid and area of the forehead on the side of the face where the pain occurs. They may also coincide with a change of seasons, and there is a strong tendency for attacks to occur during sleep, waking the patient several times a night, according to Dr. Smith.

There is a slight family predisposition, and autosomal dominance has been suggested as an inheritance pattern, Dr. Smith said. No risk factors have been identified for cluster headache, although tobacco use has been noted to be more prevalent in this patient population.

A diagnosis of cluster headache is based on the history and physical, similar to all other primary headache disorders. “The unique presentation of cluster makes diagnosis pretty apparent,” said Gary Rogg, MD, FACP, co-founder of Westchester Medical Center Headache Specialists in New York State.

“Diagnostic testing such as lab work and central nervous system imaging are only helpful in ruling out secondary causes of head pain,” said Dr. Smith. “If a secondary cause is ruled out or not suspected, then the diagnosis is made based on the distinctive features of the cluster attacks and phases.”

Still, the average time to a diagnosis in primary care is about five years, according to Stewart Tepper, MD, director of the Dartmouth Headache Center at Dartmouth-Hitchcock Medical Center in Lebanon, N.H. “We are always surprised at our headache clinic when we get a referral for cluster and it turns out to be the right diagnosis.”

Available treatments

Injectable sumatriptan, transcutaneous vagus nerve stimulation, and inhaled oxygen are the most common acute therapies for cluster headache. Nasal spray triptans may also be effective for some cluster attacks, according to Dr. Smith, although he noted that oral triptans typically act too slowly for most patients.

“The transitional medication of choice is higher doses of corticosteroids with gradual tapering off of the medication. This approach will begin to work right away, giving the cluster headache sufferer more immediate prevention of the attacks. This is often necessary because the more standard prophylaxis agents take more than two weeks to start working,” Dr. Smith said.

Dr. Rogg also recommends nerve blocks as an effective transitional therapy. For some patients, melatonin can also be effective, according to Dr. Silberstein.

Until recently, off-label verapamil or lithium was the most common prophylactic therapy for cluster headaches. In June, the FDA approved self-injectable galcanezumab-gnlm, a calcitonin gene-related peptide (CGRP) antagonist, for the treatment and prevention of episodic cluster headache in adults. The monoclonal antibody is self-injected at the onset of symptoms and then once monthly, until the symptoms subside, according to Dr. Rogg. “The drug's impact on quality of life is so great, most patients do not mind an injection, especially because there is infrequent dosing.”

In a clinical trial of 106 adults with episodic cluster headaches, galcanezumab demonstrated significant superiority over placebo, according to results of industry-funded study published July 11 in the New England Journal of Medicine. Over the course of three weeks, patients in the galcanezumab study arm reported a decrease of 8.7 cluster headaches compared with a decrease of 5.2 in the placebo arm. The study drug also had an excellent safety profile, with hypersensitivity being the only reported contraindication, according to Dr. Smith. Patients in the intervention group had more injection-site reactions than the placebo group, but most were generally mild and self-limited. (Dr. Tepper and Dr. Smith have received research grants from and served as consultants for companies developing therapies for cluster headache, and Dr. Smith has also served on a related speakers' bureau.)

Because galcanezumab is cleared by the reticuloendothelial system, there are no dosage adjustments required for patients with hepatic or renal insufficiency, Dr. Smith said, adding that urticaria, angioedema, and anaphylaxis have been reported but are rare. There are no known drug-drug interactions to be concerned with when prescribing it, he said. No data are currently available on the drug's potential use in women who are pregnant or trying to conceive.

The designated breakthrough therapy was also approved last fall as a prophylactic treatment for migraine in adults. Galcanezumab and another CGRP antagonist, fremanezumab, were found to be ineffective for chronic cluster headaches, however. Study data are available up to one year for the use of galcanezumab in episodic cluster headache. “Beyond this, it is not clear about sustainable efficacy,” Dr. Rogg said.

Galcanezumab is prescribed after other therapies have failed or if they are contraindicated, Dr. Rogg said. “The most robust results are seen by week three,” he noted, although he said that other short-term therapies can be used in the meantime.

One reason the novel therapy is not yet considered first-line therapy is access, according to Dr. Tepper. Some payers stipulate that prescriptions for galcanezumab and other novel and emerging therapies must be written only by specialists, he said. “These drugs are easy for an internist to prescribe, but payers want the consult first, which is often very difficult to get, because there is a shortage of these specialists,” he said. He noted that there are fewer than 600 board-certified headache medicine specialists in the U.S. and that several states and entire regions have none.

Off-label traditional prophylaxis methods such as triptans or steroids are much less expensive but less effective, which could lead to their overuse, according to Dr. Smith. “It becomes clear the more expensive treatment may be better for the patient's health outcomes,” he said.

The American Headache Society's 2018 position statement on integrating new migraine treatments into clinical practice includes mention of CGRP inhibitors and recommends that any licensed clinician be able to prescribe them if other grade A or B therapies have failed. Dr. Tepper said he hopes this will allow galcanezumab and other emerging treatments to be prescribed for any headache, including cluster headache, when appropriate.

“It's a big battle,” Dr. Tepper said, “because these drugs are so effective, but more expensive than the previous generic nonspecific treatments.”