Understanding Cluster Headache Diagnostically, Therapeutically


As the scientific grasp of it gets tighter, ensuring physicians have an understanding of the diagnosis of and treatment options for cluster headache becomes of utmost importance.

Dr Peter Goadsby

Peter J. Goadsby, MD, MBBS, DSc, PhD, neurologist and headache specialist at the University of California, San Francisco Medical Center

Peter J. Goadsby, MD, MBBS, DSc, PhD

An understanding of the condition of cluster headache, as well as its potential therapeutics, is an essential tool for the headache specialist to have, according to Peter J. Goadsby, MD, MBBS, DSc, PhD.1

In a special interest group presentation at the American Headache Society’s 2018 Scottsdale Headache Symposium, in Arizona, the neurologist and headache specialist at the University of California, San Francisco Medical Center detailed to a room of attendees the importance of grasping this understanding for a condition that is incredibly debilitating for the patients with it.

“It is, in principle, useful to understand as much as one can about the basis of the disorder because cluster headache patients are remarkably well-informed,” Goadsby said. “They can also be remarkably assertive about the way they’re well informed. It’s not a bad idea to know something about what you’re talking about. It’s also a good idea that, if you don’t know what you’re talking about, maybe it’s best not to say too much.”

“And it’s true to say that most of the patients have read the relevant books and articles,” he added.


Having a more complete comprehension of the diagnosis of cluster headache is a key to this understanding. Recently, the International Classification of Headache Disorders, Third Edition (ICHD-3) adjusted the boundary line of the disorder’s chronic and episodic definitions.2 The ICHD-3 now defines the condition as “attacks of severe, strictly unilateral pain which is orbital, supraorbital, temporal or in any combination of these sites, lasting 15-180 minutes and occurring from once every other day to 8 times a day. The pain is associated with ipsilateral conjunctival injection, lacrimation, nasal congestion, rhinorrhea, forehead and facial sweating, miosis, ptosis and/or eyelid oedema, and/or with restlessness or agitation.”

“We’re using 3 months now as the boundary line between episodic and chronic cluster headache. A month off and 11 months on just really didn’t seem like it was episodic," Goadsby said.

Notably, one of the challenges in diagnosis is the shared pathophysiology between trigeminal autonomic cephalalgias (TACs) and migraine headaches, which can muddy the waters in determining whether or not a patient has one or another. Goadsby said that, when comparing TACs with migraine, and more specifically, with cluster headache, the cranial autonomic features in patients with cluster tend to be naturalized to the same side as the pain, tend to be prominent, and tend to be tightly linked to the pain.

“Whereas, if you see cranial autonomic features that are a bit wishy-washy—they’re bilateral, they’re not so tightly linked, they’re not so prominent—but they’re there if you dig them out, that’s what tends to happen in migraine. It’s a very interesting dynamic,” Goadsby explained.

Additionally, Goadsby implored the attendees to ask questions about cranial autonomic features, which he called the “basis for the misdiagnosis of so many patients with sinus disease who have migraine.” Specifically, he stressed paying attention to lateralization of pain, cranial autonomic features, and migrainous phenomena.

“If you ask all cluster patients about light sensitivity, a good portion of them will say, ‘yeah, I’m sensitive to light.’ Very often you just have to ask,” Goadsby said. “Often in medicine, we have a don’t ask, don’t tell policy. If you don’t ask too many questions, people won’t hold you up. But, if you ask them a lot of questions the first time, particularly if there are things about them that they haven’t told you, it’s quite a good thing to really try and understand the phenotype of what’s going on. In cluster, in people in episodic cluster, the light sensitivity is almost invariably on the same side as the pain.”

Goadsby specifically pointed to the need to inquire about the patients’ experience with their condition—“they’re experts on what’s going on in their own condition,” he said—it can help with improving diagnostic knowledge. He explained that lateralization of symptomatology, such as lateralization of photophobia, is a good way to get into thinking the person has a TAC.


“It must keep you up at night—certainly keeps me up at night—wondering how oxygen works because it’s quite reliable,” Goadsby said. “Oxygen really works. How it might work is an important question.”

In 2009, work by Goadsby and others, including lead author Simon Akerman, PhD, combined models of trigeminovascular nociception and activation of the trigeminal-autonomic reflex using superior salivatory nucleus/facial nerve stimulation to explore the effect of oxygen on trigeminal nerve activation as well as on autonomic responses through blood flow observations of the lacrimal duct.3

“What was seen is that if you stimulate the superior salivatory nucleus, a structure that we know about, you get a nice stimulus-locked increasing lacrimal flow, which you can inhibit with oxygen,” Goadsby said. “Go figure. I find that to be a really interesting thing.”

He noted that oxygen was explored in acute cluster headache as well, in a double-blind, placebo-controlled trial by Goadsby and Cohen et al., which showed that 78% of patients treated with oxygen were pain-free in 15 minutes compared to 20% in the placebo arm (P <.001).4

Additionally, non-invasive transcutaneous vagal nerve stimulation (nVNS) has also been shown to be effective in cluster headache. Model studies have shown that spontaneous firing in the trigeminocervical neurons can be inhibited after stimulation and that the inhibition lasts for a period of time, and as well that the superior salivatory nucleus-invoked firing can be reduced.

“It’s very clear that pulses from this non-invasive vagal nerve stimulator clearly turn these trigeminal neurons off,” Goadsby explained. “If that’s true, which it is, it shouldn’t be entirely surprising to find that when you take the 2 studies that have been published—ACT 1 and ACT 2&mdash; in episodic and chronic cluster headache, that they demonstrated against sham that is clearly useful in episodic cluster headache and clearly useless in chronic cluster headache.”

“What that tells us is that the sort of model that Simon [Akerman] has developed works predictably for responses in episodic cluster headache, but there’s something we still don’t understand about chronic cluster headache,” he added.

Additionally, Goadsby noted that research has shown that calcitonin gene-related peptide (CGRP) can induce cluster headache attacks in susceptible patients, and that CGRP monoclonal antibodies are effective in the episodic form of the condition. In that work, presented at the AHS’s Scientific Session in June, galcanezumab (Emgality, Eli Lilly) showed that 78% of patients (n = 49) had a ≥50% response at 3 weeks compared to 57% (n = 57) with placebo (P = .04).5

“It’s quite interesting in the context of the [Anne Luise Haulund] Vollesen work, and also in the context of the VNS result in chronic cluster headache, that in this study, the galcanezumab study, the chronic cluster headache patients didn’t respond,” Goadsby said. “And the fremanezumab study was stopped for futility because again the chronic cluster headache patients weren’t responding.”

“Something interesting is coming in terms of differentiating between them. Yes, they’re similar— phenotypically, an attack is&mdash;but think about episodic cluster headache, it comes on the same time and it turns off, just like that. But in chronic cluster headache patients it doesn’t do that. It’s quite an interesting distinction we’re learning about the biology,” he added.


1. Goadsby PJ. Cluster headache pathophysiology. Presented at: AHS Scottsdale Symposium; Scottsdale, Arizona; November 14, 2018.

2. Headache Classification Committee of the International Headache Society (IHS). The International Classification of Headache Disorders, 3rd edition. Cephalalgia. 2018;38(1):1-211. doi: 10.1177/0333102417738202

3. Akerman S, Holland PR, Lasalandra MP, Goadsby PJ. Oxygen inhibits neuronal activation in the trigeminocervical complex after stimulation of trigeminal autonomic reflex, but not during direct dural activation of trigeminal afferents. Headache. 2009;49(8):1131-43. doi: 10.1111/j.1526-4610.2009.01501.x

4. Cohen AS, Burns B, Goadsby PJ. High-flow oxygen for treatment of cluster headache: a randomized trial. JAMA. 2009;302(22):2451-7. doi: 10.1001/jama.2009.1855

5. Martinez J. Study CGAL: A phase 3 placebo-controlled study of galcanezumab in patients with episodic cluster headache: Results from the 8-week double-blind treatment phase. AHS 2018; San Francisco, CA; June 28, 2018. Abstract IOR03LB.

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