Abstract
Background
While migraine and cluster headache share some clinical features and therapies, they differ considerably in the frequency and duration of the headache, as well as the inter-attack, or inter-bout, pathophysiology. Neither is fully understood, with their shared pathways being of interest.
Findings
Five patients for whom it was difficult to distinguish migraine from cluster headache are presented. They had aspects of their phenotypes, which could be attributed to both disorders. Each patient was thoroughly examined, excluding secondary causes of headache, and had been treated with a number of medicines.
Conclusion
A correct diagnosis is key to the appropriate treatment approach. Especially, if treatment is not successful for the suspected headache type, and enlargement of the diagnostic and therapeutic range, respectively, should be evaluated. Whether in such settings there is shared or different pathophysiology can only be speculated upon.
Introduction
Cluster headache and migraine are two distinct primary headache types clearly defined by the criteria of the International Classification of Headache Disorders- ICHD (1). Migraine is more common in the population than cluster headache. The one-year prevalence of migraine is approximately 12% of the population, while that of cluster headache is some 0.1% (2,3). Migraine is more prevalent in women und cluster headache more prevalent in men. There are interesting phenotypic overlaps, such as cranial autonomic symptoms and photophobia and phonophobia with laterality of symptoms (4). Shared features can create diagnostic issues, although by chance one would expect a proportion of patients with cluster headache to have migrainous biology, since the lifetime cumulative incidence of ICHD-defined migraine in females is 43% (5).
When typical, both migraine and cluster headache are relatively straightforward to distinguish. In cluster headache cranial autonomic symptoms, such as lacrimation, conjunctival injection, nasal symptoms, aural fullness, or ptosis, are more often lateralized to pain, more prominent and more tightly linked to the pain (6). Whereas in migraine they are more likely bilateral and less prominent. Photophobia and phonophobia are more often reported to be ipsilateral to pain in cluster headache (4). Therefore, time and frequency pattern are most helpful to distinguish between the two, as is behavior during attacks, where cluster patients are usually agitated and migraine patients seek rest and darkness. In addition, the length of the premonitory phase can be very helpful, as it is short- minutes in cluster headache and hours to days in migraine (7,8).
Although the full pathophysiology of both headache types is still not completely understood, clearly there are pathophysiological overlaps, such as imaging studies have revealed (9–11). In common the trigeminovascular system, the hypothalamus, although likely different parts, and cranial parasympathetic nerve fibers are involved in both (12,13). Furthermore, NO-donors, such as nitroglycerin (14) and the calcitonin gene-related peptide (CGRP) trigger cluster headache, when in bout, and trigger migraine irrespective of attack frequency (15,16). There is an overlap in response to treatment, in the acute setting, such as with triptans, or in prevention with anti-CGRP monoclonal antibodies) (17), although there are a range of effective anti-migraine treatments that are generally regarded as useless in cluster headache, such as propranolol and amitriptyline (18,19).
It has been questioned in a given case whether migraine with specific characteristics can coexist with cluster headache, where they differ characteristically from each other not only in the intra-individual phenotype, but also the temporal pattern. The transition of a migraine attack into a cluster headache and vice versa may be noticeable for the patient. They may report that with daily migraine there is occasionally a change in the nature of the pain to cluster-like pain, which would be in line with the higher prevalence of migraine in the general population.
In the literature there were different names for migraine or cluster headache, which did not have characteristics corresponding to both of them. Applebee and Shapiro speculate in their article on the existence of cluster-migraine (20). They present a cyclic migraine, where attacks had migraine-like character, but they recurred in intervals and temporal pattern of cluster headache. They also discussed atypical cluster headache, where the pain was described milder, typical for migraine, but with seasonal occurrence in summer.
The aim of this case series is the stimulation of the discussion, if there indeed is an overlap syndrome like “cluster-migraine”. All patients gave consent to publish their anonymized information.
Case reports
Case 1
A 44-year-old patient was referred to our outpatient clinic by the general practitioner. She reported a history of migraine for almost 20 years, after giving birth to her first child. Back then, the headaches were always on the left side, very severe, previous yawning, no aura, no major accompanying symptoms such as nausea, sensitivity to light or noise, or any cranial autonomic symptoms. After the birth of her second child, the unilateral headache worsened, up to 10/10 numeric rating scale (NRS), and was accompanied by restlessness. The duration was 1 to 1.5 hours when treated with eletriptan 40 mg, and 5 hours without acute medication. At that time the patient was suffering from about 12 to 15 episodes per month. With the headache attacks, the eyes sometimes got smaller and reddish, and sometimes she woke up in the middle of the night because of the pain.
In the past two years she additionally reported attacks of brief, untriggered stabbing pain on the back of the head. Neurological examination was normal, the brain MRI showed some unspecific deep white matter lesions.
Magnesium, riboflavin, and topiramate up to 100 mg were not successful. She was started on verapamil up to 240 mg, and did not tolerate higher doses. She additionally used intranasal zolmitriptan 5 mg, which was not more effective than the oral eletriptan 40 mg. At her three month follow up, the patient reported that the headache had slightly improved. The attacks were still only on the right side. She additionally noticed congestion of the nose (ipsilateral), conjunctival injection and a feeling of restlessness. Verapamil caused constipation and slight leg edema and was stopped. She was then put on galcanezumab 120 mg and reported a decrease to three to five attacks per month.
Case 2
A 62-year-old woman reported having a headache for 10 months, which woke her from sleep during the night. These attacks were right-sided and very strong. The patient also reported a feeling of fullness in the ear and a burning and watery eye. The attacks occurred about one-two times a week and lasted for one-two hours. She also noticed photo- and phonophobia, as well as sometimes nausea. Other than that she did not report any premonitory symptoms or postdrome. As acute treatment she took paracetamol and ibuprofen.
In addition, she reported a sudden onset of left-sided neck pain nine years before. The symptoms lasted for almost six months at that time and she was given a diagnosis of a vestibular migraine, as she also reported vertigo. Before this the patient had reported no previous headaches. Neurological examination was normal. Brain MRI showed a few unspecific white matter lesions.
At three months follow up she had a good response on intranasal zolmitriptan 5 mg, the attacks occurred on average two to three times per month.
Case 3
A 51-year-old patient complained of an episodic unilateral head pain for about five-six years, one to two times a week. As a child, he had a headache, but not of the same kind. Both his parents and his brother suffer from migraine. A migraine without aura was then diagnosed and unsuccessfully treated with propranolol up to 120 mg, osteopathy, acupuncture, and onabotulinum toxin A not using the PREEMPT protocol. He described the headache as occurring in the morning, sometimes (20%) at night, starting from the neck and radiating to one side (80% right). If the pain was very severe, there was nausea, but no photo- or phonophobia. He also reported ipsilateral rhinorrhea, sometimes conjunctival injection and tearing. The headache responded well to sumatriptan 50 mg within one hour (never untreated). Neurological examination was normal, as was a recent brain MRI.
After three months of treatment with verapamil (480 mg), there was a reduction to two attacks per week. He furthermore had a good response intranasal triptans, but not to oxygen. At follow up after three years, he reported of some efficacy of a low carb diet but was back to more than two attacks per week.
Case 4
A 36-year-old patient suffered from headache for a month. These occurred several times a day, but mostly at night. The duration was one to two hours. The headache was bitemporal, pulsating, and accompanied by photo- and phonophobia. There were no predromes nor postdromes reported, and the patient did not report any triggers. There was right-sided conjunctival injection with every attack, but no lacrimation. He also felt restless, and sometimes there were chills and cold sweats. The neurological examination was normal. He reported having headache from time to time (about once a month, for a day at most). Then, there was mild pain on the forehead without any accompanying symptoms, mostly after alcohol consumption. There was no follow up.
Case 5
This 27-year-old PhD student started to have a unilateral headache five years ago. The pain was from the neck radiating to the eye. Although he described the pain from severe to very severe, he did not take any analgesic drugs and did not have any interference with daily activities. He reported additional ipsilateral rhinorrhea and restlessness. He was treated with antibiotics and the pain went away after around two weeks. These episodes occurred every three to six months for the next three years. For the last years he had between seven to 10 headache days per month, with a constant interscapular back pain. He disliked bright lights and loud noise. The neurological examination was normal, as was repetitive brain MRI and ENT examination. He had no family history for headaches and was otherwise healthy and not smoking. So far, he failed several treatments: indomethacin 75 mg, sumatriptan 50 mg, amitriptyline 50 mg, pregabalin.
Discussion
Looking at the above-mentioned medical histories together, it is not possible to clearly classify the headaches according to the ICHD-3. In these cases of a mixed headache pattern, it is important to understand the patient's medical history in detail and to rule out other possible causes by neurological examination and further examinations (21). The type and intensity of the headache and the accompanying symptoms play an important role in the correct diagnostic process.
In the first case, the long history, the normal clinical examination and normal brain imaging clearly indicate a primary headache. The phenotype of the unilateral pain with nocturnal occurrence, the associated autonomic symptom and restlessness, as well as the lack of vegetative symptoms, would correspond with an episodic cluster headache. However, the low frequency and long duration are rather unusual here. This patient does fulfill both the probable criteria for episodic migraine and chronic cluster headache. In addition, she had headache attacks fulfilling the criteria for primary stabbing headache (1). The previous migraine-specific drugs were not successful. The treatment was switched to a regimen for cluster headaches. Zolmitriptan nasal 5 mg was used for fast-acting attack treatment and verapamil as a prophylaxis. Verapamil was increased gradually with regular ECG controls, but not tolerated in higher doses (22). She had a benefit from the new CGRP antibodies.
In the second patient, the headache cannot be clearly classified either. There are symptoms of cluster headache, e.g. the duration, the unilateral pain, the autonomic symptoms, and the nocturnal occurrence. On the other hand, there are also typical migraine features, the rather low frequency and the need for a rest. This patient fulfills both ICHD-3 criteria (Tables 1 and 2) for episodic migraine, and – in disregard of the slightly lower frequency – also for episodic cluster headache. A third possible diagnosis would be hypnic headache, although the presentation is rather atypical, and the criteria are not fulfilled. The patient tried caffeine at night without any success. The patient had a benefit from short-acting triptans, a preventive treatment was not necessary.
In the third case the episodic pattern clearly matches a migraine with a frequency of one to two attacks per week and the occurrence over the past five years. However, the typical vegetative accompanying symptoms were missing. His behavior, the severity of the attacks, the autonomic symptoms, as well as the nocturnal occurrence were in line with cluster headache. The criteria for probable cluster headache are fulfilled, but again the frequency is too low. The full criteria would allow this, but only for a shorter period of time (1). The alternating pain however is atypical and would suggest a co-occurrence of both headache types. However, the patient was not able to distinguish between the attack types. In the end, after several failed migraine treatments he had a benefit from verapamil. Would you therefore call it cluster headache?
The fourth case had an only short presentation; therefore, also a secondary headache mimicking a primary phenotype could be the cause. Still, he reported a history of headache which would fulfill criteria for tension type headache. Furthermore, there was a normal examination, a normal lab screening and normal magnetic resonance imaging. The short and recurring attacks accompanied by unilateral autonomic symptoms are consistent with cluster headache. However, the pain was bilateral. The accompanying symptoms also are consistent with migraine, but the nocturnal occurrence and especially the higher frequency speak against it. Unlike the other patients, indomethacin was tried. Unfortunately, there was no follow up.
The last case presented initially with a circannual pattern of longer lasting episodes of trigemino-autonomic pain. However, for the past period of two years there were also migraine features. Finally, the current headaches fulfill the criteria for episodic migraine and not for cluster headache.
In conclusion, the correct diagnosis effects choice of therapy at all stages. If differential diagnoses are evaluated in the beginning, a long odyssey of treatment failures could be avoided. Headaches that have the characteristics of both migraine and cluster headache maybe be diagnosed as an overlap-syndrome, or viewed by their predominant phenotype. Furthermore, drugs of choice should be the ones with evidence in both types, or for the dominant phenotype, such as fast-acting triptans for acute treatment and preventive drugs with evidence for both headache types, i.e. topiramate (23,24), verapamil (25,26) and galcanezumab (17,27). Oxygen therapy has not always its desired effect, if there are no autonomic symptoms (28,29).
The third edition of International Classification of Headache Disorders (ICHD-3) plays a very important role not only in the research context, but also in clinical practice. An addition of an overlap syndrome, when a distinct phenotype does not fulfill both or neither of migraine or cluster headache could provide further evidence, for or against its existence, when studied accordingly. More clinical and ideally pathophysiological information on further cases would help elucidate this issue.
Finally, diagnosis is very important for the implementation of an appropriate therapy, and this is probably the most essential for patient. In the absence of response to treatment, it is important to re-evaluate the diagnosis.
Comparison of the diagnostic criteria of the ICHD-3 (1) and additional discriminating features of migraine and cluster headache. The ICHD-3 criteria of each diagnosis are marked with the letters A–D and numbers (i.e. C3). The discriminating characteristics are in italic. CH: Cluster Headache, M: Migraine, n.s.: not specified or non-specific.
Presentation of the cases fulfilling the different criteria and additional features. M, migraine; C, cluster headache; MC, both; U, unspecific; n.r., not reported.
Clinical implications
A detailed anamnesis of the patient plays the most important role in establishing the diagnosis and treatment of the patient. The treatment of choice should be those with evidence in both types of migraine headaches and cluster headaches, or for the dominant phenotype. If there is no response to treatment, the diagnosis and treatment should be reassessed.
Footnotes
Declaration of conflicting interests
The authors declared the following potential conflicts of interest with respect to the research, authorship, and/or publication of this article:
MC has nothing to report.
PJG reports, over the last 36 months, not related to the paper, grants and personal fees from Eli-Lilly and Company, grant from Celgene, and personal fees from Aeon Biopharma, Allergan/Abbvie, Amgen, Biodelivery Sciences International, Biohaven Pharmaceuticals Inc., CoolTech LLC, Dr Reddys, Epalex, Impel Neuropharma, Lundbeck, Novartis, Praxis, Sanofi, Satsuma and Teva Pharmaceuticals, and personal fees for advice through Gerson Lehrman Group, Guidepoint, SAI Med Partners, Vector Metric, and fees for educational materials from CME Outfitters, Omnia Education, WebMD, and publishing royalties or fees from Massachusetts Medical Society, Oxford University Press, UptoDate and Wolters Kluwer, and for medicolegal advice in headache, and a patent magnetic stimulation for headache (No. WO2016090333 A1) assigned to eNeura without fee.
ARG reports, over the last 36 months, not related to the paper, grants and personal fees from Allergan/Abbvie, Almirall, BioMed, Curatis, Eli-Lilly, Grünenthal, Lundbeck, Neurolite, Novartis/Amgen, Sanofi, Teva/Mepha, and fees for educational materials from medinform, MedScape, SIM.
Funding
The authors received no financial support for the research, authorship, and/or publication of this article.
