Abstract
Introduction:
Paroxysmal hemicrania (PH) is a primary headache disorder characterised by frequent, short-lasting, very severe, strictly unilateral attacks occurring in association with cranial autonomic features. A striking feature of this disorder is its clear response to indomethacin.
Case report:
In contrast to this stereotypic presentation, we describe a man with indomethacin-responsive headaches that have a temporal profile similar to that of PH but whose attacks have a bilateral distribution without associated cranial autonomic features.
Discussion:
There have been several case reports of patients presenting with short-lasting, frequent, bilateral headaches responding to indomethacin, without cranial autonomic features. These cases have been described as representing bilateral PH although strict unilaterality of pain and cranial autonomic phenomena are cardinal features of PH. These cases may represent a novel indomethacin-responsive syndrome and therefore, for now, should be studied separately from PH until their pathophysiological basis is better understood.
Keywords
Introduction
Paroxysmal hemicrania (PH) is a rare but disabling primary headache disorder that has a highly characteristic clinical phenotype (1). The typical age of onset is 30–40 years, although it may present at any age. It has an equal prevalence in males and females (2). The headache is strictly unilateral and without side shift in the majority of patients. The pain is often localised to the orbital, supraorbital or temporal regions and is typically stabbing or throbbing in character. The pain is very severe and usually lasts between 2 and 30 minutes. Attacks of PH occur in association with ipsilateral cranial autonomic features, including conjunctival injection, lacrimation, nasal congestion, rhinorrhoea, eyelid oedema, forehead and facial sweating, and miosis or ptosis. Migrainous symptoms including photophobia, phonophobia, nausea and vomiting may also be present. A prospective clinical study of patients with PH reported presence of photophobia and phonophobia in 65% of cases, while 39% experienced nausea and vomiting during an attack (2). Patients may also become restless or agitated during an attack. Trigger factors may be present in some patients, with head or neck movements precipitating an attack (3). The attacks occur at a high frequency, ranging from 2 to 40 daily. A striking feature of this disorder is its clear response to indomethacin if it is given at a sufficient dosage.
There have been limited case reports of short-lasting, frequent, bilateral, indomethacin-responsive headache without cranial autonomic features. We present a case of a man with headaches resembling PH in temporal profile and responding to indomethacin but without the unilaterality and the cranial autonomic symptoms characteristic of the disorder, which broadens the clinical phenotype of this entity.
Case report
A 70-year-old right-handed man presented with a four-year history of headaches. There were no clear precipitants at onset. The headaches occurred in bouts lasting four to six weeks. He had one bout per annum, which generally occurred between May and June. He had 12–25 attacks daily, with each attack lasting 10–30 minutes. He described bilateral attacks centred over the occiput and parietal region. The pain was excruciating and had a sharp or throbbing quality. He was very restless during an attack. There were no associated cranial autonomic features, migrainous symptoms or auras. There were no triggers. He did not report any features suggestive of cervicogenic headache, such as precipitation of pain with neck movement and pain or tenderness over the neck.
His past medical history included ischaemic heart disease. He was taking diltiazem, lisinopril and aspirin. He had tried ibuprofen 400 mg and diclofenac 75 mg during the previous bouts with only mild benefit (5−10% improvement). There was no family history of headaches. He was an ex-smoker (quit aged 59 years) and drank 14 units of alcohol per week.
The neurological examination was unremarkable. He had the full range of neck movement with no localised tenderness. MRI scan of the brain was reported to show numerous white matter lesions consistent with small-vessel disease; intracranial appearances were otherwise normal. MRI scan of the cervical spine was reported to show minor degenerative changes of the cervical discs with thickening of the posterior longitudinal ligaments and shallow central disc bars at C4/C5, C5/C6 and C6/C7 levels but no evidence of cord or root compression.
When the patient entered the next bout, he was started on indomethacin 25 mg three times daily, which rapidly reduced the frequency, intensity and duration of attacks. Thereafter, he reported having nine attacks daily, each of shorter duration (10–16 minutes). Furthermore, the intensity of the attacks decreased dramatically (verbal rating scale [VRS] 2–4). The indomethacin dose was increased to 50 mg three times daily, which completely suppressed his attacks. However, the patient developed diarrhoea and so indomethacin was discontinued. Withdrawal was associated with a rapid recrudescence of his headaches (within 48 hours of the last dose), and therefore he restarted indomethacin 25 mg daily, which rendered him pain-free for 20–24 hours, with no side effects. He was maintained on this low dose until he cycled out of his bout.
Discussion
The trigeminal autonomic cephalalgias (TACs), which include cluster headache (CH), PH and short-lasting unilateral neuralgiform headache attacks with conjunctival injection and tearing (SUNCT), are characterised by unilateral headaches occurring in association with cranial autonomic features (4). The features of the headache reported in this case closely resemble those of PH, with similarity in terms of attack duration and frequency as well as response to indomethacin. However, the absence of unilaterality and cranial autonomic symptoms raises the issue whether this case truly represents a bilateral variant of PH or an entirely different and novel indomethacin-responsive headache syndrome (5).
Clinical characteristics of patients with “bilateral paroxysmal hemicrania”.
There are similarities in the phenotypes of PH and the bilateral pain cases reported in the literature and here. These include the age of onset, the site and character of pain, the short duration and high frequency of the attacks, and the absolute response to indomethacin. However, four of the five bilateral pain cases differ from PH in the absence of associated cranial autonomic features. It is notable that cranial autonomic features are not observed in the majority of bilateral pain cases, thereby suggesting that this is unlikely to be a chance finding. In addition, in contrast to PH, there was a paucity of migrainous symptoms in those with bilateral pain.
Pain and cranial autonomic features may dissociate in TACs, with reports of absence of the latter in 6.9% of CH and 3% of PH patients (2,10). It has been postulated that pain and cranial autonomic features are two separate phenomena, which may be triggered independently following activation of a central generator, such as the hypothalamus (11). It has also been suggested that both sides of the hypothalamus may have the potential for generating symptoms, although in most cases only one side becomes active, possibly due to suppression of the contralateral side. However, if both sides become simultaneously activated, with failure of contralateral suppression, bilateral attacks may ensue (12). Different hypothalamic activation thresholds for the trigeminal and parasympathetic pathways may explain the different combinations of pain and autonomic features observed (13).
Interestingly, there have also been reports of bilateral CH in the literature (12,14,15). All three cases were males, with mean age of onset ranging from 24–41 years. The headaches side shifted within a bout before becoming bilateral in two cases, while another patient had entirely bilateral headaches during one cycle. The duration of the headaches ranged from 15 to 90 minutes, with a frequency of two to nine attacks daily. Predictable nocturnal attacks were reported in two patients. There were associated cranial autonomic features in two patients, although these were reported to be less prominent when the headaches became bilateral. While we acknowledge that there may be phenotypic overlap between the two disorders, the high frequency of attacks and the absolute response to indomethacin in our patient argues against this case being bilateral CH. Likewise, primary stabbing headache and occipital neuralgia were excluded clinically due to the pain character, duration of the attacks and the presence of circannual periodicity.
Are these differences sufficient to consider classifying the bilateral headache phenotype as a novel indomethacin-responsive primary headache syndrome rather than a variant of PH? The clinical phenotype of four of the five case reports of bilateral headaches considered here differ substantially from PH, and we consider these differences to be sufficient to raise the possibility that such bilateral headaches without autonomic symptoms represent a novel headache syndrome. Matharu and Goadsby have previously proposed that bilateral, short-lasting, frequent headaches with the temporal profile of PH but lacking cranial autonomic features should be classified separately from PH and suggested the term “bilateral paroxysmal cephalalgia” to describe this novel phenotype (5).
Further cases are required, to allow similarities and differences with PH, as currently defined, to be fully characterised, and thereby determine whether they are variants of the same disorder or entirely different.
Finally, this and previous case reports highlight the potential value of a trial of indomethacin in patients who present with short-lasting, frequent headaches, with or without cranial autonomic features, regardless of whether the headache is unilateral or bilateral. Indomethacin has been reported to be beneficial in several short-lasting primary headache syndromes, including PH, but its mechanism of action is poorly understood. Neurogenic vasodilatation, which is thought to be induced by calcitonin gene-related peptide (CGRP) release, was found to be significantly inhibited by indomethacin. However, there was lack of inhibition of CGRP-induced vasodilatation, thus suggesting that its effect was mediated via pre-synaptic inhibition of CGRP release from trigeminovascular neurons (16). Indeed, levels of this neuropeptide were found to normalise following indomethacin treatment in a case of PH (17). Moreover, indomethacin was found to be the only non-steroidal anti-inflammatory drug that inhibited nitric oxide (NO) induced dural vasodilatation, which may contribute to its effect in PH (16).
Footnotes
Acknowledgements
We thank Dr Robin Howard, Consultant Neurologist at The National Hospital for Neurology and Neurosurgery and St Thomas’ Hospital, London, for referring the patient.
Conflicts of interest
There are no competing interests. NAB has no disclosures. DC receives research support from the Multiple Sclerosis Society of Great Britain and Northern Ireland, and holds stock in GlaxoSmithKline. MSM serves on the advisory board for Allergan and St Jude Medical, and has received payment for the development of educational presentations from Allergan, Merck Sharpe and Dohme Ltd, and Medtronic. This work was undertaken at University College London/University College London Hospitals and was funded in part by the Department of Health NIHR Biomedical Research Centres funding scheme.