Obscure diagnosis - hemicrania continua
Our series of uncommon conditions continues with consultant neurologist Dr Richard Davenport, and neurology registrar Dr Louise Davidson exploring hemicrania continua
A few weeks after striking her head on the tailgate of her car, a 58-year-old female reported the onset constant pain affecting the right periorbital, temporal and parietal areas. Although constant, the pain varied in severity. Much of the time it was of moderate intensity, which annoyed her but allowed life to continue, but up to three times per week it would become incapacitating, associated with intense agitation and watering of the right eye.
She was previously well, and had a history of migraine without aura as a teenager that had settled in her early 20s. She was on no medication, and otherwise well. In the five months she had experienced the symptoms, she had visited her GP and local emergency department (ED) on numerous occasions, undergone two CT head scans, one lumbar puncture, a temporal artery biopsy and blood tests, all of which were normal. Various diagnoses had been suggested, including cluster headache, but all attempts at treatment had failed. She was awaiting a routine neurology outpatient appointment when she was seen in the ED by a neurology registrar, who recognised the history and diagnosed HC. Indometacin 50mg tds brought rapid and complete relief of her symptoms, confirming the exquisite sensitivity of HC to this drug, as several previous NSAIDs had made no difference.
Hemicrania continua (HC) is a Latin term that means half the head hurts.1 It is used to describe a rare primary headache disorder characterised by continuous unilateral pain, with episodes of exacerbations of pain associated with autonomic features.2 The hallmark of this condition is the absolute response to indometacin.2 The prevalence and pathophysiology of HC remain unknown.2,3 Although rare, HC is under-recognised and often misdiagnosed.4,5 Correct and early diagnosis is vital as HC can be a very disabling condition. Remission of symptoms will only occur with the appropriate treatment and will allow patients to maintain a good quality of life.5,6
In 1981, a response to indometacin was reported in 54 patients with a strictly unilateral, continuous headache, who were described as having a variant of cluster headache.2,7 The disorder was subsequently labelled HC in 1984, following a description of two patients.2,8 These initial descriptions were followed by over 100 case reports.2,6 Many consider HC to be part of the trigeminal autonomic cephalalgias (TACs) as the phenotype is similar to cluster headache and paroxysmal hemicrania.2,9
HC was first recognised in the ICHD-II criteria under the ‘Other primary headache disorder’ category and defined as a strictly unilateral headache of more than three months duration, without pain-free intervals and associated with either conjunctival hyperaemia or tearing, nasal congestion or rhinorrhoea, or ptosis or miosis.10 In 2010, one study reported cases of HC with side-alternating pain and a wider proportion of autonomic features.2 This led to revision of the diagnostic criteria in ICHD-3 Beta (see table 1) and its inclusion under the ‘Trigeminal autonomic cephalalgia’ category;11 the new classification has not found favour with all observers. 12
ICHD-3 beta diagnostic criteria for hemicrania continua11
A. Unilateral headache fulfilling criteria B-D
B. Present for more than three months, with exacerbations of moderate or greater intensity
C. Either or both of the following:
1. At least one of the following symptoms or signs, ipsilateral to the headache:
a) Conjunctival injection or lacrimation
b) Nasal congestion or rhinorrhoea
c) Eyelid oedema
d) Forehead and facial sweating
e) Forehead and facial flushing
f) Sensation of fullness in the ear
g) Miosis or ptosis
2. A sense of restlessness or agitation, or aggravation of the pain by movement
D. Responds absolutely to therapeutic doses of indometacin
E. Not better accounted for by another ICHD-3 diagnosis
The new classification recognises episodic and chronic forms of HC,.11 Episodic forms are referred to as ‘remitting subtypes’ where patients may become pain free for one day or more without treatment. Chronic or ‘unremitting subtypes’ are defined as pain that is continuous for one year without periods of remission for one day or more.2,11
The incidence and prevalence of HC is unknown.2 Although thought to be rare, it is probably under-recognised and often misdiagnosed.4,5 An epidemiological study of headache patients suggested a prevalence of one in 1,838, although this study had significant methodological problems.2,13 The condition can occur at any age, with one study quoting an average age of 38.7 years with a slight female predominance of 1.6:1.2
A typical presentation of HC is a mild to moderate, continuous and strictly unilateral headache in the temporal, periorbital or occipital regions.2,6 This has been challenged by a study that suggested that the distribution of pain can be more widespread and include the face and neck.2 An acute exacerbation usually consists of a severe headache, with a duration of hours or days, associated with ipsilateral autonomic features.2,14 The more frequently-observed autonomic features include conjunctival injection and lacrimation, rhinorrhoea and ptosis or miosis.4 More atypical cases have been reported, and autonomic symptoms may not accompany every exacerbation.14 There have been reports of autonomic features occurring contralateral to the pain, and in some cases, bilateral. There are also cases of the pain changing sides.15,16
Two-thirds of the cases reported had a personal or family history of migraine, and it was suggested that this reflects a predisposition to primary headache disorders.2 This is supported by the observation that patients with other forms of TACs have a history of migraine.2 To complicate matters, there can be simultaneous migrainous features such as photophobia, phonophobia and nausea during HC.6 One study described a cohort of 10 patients in which all had a unilateral, continuous headache sensitive to indometacin.17 70% had autonomic features and 30% migrainous features, but only 10% responded to migraine treatment.17 In one series, the behaviour of patients during acute exacerbations was predominantly agitation and restlessness (69%), although patients have also reported a worsening of the pain during movement.2
Conditions that can masquerade as HC include other primary headache disorders, such as unilateral chronic migraine, new daily persistent headache (usually migrainous), and other TACs such as cluster headache and paroxysmal hemicrania.2 A careful history and positive response to indometacin will distinguish HC from migraine and new daily persistent headache.2 Differentiating HC from other TACs can be more challenging.2 HC has less prominent autonomic features than paroxysmal hemicrania and the background pain in HC is more severe.2 The painful exacerbations are also usually less frequent and longer in duration than paroxysmal hemicrania, where they are often very frequent and short, lasting for minutes.2
One study described 25 patients that satisfied the ICHD-II criteria for HC out of a total of 1,612 patients attending an Italian headache centre during a period of three years.5,18 The median time to diagnosis was five years, with 85% of patients visiting a doctor within five months of symptom onset.5,18 52% had been incorrectly diagnosed with migraine, supportive of the notion that migrainous features are not uncommon in HC,5 and 40% of these patients met ICHD-II criteria for migraine during an exacerbation.5,18 28% of patients had previously been misdiagnosed as cluster, perhaps because patients reported the severe exacerbations and not the persistent milder headache.5,18 Other case reports have described cases of HC that were misdiagnosed as cervicogenic headache, sinus headache, temporomandibular disorders and dental pain, which not infrequently led to unnecessary treatments such as tooth extraction or ENT surgery.5,19,20
The pathophysiology of HC is unknown,3 and it is regarded as an idiopathic disorder.6 However, there have been case reports of ‘secondary HC’ that are also often responsive to indometacin.6,21 Possible underlying causes have included cervical disc herniation, trauma and intracranial tumours. In our case, we doubted the minor head trauma was significant, but perhaps unsurprisingly, the patient thought otherwise..
As the clinical phenotype of HC overlaps with cluster headache, paroxysmal hemicrania and migraine, it has been hypothesised that they share the same pathophysiological mechanism.6 Studies with functional MRI have demonstrated activation of the contralateral posterior hypothalamus and ipsilateral dorsal pons in HC. It has been suggested that there is disinhibition of the posterior hypothalamus, resulting in the release of the trigeminal autonomic reflex that subsequently causes headache.2,6,22,23,24
How can GPs diagnose HC with certainty?
The diagnosis of HC is clinical and relies on a clinical history, normal neurological examination and a positive response to indometacin (see below).6 Recognising that patients may have more than one type of primary headache disorder such as migraine and HC is important, and asking patients to keep a headache diary is often helpful in highlighting this. In addition, it is noteworthy that there may be superimposed migrainous features during HC exacerbations which should not deter a trial of indometacin. Establishing whether there is a less severe, persistent headache between acute episodes is key.
However, the diagnosis can be difficult if there is a history of analgesia overuse, which has led to a chronic daily headache. In this situation, the first step is to encourage cessation of all regular analgesics. If a continuous, unilateral headache persists, then a trial of indometacin is warranted.6,25
Due to the small possibility of an underlying cause, it is recommended that head MRI be performed in all patients, although the identification of relevant abnormalities is likely to be exceedingly low, and probably outweighed by incidental findings.21
Prompt diagnosis and early treatment is important in HC to reduce morbidity.6 Due to the absence of prospective controlled studies, there is no good evidence base for treatment, so the management of HC is largely anecdotal and guided by clinical experience and assessment of retrospective case series.6
Indometacin remains the gold standard treatment, although the mechanism of action is not known.2,6 It should be used as a therapeutic test for all patients presenting with continuous, chronic, unilateral headache,6,26 and remains the first-line treatment for long-term management.2,6,11 The suggested starting dose is 25mg three times daily, titrated gradually depending on response and tolerability. Most patients will achieve remission at a dose of 100 to 150mg daily in divided doses.2 Treatment failure should only be considered if the patient is not responsive to a total daily dose of 300mg.27
Once an effective dose is established, this should be continued for several weeks, following which the dose should be gradually tapered until the lowest effective dose is reached.6 Tolerability is a problem, particularly upper gastrointestinal symptoms and renal failure.6 The most common cause of treatment failure is the development of adverse effects. Adverse effects are frequently dose-dependent, reinforcing the need for establishing the lowest effective dose.6 Research has shown that, over time, 42% of patients were able to reduce their dose by up to 60% and remain pain free.6,28 Another study has suggested that the addition of melatonin to indometacin can help reduce the dose required for remission.6,29
Where indometacin is contraindicated or not tolerated, there have been reports of gabapentin, amitriptyline and topiramate acting as beneficial prophylactic agents.6 In addition, greater occipital nerve blocks with methylprednisolone and lidocaine have been reported in some patients.30 Oxygen, sumatriptan, carbamazepine, valproate, aspirin, ibuprofen and verapamil are generally not effective.6 More recent studies looking at the benefit of botulinum injections and radiofrequency ablation have shown possible promise.31,32
When to refer
If the history is suggestive, that is, a persistent unilateral headache with or without autonomic features, then a trial of indometacin in primary care is reasonable, provided there are no contraindications and the possibility of the headaches being caused by analgesia overuse has been excluded. However, given that this may commit patients to lifelong treatment, the potential need for head MRI and atypical cases, a referral to neurology services is appropriate in most cases.
Dr Richard Davenport is a consultant neurologist at Western General Hospital, Edinburgh.
Dr Louise Davidson is a neurology registrar at Western General Hospital, Edinburgh.
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