Abstract
Hemicrania continua (HC) is a strictly unilateral, side-locked without side shifting, continuous headache of moderate intensity, with superimposed exacerbations of severe intensity that are accompanied by at least one of the following cranial autonomic features ipsilateral to the side of the pain: conjunctival injection, lacrimation, nasal congestion, rhinorrhoea, ptosis or miosis. A complete response to indomethacin is a prerequisite for diagnosis by the classification criteria of the International Headache Society (IHS) (1).
HC was first described by Medina and Diamond in 1981 (2). Sjaastad and Spierings described two further cases and coined the term ‘hemicrania continua’ (3). Since then, over 130 cases have been described in the literature. HC was thought to be a very rare syndrome, but headache clinics which have systematically sought this entity have rapidly identified significant number of patients with HC, thereby suggesting that the condition is under-diagnosed and more common than has been appreciated (4, 5). The disorder has a female preponderance with a sex ratio of 2.4 : 1. It usually begins in adulthood, at a mean age of 28 years, although the onset ranges from 5 to 67 years (4).
The pathophysiology of HC is poorly understood, though developments in functional neuroimaging have provided new insights. A positron emission tomography study in HC demonstrated activation of the contralateral posterior hypothalamus, ipsilateral dorsal rostral pons and the ipsilateral ventrolateral midbrain region straddling the red nucleus and the substantia nigra (6). These brain regions are likely to play a pivotal role in the pathophysiology of this syndrome.
The natural history of HC is poorly defined, although it appears to be a chronic condition in most patients (7). Patients have an enduring response to indomethacin 25–300 mg daily without developing tachyphylaxis, though between a quarter to half develop gastrointestinal side-effects (7, 8). Patients who cannot tolerate indomethacin pose a difficult management challenge as no other drug is consistently effective in HC.
We describe two HC patients with previously unreported responsiveness to topiramate. In addition, we report a patient with the unusual presentation of side-alternating attacks.
Case reports
Case 1
A 40-year-old woman presented in June 2004 with a history of a constant headache since 1991. There were no precipitants at the onset of the headache. She described a strictly unilateral headache on the right centred over the parietal and occipital regions with radiation to the forehead and the orbit. The intensity of the headache fluctuated between moderate and severe. It had a throbbing quality and was associated with ipsilateral lacrimation, nausea, phonophobia and worsening with movement. She denied all other migrainous and cranial autonomic features. She described an infrequent visual aura in the form of flashing lights in the right visual field for 1–2 min. The headache was exacerbated by alcohol, over-sleeping, lack of sleep, over-exertion and menstruation.
She described migraine with aura since childhood, occurring three to five times annually, with each episode lasting 1–2 days. These headaches were bilateral, centred on the forehead and temples, severe in intensity, and had an aching or throbbing quality. They were associated with nausea, photophobia and phonophobia and were worsened by movement. She denied vomiting and any cranial autonomic features. She reported a visual aura in the form of flashing lights in the right visual field for 1–2 min at the peak of the headache. These headaches were triggered by chocolate, alcohol, bright lights and menstruation.
The past medical history included: a right-sided head injury at the age of 2 years, following which she was left with a mild residual left hemiatrophy and hemiparesis, iron-deficiency anaemia secondary to menorrhagia, restless leg syndrome and anxiety neurosis. Her medications included amitriptyline 50 mg daily and cocodamol two tablets twice daily, both of which were ineffective. There was no family history of headaches. She was a non-smoker and rarely drank alcohol.
General and cranial nerve examination was normal. She had left hemiatrophy. Tone was increased in the left limbs. She had a pyramidal distribution left hemiparesis of Medical Research Council grade 4 to 4+. The left-sided reflexes were brisk and the left plantar response was extensor. The sensory examination revealed reduced pin prick, soft touch and temperature in the left leg. Co-ordination and gait were normal.
Routine haematological and biochemical screening was normal. Magnetic resonance imaging (MRI) scan of the brain revealed a region of encephalomalacia in the right fronto-temporal area, with some associated intracranial calcification. The patient was started on indomethacin 25 mg t.d.s., which rendered her completely pain-free within 2 days. On stopping indomethacin 2 weeks later, the headache recurred within 3 days. This exquisite response to indomethacin confirmed the diagnosis of HC.
Indomethacin was restarted and she remained pain free over the next month but then complained of facial flushing for an hour after taking each dose of indomethacin. She was started on topiramate, in a dose which was gradually increased to 50 mg b.d. Since stopping indomethacin, she has remained pain free on topiramate for 9 months. Reduction of the topiramate dose on two occasions led to recurrence of the headaches within 2–3 days. She has experienced no side-effects from topiramate.
Case 2
A 64-year-old man presented in April 2004 with a history of a constant headache since 1985. There were no precipitants at the onset of the headache. He described a strictly unilateral headache that was usually on the left side, but switched over to the right side once a month for 2–3 days. The pain was centred over the parietal and occipital regions. The intensity of the headache fluctuated between moderate and severe. It had a throbbing quality and was associated with ipsilateral lacrimation and ptosis, phonophobia and worsening with movement. He denied all other migrainous and cranial autonomic features. He reported a visual aura in the form of flashing lights for approximately 5 min on one or two occasions per month. The headache was exacerbated by psychological stress, lack of sleep or over-sleeping.
The past medical history included: duodenal ulcers diagnosed on gastroscopy and attributed to non-steroidal anti-inflammatory drugs (NSAIDs), depression secondary to the headache since 1993, chronic obstructive pulmonary disease, appendectomy and a left hernia repair. His medications included pizotifen 1.5 mg daily, cocodamol two tablets four times daily and paracetamol 1 g as required, all of which were ineffective. He was also taking ranitidine 150 mg twice daily, mirtazapine 30 mg once nocte, beclomethasone inhaler two puffs twice daily and salbutamol inhaler as required. He had previously tried aspirin and naproxen, which were partially effective but had to be discontinued when he developed duodenal ulcers. A trial of amitriptyline had been ineffective. There was no family history of headaches. He smoked 25–50 g of tobacco per week and rarely drank alcohol.
Physical and neurological examination was entirely unremarkable. Routine haematological and biochemical screening was normal. MRI of the brain was normal.
He was started on indomethacin 25 mg t.d.s., with which he was rendered completely pain free after the first dose. This rapid response to indomethacin confirmed the diagnosis of HC. He remained asymptomatic while taking indomethacin but developed dyspepsia and diarrhoea, thereby necessitating cessation of indomethacin, which led to recurrence of the headache. He was then started on rofecoxib 25 mg twice daily which rendered him pain free but he felt non-specifically unwell. Rofecoxib was substituted with celecoxib 200 mg twice daily, which rendered him pain free but he developed dyspepsia.
He was started on topiramate. The dose was gradually increased to 100 mg b.d. On stopping celecoxib, the patient remained pain-free on topiramate for 3 months. However, he developed intolerable side-effects with topiramate, consisting of cognitive slowing, poor memory, aggressive behaviour, depression and paraesthesias in the hands. When topiramate was stopped the headache recurred. He is currently undertaking a trial of gabapentin.
Discussion
The two patients we describe fulfil the IHS diagnostic criteria for HC except the requirement for strictly unilateral, side-locked without side-shifting headache in case 2. Though the majority of HC patients suffer from strictly unilateral headaches without side shift, three patients with attacks that alternated sides (9–11) and three with bilateral attacks have been reported (12). Our patient provides further support for the notion that the headache can alternate sides in HC, although this is a rare presentation.
Both patients demonstrated an exquisite response to indomethacin but developed side-effects that necessitated cessation of treatment. Patients who cannot tolerate indomethacin pose a difficult management challenge as no other drug is consistently effective in HC. Other NSAIDs are generally of little or no benefit. Drugs reported to be partially or completely effective, usually in isolated cases, include aspirin (13), ibuprofen (7, 14), naproxen (15), piroxicam β-cyclodextrin (16) and paracetamol with caffeine (15).
There has been some limited success in treatment of HC with the cyclooxygenase-2 (COX-2) inhibitors, rofecoxib and celecoxib; three of nine patients treated with rofecoxib and three of five patients treated with celecoxib were rendered pain free (17). However, prolonged use of both these agents has recently been linked with an increased risk of myocardial infarctions and strokes and this culminated in the withdrawal of rofecoxib from the market worldwide (18). In view of this, the available COX-2 inhibitors should be prescribed only with great caution in HC.
Our two patients demonstrated a complete response to topiramate and withdrawal of the agent rapidly led to recurrence. This is the first report of the effectiveness of topiramate in the treatment of HC. However, this drug's use was limited by side-effects in one of our patients. The dose of topiramate required to give complete relief of pain was somewhat less than that usually needed for the anticonvulsant effect of the drug. It is interesting to note that topiramate has also been reported to be beneficial in prophylactic treatment of migraine (19), chronic daily headache (20), trigeminal neuralgia (21), cluster headache (22) and short-lasting unilateral neuralgiform headache with conjunctival injection and tearing (23).
Topiramate has multiple mechanisms of action (24). These include blockade of the voltage-mediated sodium channels, enhancement of GABA-mediated chloride influx to GABAA, antagonism of the glutamate kainate/AMPA receptor and carbonic anhydrase inhibition. The mechanism(s) of action responsible for the beneficial effect in various headache syndromes is currently unknown. Whatever the mechanism, if the favourable response observed in our patients can be confirmed in other cases, it would broaden the therapeutic armamentarium available for the treatment of this severe and sometimes incapacitating condition.