Abstract
Short-lasting unilateral neuralgiform headache attacks with conjunctival injection and tearing (SUNCT) is a rare and debilitating headache form generally unresponsive to treatment. Following a recent report of a SUNCT patient who responded to lamotrigine, we tried this drug in two new SUNCT patients, reported here. In both cases prophylaxis was successful, suggesting lamotrigine might be the first effective treatment for this rare and debilitating headache syndrome.
Introduction
Short-lasting unilateral neuralgiform headache attacks with conjunctival injection and tearing (SUNCT), first described by Sjaastad et al. in 1989 (1), is a distinctive and rare headache form characterized by brief side-locked unilateral pain episodes accompanied by local autonomic manifestations. The attacks typically last 5–120 s, are stabbing or burning in quality, abrupt in onset, and accompanied by lacrimation, conjunctival injection, and nasal congestion or rhinorrhoea, all ipsilateral to the pain (2). These pain episodes usually occur in periods separated by spontaneous remission. The frequency varies from less than one per day to more than 30 per hour. A few patients with typical SUNCT syndromes had a posterior fossa lesion (3).
The pathophysiology of primary SUNCT is largely unknown. Goadsby & Lipton (2) have proposed classifying this headache form among the trigeminal-autonomic cephalalgias (TACs), a nosological category in which, they argue, the pain is due to activation of trigeminal afferents, while the autonomic features are the result of cranial parasympathetic outflow (the so-called trigemino-facial reflex). In a recent functional magnetic resonance imaging (MRI) study May et al. found activation of the posterior hypothalamic grey matter homolateral to the pain during spontaneous SUNCT attacks, and suggested this area may play a crucial role in SUNCT pathogenesis (4).
The treatment of SUNCT is problematic, since it is frustratingly unresponsive to pharmacotherapy. Non-steroidal anti-inflammatory drugs, calcium channel blockers, sumatriptan, and carbamazepine are generally of little benefit (5, 6). Recently, D'Andrea et al. reported a SUNCT patient who responded to lamotrigine (7). We describe two new SUNCT patients who were successfully treated with this drug.
Case reports
Case A
This 72-year-old woman has suffered from intense, brief (5–120 s) unilateral headache attacks for 9 years. Described as like electric shocks or stabs, they occur in the right fronto-temporal region, and are accompanied by conjunctival injection, abundant lacrimation, moderate ptosis and rhinorrhoea, all homolateral to the pain. Nausea, vomiting, photophobia and phonophobia are absent. Precipitating factors are sudden movements of the head or neck, mastication, swallowing, brushing the teeth and drying the face. Initially the attack periods, characterized by around 15 attacks per day, lasted about 15 days and recurred about 3–4 times a year, typically in spring or autumn.
When the woman came to our attention an ongoing attack period had lasted 6 months and crises were occurring every 10 min, up to a 100 times a day, repeatedly waking her during the night. There was no family history of headache. The patient was hypertensive but this was well controlled with calcium antagonists and ACE inhibitors. General and neurological examinations, and cerebral MRI were unremarkable.
Carbamazepine (400 mg/day) was tried with no effect on the frequency or severity of the attacks; this was stopped after the appearance of instability and vertigo. We next tried indomethacin (50 mg tid), but this was withdrawn after 7 days due to inefficacy. We then tried lamotrigine, increasing the dose every 5 days (25, 50, 75 mg/day). At 75 mg/day there was a reduction in headache frequency and intensity but after a week the crises returned to their previous levels. We increased the dose to 100 mg (25 mg qid) and again there was benefit, but after 10 days the crises returned as before. We further increased the dose to 125 mg/day and the headaches almost totally disappeared. Six months later the patient is continuing with the medication at this dose which is well-tolerated. She has sporadic days, apparently coinciding with changes in the weather, on which she suffers one or two attacks. On occasions she has neglected to take the medication and the attacks have returned—indicating that the benefit is due to lamotrigine and that her condition is now chronic.
Case B
This 58-year-old man has suffered a severe head pain symptomatology for 5 years. The attacks, of duration about 10 s and frequency up to 200 per day (concentrated in the morning), affect the external corner of the right eye and have a burning quality or are like electric shocks. They are accompanied by conjunctival injection, abundant lacrimation, rhinorrhoea and facial reddening homolateral to the pain. Nausea, vomiting and phonophobia are absent. Triggering factors are sudden movements of the head and neck, eye movements, mastication, strong light, cold air, and touching the right fronto-parietal region of the head. Compression of the right eyebrow reduces the pain. The attacks occur in periods lasting about 15 days which recur two-to-three times a year. One attack period lasted a month.
Detailed elicitation of history revealed nothing remarkable; family history was negative for headache; general and neurological examinations and cerebral MRI were also normal. During a previous crisis period (April 1999) the patient had been given indomethacin (50 mg tid for 10 days) without benefit. We first saw the patient at the beginning of March 2000, 7 days after the onset of a new attack period. The attacks rapidly increased in frequency and intensity and on day 10 of the crisis period, when we decided to try lamotrigine, were occurring every 2 min. Starting at 50 mg/day (25 mg bid) we increased the dose to 75 mg/day (25 mg tid) after 3 days and to 100 mg/day (25 mg qid) after another 3 days. After 48 h at the latter dosage the crises almost completely disappeared. Sporadic attacks still occurred (maximum four per day) but were less intense and better tolerated.
To assess whether the improvement was due to the medication or to spontaneous resolution of the pain period, with the patient's agreement we tapered the dose in 25 mg/day steps (2 days each) down to zero. The attacks worsened again (seven-to-eight per hour) but were considered by the patient not frequent and severe enough to reinstate lamotrigine. Seventeen days after discontinuation of lamotrigine the attacks had disappeared.
Discussion
The two new SUNCT cases described here did not respond to other attempts at pharmacological prophylaxis but did improve with lamotrigine. In the first case the attacks had been occurring with high frequency on a daily basis for 6 months and neither carbamazepine nor indomethacin had had any effect. Lamotrigine dramatically reduced the frequency and intensity of the attacks in this woman. When she stopped taking it the attacks reappeared, only to disappear when she resumed regular assumption of the drug. In the second patient indomethacin had been ineffective in a previous crisis period. In the latest crisis period the frequency and intensity of attacks were increasing on a daily basis and on day 10 we started lamotrigine. Two days after reaching 100 mg/day the headaches improved markedly. While tapering the dose to zero the crises worsened, suggesting the improvement was due to the drug. In both cases lamotrigine was well-tolerated and no undesired side-effects were reported. However, since lamotrigine was given openly in both cases we cannot definitively exclude that the improvements were due to a placebo effect. Nevertheless, our experience, together with that of D'Andrea (7), suggests that lamotrigine might be the first effective SUNCT prophylactic, and certainly indicates it is worth trying the drug in future SUNCT cases.
Lamotrigine is a new anti-epileptic drug thought to act by stabilizing the neuronal sodium channel (8). Interestingly, it is also effective against trigeminal neuralgia (9), a short-lasting headache form classified by Goadsby & Lipton (2) among the trigeminal cephalalgias without autonomic involvement. Whether, from the clinical point of view, SUNCT should be regarded as a special form of trigeminal neuralgia or a special form of cluster headache disorder is a matter of debate (10). The dichotomy is brought into relief by noting that SUNCT appears as a variant of cluster headache differing from typical forms by the extreme brevity of the attacks, which are nevertheless often induced by factors that typically trigger trigeminal neuralgia. SUNCT and trigeminal neuralgia are distinguished principally by the presence of autonomic phenomena in the former. The efficacy of lamotrigine in trigeminal neuralgia and in SUNCT (if confirmed) suggests that SUNCT may be nosologically closer to trigeminal neuralgia than to cluster headache disorders, particularly since drugs such as verapamil, lithium, methysergide, prednisone, indomethacin and sumatriptan, which are active against cluster headache (11, 12), are almost always ineffective against SUNCT (5, 6).
The mechanism of action of lamotrigine in trigeminal neuralgia in unclear. The efficacy of the drug in controlling neuropathic peripheral pain (as in diabetic neuropathy (13)) suggests that it may act directly on the nerve. Since lamotrigine also inhibits the firing of central neurones (8) it cannot be excluded that it has a central action in SUNCT, perhaps by reducing the hypothalamic activation observed on functional MRI in this headache form.
If lamotrigine were confirmed as an effective prophylactic of SUNCT attacks this might therefore help to clarify the mechanisms underlying this syndrome as well as its relationship with the other lamotrigine-responsive short-lasting unilateral cephalalgias (trigeminal neuralgia) in which autonomic manifestations are absent.