Sustained response to botulinum toxin in SUNCT syndrome

Abstract

Introduction: Short-lasting, unilateral, neuralgiform headache attacks with conjunctival injection and tearing (SUNCT) is a rare condition grouped in the category of trigeminal autonomic cephalalgia. The syndrome is characterized by very frequent, unilateral attacks of pain in the ocular and periocular region accompanied by ipsilateral conjunctival injection and lacrimation. The aetiology is unknown, although there have been reports of cases secondary to structural lesions, and treatment is usually ineffective.

Patients and Methods: We present the case of a patient diagnosed with SUNCT refractory to pharmacological treatment; duration of the SUNCT was 20 years. OnabotulinumtoxinA was infiltrated at four points around the orbit.

Results: The pain showed a dramatic response to onabotulinumtoxinA infiltration. Efficacy has been maintained for 18 months with 3-monthly infiltrations, with no adverse effects.

Conclusions: OnabotulinumtoxinA should be added to the limited therapeutic arsenal available for the treatment of refractory cases of SUNCT.

Introduction

The term ‘short-lasting, unilateral, neuralgiform headache attacks with conjunctival injection and tearing’ (SUNCT) was coined by Sjaastad et al. (1) in 1989 based on a previous description of the syndrome to which it refers, published in 1978 (2). The condition is characterized by recurrent attacks of very intense, unilateral neuralgiform-type headaches in the orbit or periorbital region and associated with ipsilateral autonomic phenomena, such as conjunctival injection and lacrimation. The headaches are of sudden onset and resolution, lasting for 5–240 seconds, and typically present a plateau-like temporal profile, although they may occasionally have a saw tooth pattern, with recurrent episodes of differing intensity. Although the attacks can develop spontaneously, in some cases they are triggered by mechanical or sensory stimuli. From a pathophysiological point of view, the symptoms are suggestive of an activation of the parasympathetic supply of the face, producing the characteristic autonomic phenomena of the syndrome and of the associated cardiovascular phenomena (3,4). Nociceptive stimulation of the first branch of the trigeminal nerve would induce cranial parasympathetic activation with a characteristic lacrimation response mediated by neurotransmitters, such as acetylcholine and vasoactive intestinal peptide (3). In addition, there appears to be clear evidence of the influence of the hypothalamus as an initiator of the condition or as an integrating element in the dysfunctional antinociceptive control circuit (5); however, the therapeutic implications of this factor are unknown.

SUNCT was included in the 2004 review of the International Classification of Headache Disorders (ICHD-II), and the diagnostic criteria were established (6). It is a rare disorder that is more common in men (male-to-female ratio 2 to 1), and onset is typically between 40 and 70 years of age. Although its aetiology and pathogenesis are unknown, there have been case reports of SUNCT secondary to vascular malformations (7), hypophyseal adenomas (8), prolactinomas (9), multiple sclerosis (10) and other disorders. SUNCT is considered to be refractory to treatment, although some studies have suggested that certain drugs, such as lamotrigine (11), gabapentin (12), topiramate (13), carbamazepine (14) and zonisamide (15), can be effective; also methylprednisolone has been useful for short-term prevention (16). Neurosurgical approaches have also been attempted, from nerve blocks (14) to bilateral occipital nerve stimulation (17), deep brain stimulation (18) or gamma knife surgery (19).

Patient and Methods

The patient was a 55-year-old man with a past history of hypertension controlled on atenolol. He was seen in neurology outpatients for a 20-year history of headache presenting as episodes of moderate to severe right orbital and periorbital pain that occasionally radiated to the ipsilateral maxillary and temporal regions. The pain occurred almost every day, with remissions that never exceeded 1–2 weeks. The patient described the pain as piercing and stated that the episodes, which lasted for 1–2 minutes, recurred with a variable frequency of 20–30 episodes over the course of a day. Pain attacks were associated with prominent right conjunctival injection and ipsilateral tearing; sweating of the forehead and mild rhinorrhoea accompanied most of the attacks. Although the headaches occurred mainly during the day, there were occasional episodes at night. In sporadic attacks he reported specific triggers, including environmental cold, chewing and shaving. An attack was observed in the clinic by gently touching the right infraorbital region. During periods of multiple attacks, he reported having to shave at night, when the attacks stopped.

Initially the patient had been evaluated in the neurosurgery department, where he was diagnosed with trigeminal neuralgia, which was treated by thermocoagulation of Gasser’s ganglion and various anticonvulsants, analgesics and non-steroidal anti-inflammatory drugs, observing an improvement only with carbamazepine. In 2002 he was seen in neurology outpatients, where a diagnosis of SUNCT was established, based on the criteria of the International Headache Society. Blood tests and cranial magnetic resonance imaging were normal. Treatment was started with carbamazepine, which led to a transitory improvement, with the subsequent addition of topiramate, which had no effect whatsoever. Different drugs were then tried, including antiepileptic drugs (phenytoin, valproate, clonazepam, pregabalin), non-steroidal antiinflammatory drugs (indomethacin, naproxen) and others (verapamil, amitriptyline, opioids), but the effects were variable and the patient was lost to follow-up. In 2009 he returned after a severe exacerbation of the pain, reporting more than 30 attacks a day with an intensity of 9–10 on a visual analogue pain scale (VAS). Treatment was started with lamotrigine in monotherapy, which produced a significant improvement both in the pain and in the autonomic symptoms. After a few months, gabapentin was added to the treatment, which produced a reduction both in the frequency of the attacks and in the intensity of the pain. At the end of 2009, the severity of the syndrome increased, and clomiphene (20) was added to the previous drugs, but had no beneficial effect. After this last therapeutic failure, and despite finding no publications on the use of onabotulinumtoxinA for the treatment of SUNCT after an exhaustive review of the literature, the patient was offered treatment with onabotulinumtoxinA as reported in the treatment of cluster headaches (21). Pre-injection VAS scores ranged between 8 and 10. OnabotulinumtoxinA was infiltrated at four points around the orbit, injecting 10 U at each site. Treatment with lamotrigine (900 mg/d) and gabapentin (1600 mg/d) was continued. Within a few weeks the intensity of the headaches started to decrease and there was a dramatic fall in the number of attacks. There was no wearing off effect from the prior injection in the days to weeks before the next injection. Since that time, we have performed infiltrations every 3 months, and the patient has remained stable up to the time of writing this article. The intensity of the pain varies between 2 and 3 on the VAS, with occasional attacks of intensity 5. The patient now has an active social life; before treatment with onabotulinumtoxinA he had remained shut in at home for days at a time because of the disabling pain. At the time of writing, the patient has chosen to continue on the pre-injection dose of lamotrigine and gabapentin resulting from his great fear of a possible deterioration in his symptoms. Recently the patient has been having six or eight attacks a week, almost all during the day. The follow-up was 2.5 years, during which we have given him ten cycles of onabotulinumtoxinA.

Discussion

In a very recent trial Wu et al. (22) have demonstrated the efficacy of onabotulinumtoxinA in the treatment of trigeminal neuralgia; they treated 40 patients, achieving a significant reduction in pain intensity and frequency of pain attacks, with few treatment-related adverse events. OnabotulinumtoxinA has an antinociceptive effect in the control of headache; recently PREEMPT trials have proven more effectiveness than placebo in the treatment of chronic migraine, and opened a promising path to the treatment of this illness (23–26). Also, there is preliminary evidence in its effectiveness on cluster headache (21).

Relieving of pain in chronic migraine is thought to be a consequence of blocking peripheral signals to the central nervous system and indirectly inhibit central sensitization. The mechanisms of analgesic effect of onabotulinumtoxinA are not well known; however, there is evidence of the possibility that onabotulinumtoxinA prevents the release of neurotransmitters other than acetylcholine, such as substance P, calcitonin gene-related peptide and glutamate, which are involved in pain perception and neurogenic inflammation (27–29). The explanation of efficacy of onabotulinumtoxinA in SUNCT syndrome may be related to those mechanisms and the possible action on the hypocretinergic system, which appear to be involved in the genesis of the attacks (5,30). In any case, the possible mechanism of action of onabotulinumtoxinA in SUNCT syndrome is unknown and these hypotheses are merely speculative.

The aetiology and pathophysiology of the syndrome are unknown and at present there is no drug that is effective in all cases. In view of its profile of adverse effects, we consider that onabotulinumtoxinA should be evaluated for the second-line or adjuvant treatment of patients who do not show an adequate improvement with antiepileptic drugs.