Short-lasting unilateral neuralgiform headache attacks: Treatment and prognosis

INTRODUCTION — The trigeminal autonomic cephalalgias (TACs) are a group of primary headache disorders characterized by unilateral trigeminal distribution pain that occurs in association with ipsilateral cranial autonomic features [1,2]. The TACs include cluster headache, paroxysmal hemicrania, short-lasting unilateral neuralgiform headache attacks, and hemicrania continua [3].

There are two subtypes of short-lasting unilateral neuralgiform headache attacks [3]:

●Short-lasting unilateral neuralgiform headache attacks with conjunctival injection and tearing (SUNCT)

●Short-lasting unilateral neuralgiform headache attacks with cranial autonomic symptoms (SUNA)

Although SUNCT and SUNA were once considered to be refractory to therapy, beneficial responses with several medications have been reported in small numbers of patients. However, the evidence consists mainly of case reports and small case series.

This topic will review the treatment and prognosis of SUNCT and SUNA. The clinical features and diagnosis of these syndromes are reviewed elsewhere. (See "Short-lasting unilateral neuralgiform headache attacks: Clinical features and diagnosis".)

Other TACs are also discussed separately.

●(See "Cluster headache: Epidemiology, clinical features, and diagnosis" and "Cluster headache: Treatment and prognosis".)

●(See "Paroxysmal hemicrania: Clinical features and diagnosis" and "Paroxysmal hemicrania: Treatment and prognosis".)

●(See "Hemicrania continua".)

ACUTE MANAGEMENT — We suggest acute therapy with an intravenous lidocaine infusion for patients with frequently recurring and debilitating attacks of SUNCT or SUNA. For patients who do not respond to or are unable to tolerate a lidocaine infusion, we offer alternative medications used for the acute treatment of other trigeminal autonomic cephalgias (TACs) (table 1).

For patients with infrequent or less severe attacks, we treat with a preventive medication alone.

Frequent and debilitating attacks — For patients with frequent and debilitating attacks of SUNCT or SUNA, we suggest initial acute therapy with an intravenous lidocaine infusion. In addition, we typically start a preventive medication after lidocaine infusion has completed to help prevent recurrence of attacks. For those patients already taking a preventive medication, we typically continue this agent during acute infusion therapy to reduce headache recurrence. (See 'Preventive management for all patients' below.)

Lidocaine — Intravenous lidocaine may be particularly useful for some patients with SUNCT who experience acute, severe exacerbations characterized by frequent, easily triggered, high-intensity pain [4,5]. Such patients may not be able to eat or drink because these actions trigger attacks, and the need for acute intervention is urgent.

Limited data suggest that SUNCT and SUNA are responsive to treatment with parenteral lidocaine given in the hospital for one to seven days; the supporting evidence comes from small case series [4-9]. Among 15 patients (11 with SUNCT and 4 with SUNA) treated with intravenous lidocaine for up to seven days, partial relief to total abolition of symptoms was observed in 14 patients; 1 patient with SUNCT was lost to follow-up [4]. Pain-free periods were variable; the shortest lasted only as long as the duration of the infusion. The longest pain-free periods were 3 weeks in a patient with chronic SUNCT, 12 weeks in a patient with chronic SUNA, and 6 months in another patient with episodic SUNCT. In another report of 14 patients with SUNCT or SUNA who had 17 attacks treated with lidocaine (14 by subcutaneous infusion and 3 by intravenous infusion), there was complete resolution of pain in 13 attacks (76 percent) [6].

In addition to rapid amelioration of pain, some patients with a successful response to lidocaine infusion are pain-free for weeks after the infusion. This may allow a period of time for either a drug-free interval or for titration and optimization of preventive medications. (See 'Preventive management for all patients' below.)

●Preparation – Prior to dosing, patients should have a baseline electrocardiogram (ECG) and liver enzyme and renal function testing. Hypokalemia and hypomagnesemia should be corrected before the drug is given and throughout treatment.

●Dosing and monitoring – Intravenous lidocaine is administered in the hospital by continuous infusion (eg, 1.3 to 3.4 mg/kg per hour, titrate as needed to suppress symptoms), with an optional loading dose of 1 mg/kg over 15 minutes [5]. Lower doses should be used in patients with hepatic or kidney function impairment.

Continuous ECG monitoring is required during intravenous lidocaine administration. Hemodynamic parameters should be monitored with initiation and with any increase in the dose according to hospital protocol. We monitor the pulse rate and blood pressure every five minutes for the first 30 minutes, then every 15 minutes for four hours, then every four hours. The total duration of the infusion should not exceed seven days. Lidocaine serum levels should be monitored daily. If the level exceeds 5 mcg/mL (21 micromoles/L) or there are signs of toxicity, the dose should be reduced. (See "Major side effects of class I antiarrhythmic drugs", section on 'Lidocaine (intravenous)'.)

A response is considered positive if the attacks are mostly or entirely suppressed for the duration of the infusion or longer.

●Adverse effects – Lidocaine infusion is associated with the potential for serious adverse events, especially when high doses are utilized [7-9]. These events include cardiac arrhythmias, cognitive impairment, dizziness, tremor, nausea, and diarrhea. In addition, we have noted some patients develop neuropsychiatric symptoms such as acute depression or paranoia [10]. While these adverse events always resolve, supportive or symptomatic management may be needed.

●Contraindications – Intravenous lidocaine should not be used in patients with any degree of cardiac conduction system abnormality or heart block who do not have an artificial pacemaker. It is also contraindicated in patients with hypersensitivity to lidocaine or another local anesthetic of the amide type. Lidocaine crosses the placenta; caution is advised for use in pregnancy and during breastfeeding [11,12].

Alternative acute treatments — For those unresponsive or unable to tolerate lidocaine, acute treatments used for other TACs, including oxygen [5,13], oral and intramuscular indomethacin [5,14-20], and occipital nerve blocks [21], may be tried but have not been consistently effective for SUNCT or SUNA.

There is no clear benefit to support using simple analgesics, combination analgesics, or opioids for the acute treatment of SUNCT or SUNA [5,13,22,23].

Infrequent or nondebilitating attacks — For patients with less severe pain during attacks, those with very brief attacks with long (months) interictal intervals, and those with interictal pain between attacks, we treat with a preventive medication. (See 'Preventive management for all patients' below.)

PREVENTIVE MANAGEMENT FOR ALL PATIENTS — SUNCT and SUNA headaches were once considered to be refractory to treatment. However, data from small open-label studies suggest that lamotrigine, topiramate, and gabapentin are moderately effective as preventive therapy for some patients with SUNCT and SUNA (table 1).

Treatment approach — Based on available data and clinical experience, we suggest lamotrigine as initial preventive medical therapy for patients with frequent or debilitating attacks of SUNCT or SUNA [21]. (See 'Initial therapy with lamotrigine' below.)

For patients who do not respond to or are unable to tolerate lamotrigine, we use an alternative medication. These medications include oxcarbazepine, topiramate, carbamazepine, duloxetine, and gabapentin [21]. The data supporting these medications are from case reports and one small trial; comparative efficacy among options is lacking. For most patients, we use patient comorbid conditions and concomitant medications help to select among options. We offer topiramate for those with headache features consistent with SUNCT based on some comparative efficacy data for patients with SUNCT versus those with SUNA [21,24]. (See 'Alternative therapy if lamotrigine ineffective or not tolerated' below.)

Combination therapy may be used for patients who report partial response with monotherapy. In addition, combination therapy may be useful when lower doses of two agents would cause fewer side effects than a higher dose of a single agent. Details about specific drug interactions can be found using the drug interactions program included within UpToDate.

Initial therapy with lamotrigine — Lamotrigine is started at 25 mg daily for two weeks, then increased to 50 mg daily for two weeks. The dose may be further titrated as needed and as tolerated. After four weeks, the daily dose can be increased by 50 mg every one to two weeks. The usual maintenance dose is 200 mg daily given in two divided doses, but total daily doses up to 400 mg given in two divided doses have been used.

Dose adjustments may be needed for interacting medications. Lamotrigine levels are markedly increased by an interaction with valproate, which inhibits lamotrigine metabolism, and decreased in the presence of drugs that induce lamotrigine metabolism (including phenytoin, carbamazepine, phenobarbital, primidone, estrogen-containing oral contraceptives, rifampin, and protease inhibitors such as lopinavir-ritonavir). These interactions lead to different dosing schemes, as discussed in greater detail separately. (See "Antiseizure medications: Mechanism of action, pharmacology, and adverse effects", section on 'Lamotrigine'.)

Systemic side effects of lamotrigine include rash and nausea. A benign rash may develop in up to 10 percent of patients during the initial one to two months of therapy and necessitates discontinuation of the drug. The risk of developing a life-threatening rash such as Stevens-Johnson syndrome, toxic epidermal necrolysis, or angioedema is approximately 1 in 1000 adults; this risk is increased in children. The risk of developing a serious rash may be increased if the initial dose escalation is too rapid.

Lamotrigine may be the most effective preventive medication for SUNCT and SUNA. In a prospective, single-center, open-label study, 76 percent of 128 patients improved with lamotrigine and 56 percent reported at least 50 percent reduction in attack frequency [21]. Lamotrigine (up to 300 mg daily) was effective in several other case series and case reports [6,22,24-28]. However, lamotrigine was ineffective in other reports, including patients with chronic SUNCT or SUNA and those with secondary causes of short-lasting unilateral neuralgiform headache pain, such as due to trigeminal nerve compression [6,15,29,30].

Alternative therapy if lamotrigine ineffective or not tolerated — Alternative agents may be used when patients are unresponsive or unable to tolerate lamotrigine. Data from case reports and systematic reviews suggest benefit with oxcarbazepine, topiramate, carbamazepine, duloxetine, and gabapentin [21]. The choice among these options is guided by patient comorbidities and the effort to avoid medication interactions.

Oxcarbazepine — In an open-label study, SUNCT and SUNA symptoms improved in 71 percent of patients who received oxcarbazepine [21]. Nearly 50 percent were responders (at least 50 percent improvement in symptoms compared with baseline). Benefit was also shown in other case reports [31,32].

Oxcarbazepine is typically started at 300 mg twice daily. The dose may be increased by 600 mg each week up to 2400 mg daily as needed and tolerated.

Common adverse effects are similar to those of carbamazepine and may include nausea, vomiting, sedation, headache, rash, and hyponatremia.

Topiramate — Topiramate may be useful as a preventive medication for SUNCT and SUNA [4,24,33]. In a single-center, open-label study, 47 percent of 76 patients improved with topiramate and 25 percent reported at least 50 percent reduction in attacks [21]. In two studies, topiramate was more effective for patients with SUNCT than those with SUNA [21,24].

The usual starting dose of topiramate is 15 to 25 mg daily; the dose can be increased by 25 mg increments every two weeks up to 100 mg total daily in two divided doses, and thereafter by 50 mg increments every few weeks up to 400 mg total daily, if required and tolerated. However, the optimal dose for SUNCT and SUNA is unknown.

Common adverse effects include impaired cognition and acral paresthesias. Metabolic acidosis and tachypnea may result from renal bicarbonate loss due to the inhibitory effect of topiramate on carbonic anhydrase; patients taking topiramate for prolonged periods may develop kidney stones due to carbonic anhydrase inhibition. Some patients report weight loss. Additional side effects include headache, fatigue, dizziness, depression, and mood problems. Acute myopia and secondary angle closure glaucoma are rare side effects.

Carbamazepine — Several case series and reports support the effectiveness of carbamazepine for some patients with SUNCT and SUNA [34-36]. In one study, 50 percent of 84 patients who received carbamazepine reported symptom improvement and 26 percent reported 50 percent or greater improvement compared with baseline [21].

Carbamazepine is started at 200 mg twice daily. The dose can be increased by 200 mg weekly up to 1600 mg daily as tolerated.

Adverse effects with carbamazepine include nausea, vomiting, diarrhea, hyponatremia, rash, and leukopenia.

Duloxetine — In one study, 49 percent of 37 patients who received duloxetine reported symptom improvement and 30 percent reported 50 percent or greater improvement compared with baseline [21].

Duloxetine is started at 30 mg daily and can be increased one week later to 60 mg daily. Further weekly increases by 30 mg up to the daily maximum dose is 120 mg can be attempted if needed for optimal effectiveness but higher doses are limited by risk of adverse effects, including abdominal pain, nausea, vomiting, weight loss, fatigue, and headache.

Gabapentin — Several case series and reports indicate that gabapentin may useful as preventive therapy in SUNCT and SUNA [17,24,37-39]. In one study, 33 percent of 80 patients reported some improvement but only 10 percent reported at least 50 percent improvement compared with baseline symptoms [21]. In another series of 27 patients with SUNCT or SUNA, treatment with gabapentin (up to 3600 mg daily) was associated with a good response in 13 (48 percent) [4].

Although regimens vary, we start with an initial dose of 300 mg daily, increasing gradually to 300 mg twice a day and then to 300 mg three times a day. Thereafter, the dose may be increased slowly as needed to 1800 mg a day in three divided doses, although some patients require total doses up to 3600 mg daily. In neuropathic pain conditions, typical maintenance gabapentin doses range from 900 to 2400 mg/day, and the drug is usually well tolerated at doses up to 3600 mg daily when titrated up cautiously.

The major side effect of gabapentin is sedation. Others include diarrhea, mood swings, ataxia, fatigue, nausea, lower extremity edema, and dizziness.

Other medications — A variety of other medications, alone or in combination, have been employed to treat SUNCT and SUNA, including clomiphene [40,41], valproate [5,19,42,43], verapamil [20,44], lithium, zonisamide [45], onabotulinumtoxinA (botulinum toxin A) injections [46], and glucocorticoids [13,16,18,47-49]. However, none has been consistently effective.

INVASIVE PROCEDURES FOR REFRACTORY CASES — We reserve invasive procedures for patients who do not achieve satisfactory results with acute and preventive oral medications. Several invasive procedures have been associated with improvement of symptoms in patients with medically refractory SUNCT or SUNA [50]. These take the form either of local blockades, surgical procedures involving the trigeminal nerve, or neuromodulatory procedures.

Greater occipital nerve blockade or stimulation — Limited observational data show some benefit from greater occipital nerve procedures for patients with SUNCT and SUNA [50]. In patients responsive to treatment, pain-free times ranged from one week to six months. In one study, ipsilateral greater occipital nerve block was associated with improvement in 6 of 12 patients with SUNCT and in 3 of 4 patients with SUNA [24]. However, not all reports showed that nerve block was effective for patients with SUNCT and SUNA [43]. In another study, only 11 of 47 patients with SUNCT and 10 of 31 patients with SUNA had a good or excellent effect of greater occipital nerve block [21].

Bilateral occipital nerve stimulation was evaluated in a prospective observational study of 31 patients with intractable SUNCT or SUNA [51]. At a median follow-up of 45 months, the mean daily attack frequency decreased from baseline by 69 percent. The rate of adverse events was low.

Nociceptive pathways in the head involve an important interaction between trigeminal and cervical afferents in the trigeminocervical complex [52,53]. This mechanism might be involved in the referral of pain from trigeminal to cervical structures. Thus, either greater occipital nerve blockade or stimulation may play a role in modulating these trigeminocervical connections.

Though the mechanism of action of the two treatment modalities is poorly understood, they probably work by completely different mechanisms. Greater occipital nerve blockade reduces afferent traffic along the trigeminal-occipital input, while occipital nerve stimulation increases traffic along this pathway and probably acts by bringing about neuroplastic changes in the pain network.

Given the small numbers of patients studied, treatment of SUNCT and SUNA with greater occipital nerve procedures (either blockade or stimulation) should be considered investigational.

Other local blockades — Local blockades of other pericranial nerves (supraorbital, infraorbital, lacrimal), the retrobulbar region, pericranial ganglia (stellate, pterygopalatine, superior cervical), and orbicularis oculi muscles have generally failed to show durable effectiveness [43,54].

Trigeminal nerve decompression — Small case reports and studies have suggested that trigeminal microvascular decompression is beneficial for patients with refractory short-lasting unilateral neuralgiform headache attacks who have an abnormal vascular loop in contact with the symptomatic trigeminal nerve at the root entry zone [50]. One of the largest series reported 47 patients with intractable SUNCT or SUNA [55]. At a mean follow-up of 57 months after microvascular decompression, 37 patients (79 percent) reported at least 75 percent reduction in weekly headache frequency. Four patients developed a postoperative cerebrospinal fluid leak requiring surgical repair and three patients developed persistent neuropathic pain at the incision site. Additional studies are required to identify patients likely to respond to this procedure and determine its role in the treatment of patients with SUNCT or SUNA.

Procedures not recommended

●Destructive trigeminal nerve procedures – In our experience, invasive, destructive trigeminal nerve procedures are of no value or are harmful in patients with SUNCT and SUNA. The available evidence is limited to a few patients who were treated with glycerol rhizotomy, gamma knife radiosurgery, or radiofrequency thermocoagulation of the trigeminal nerve [5,18,29,56,57]. Some experts recommend that trigeminal surgery be considered only as a last resort and then with extreme caution, given its uncertain outcomes and the potential for permanent loss of nerve function. However, our view is that destructive procedures have no place in the current management of SUNCT and SUNA.

●Deep brain stimulation – Functional imaging studies found that activation of the posterior hypothalamus was linked to attacks of SUNCT [30,58] suggesting that deep brain stimulation (DBS) might be a therapeutic option [59,60]. Other reports suggested that the midbrain tegmentum might be the preferred target of DBS [61]. (See "Pathophysiology of the trigeminal autonomic cephalalgias".)

In one uncontrolled observational study, 11 patients with refractory short-lasting unilateral neuralgiform headache attacks were treated with ipsilateral DBS targeting the ventral tegmental area of the midbrain [62]. Treatment was associated with a median reduction in daily attack frequency of 78 percent. The response rate, defined as the proportion of patients with a ≥50 percent improvement in daily attack frequency, was 82 percent.

Although these results are promising, further study is needed to define the role and utility of DBS for patients with SUNCT and SUNA.

PROGNOSIS — SUNCT or SUNA may resolve for some patients over a period of months or years but many others may report lifelong persistent or recurrent symptoms. Prognostic data available for other trigeminal autonomic cephalgias suggest many patients may report lifelong symptoms that decrease in frequency with age [63]. However, there are no large-scale observational studies to allow for an accurate estimate of long-term prognosis for patients with SUNCT and SUNA.

SOCIETY GUIDELINE LINKS — Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Migraine and other primary headache disorders".)

SUMMARY AND RECOMMENDATIONS

●Terminology – There are two subtypes of short-lasting unilateral neuralgiform headache attacks (see 'Introduction' above):

•Short-lasting unilateral neuralgiform headache attacks with conjunctival injection and tearing (SUNCT)

•Short-lasting unilateral neuralgiform headache attacks with cranial autonomic symptoms (SUNA)

●Acute treatments – For patients with acute, frequent, and debilitating attacks of SUNCT or SUNA, we suggest initial therapy with an intravenous lidocaine infusion (Grade 2C). Continuous electrocardiogram monitoring is required during intravenous lidocaine administration, along with close observation for adverse effects. (See 'Acute management' above and 'Frequent and debilitating attacks' above.)

•For patients unresponsive or unable to tolerate lidocaine, acute treatments used for other trigeminal autonomic cephalalgias, including oxygen, oral and intramuscular indomethacin, and occipital nerve blocks may be tried but have not been consistently effective for SUNCT or SUNA (table 1).

•For patients with less severe pain during attacks, those with very brief attacks with long (months) interictal intervals, and those with interictal pain between attacks, we treat with a preventive medication.

●Preventive treatments – For most patients with SUNCT or SUNA, we suggest initial preventive therapy with lamotrigine (Grade 2C). (See 'Preventive management for all patients' above and 'Initial therapy with lamotrigine' above.)

•For patients who do not respond to or are unable to tolerate lamotrigine, we use an alternative medication such as oxcarbazepine, topiramate, carbamazepine, duloxetine, or gabapentin (table 1). We use patient comorbid conditions and concomitant medications to help select among options. (See 'Alternative therapy if lamotrigine ineffective or not tolerated' above.)

•We reserve invasive procedures for patients who do not achieve satisfactory results with acute and preventive oral medications. Several invasive procedures have been attempted to alleviate SUNCT or SUNA symptoms. These take the form either of local blockades, surgical procedures involving the trigeminal nerve, or neuromodulatory procedures. (See 'Invasive procedures for refractory cases' above.)

●Prognosis – SUNCT or SUNA may resolve for some patients over a period of months or years, but many others may report lifelong persistent or recurrent symptoms. (See 'Prognosis' above.)