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SUNCT and SUNA: Clinical features and medical treatment
Available online at www.sciencedirect.com
Journal of Clinical Neuroscience 15 (2008) 526–534 www.elsevier.com/locate/jocn
Clinical Study
SUNCT and SUNA: Clinical features and medical treatment Max H. Williams a,*, Simon A. Broadley a,b a
Department of Neuroscience, Gold Coast Hospital, 108 Nerang Street, Southport, Queensland 4215, Australia b School of Medicine, Griffith University, Queensland, Australia Received 24 July 2006; accepted 12 September 2006
Abstract Short-lasting unilateral neuralgiform headache with conjunctival injection and tearing (SUNCT) and short-lasting unilateral neuralgiform headache attacks with cranial autonomic symptoms (SUNA) are considered to be rare primary headache disorders. The purpose of this study was to define the clinical features, response to prophylactic treatment and efficacy of lignocaine by subcutaneous infusion for periods of acute exacerbation requiring hospitalisation. Over a period of 6 years (March 2000–February 2006) all cases of SUNCT and SUNA in neurology clinics at the Gold Coast Hospital, Australia, were reviewed. International Headache Society diagnostic criteria were used. Clinical features and response to treatment were prospectively recorded using headache diaries and magnetic resonance imaging of the brain was carried out. Twenty-four subjects with SUNCT or SUNA were identified. The incidence of these conditions was 1.2/100,000 and the prevalence 6.6/100,000. An episodic disease course was evident in 14/24 (58%) cases, whereas 10/24 (42%) had a chronic course. An aberrant vessel in close association with the fifth cranial nerve was seen in 88% of cases. A good or excellent response to lamotrigine was seen in 11/19 (58%) and was more effective in the episodic group (100%). A subcutaneous infusion of lignocaine proved completely effective on 11/14 (78%) occasions. SUNCT and SUNA are not rare conditions. Characterisation into episodic and chronic disease course appears to be of prognostic and therapeutic importance. Lamotrigine is effective in the majority of cases and subcutaneous lignocaine is useful as acute treatment for severe recalcitrant attacks. Crown Copyright Ó 2007 Published by Elsevier Ltd. All rights reserved. Keywords: SUNCT; SUNA; Headache; Lamotrigine; Lignocaine
1. Introduction Short-lasting unilateral neuralgiform headache with conjunctival injection and tearing (SUNCT) is classified by the International Headache Society as a primary headache disorder.1 The hallmark of SUNCT syndrome is a tendency to recurrent attacks of moderate to severe stabbing pain around the eye or temple with associated autonomic features. The duration of the pain should be between 5 and 240 s with an attack frequency of 3 to 200 per day. Short-lasting unilateral neuralgiform headache attacks with cranial autonomic symptoms (SUNA) have similar features but there is a broader range of attack durations, between 2 s and 10 min, with an attack *
Corresponding author. Tel.: +61 7 5571 8161; fax: +61 7 5519 8613. E-mail address: [email protected] (M.H. Williams).
frequency of one or more per day.1 As for the other trigeminal autonomic cephalgias, cluster headache and paroxysmal hemicrania, episodic and chronic forms of SUNA, but not specifically SUNCT, are recognised by the International Headache Society.1 Trigeminal neuralgia usually involves the second or third division of the trigeminal nerve with brief shock-like pains lasting from a fraction of a second to 2 min, and has a refractory period to trigger factors.1 First division trigeminal neuralgia is uncommon, but can be associated with mild autonomic features and there have been reports of cases that appear to have evolved from this form of trigeminal neuralgia to SUNCT.2–4 Prominent autonomic features, attack duration, lack of refractory period to trigger factors and relative resistance to carbamazepine are cited as distinguishing features separating SUNCT from trigeminal neuralgia.4–7
0967-5868/$ - see front matter Crown Copyright Ó 2007 Published by Elsevier Ltd. All rights reserved. doi:10.1016/j.jocn.2006.09.006
M.H. Williams, S.A. Broadley / Journal of Clinical Neuroscience 15 (2008) 526–534
Medical treatment of SUNCT is frequently disappointing.7 There are anecdotal reports in the literature of various agents that have been effective in individual patients. These include verapamil,8 gabapentin,9,10 lamotrigine11–13 and topiramate.14,15 One difficulty in assessing medication response is that spontaneous remission may occur and can be prolonged.16 An intravenous infusion of lignocaine (known as lidocaine in the US) has been successful in controlling chronic daily headache17,18 but not acute migraine.19 A short infusion of 4 mg per min over 48 h with a 100 mg bolus of lignocaine was ineffective in two subjects with SUNCT syndrome.7 However, Matharu et al. found that an intravenous lignocaine infusion was at least temporarily effective in SUNCT syndrome, allowing time for the introduction of prophylactic medication in four subjects.20 Subcutaneous lignocaine infusion giving blood levels of 2 to 5 lg/mL has been shown to be effective in controlling neuropathic cancer pain.21 To our knowledge this mode of treatment has not been reported in cases of SUNCT. Here we describe a case series of SUNCT and SUNA identified at the Gold Coast Hospital over a 6-year period. The clinical features and response to medication for these cases are described. 2. Patients and methods 2.1. Study design Over a 6-year period (March 2000–February 2006) all subjects who met the International Headache Society criteria for SUNCT and SUNA were included. The subjects were seen in neurology clinics at the Gold Coast Hospital, Australia. Data were collected prospectively via a headache diary following the initial consultation. This included the site, severity, duration and pattern of pain and the presence or absence and duration of relapses and remissions. Subjects were instructed to note the presence and severity of autonomic features including conjunctival injection, tearing, eyelid oedema, ptosis, erythema, sweating, rhinorrhoea or nasal congestion. Retrospective information, based on subject or witness recall, was included where appropriate. Follow-up data were collected by chart review, direct re-interview or by telephone. Only subjects with prominent autonomic features were included. ‘Prominent’ was defined as conjunctival injection that was obvious to the subject or witness and was accompanied by lacrimation. If nasal congestion or rhinorrhea was associated with conjunctival injection and/or tearing this was also regarded as ‘prominent’. Thus subjects who had only conjunctival injection or tearing were excluded even though they may have met the International Headache Society criteria for SUNA. Episodic SUNCT or SUNA was defined according to the International Headache Society criteria for episodic SUNA1 as attacks lasting 7 days to 1 year, separated by a pain-free period lasting 1 month or longer. Chronic SUNCT or SUNA was defined as attacks occurring for
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more than 1 year without remission or with remission lasting less than 1 month. To exclude symptomatic SUNCT an MRI of the brain was carried out using a 1.5 T scanner. Dedicated views of the fifth cranial nerve were obtained in all subjects from 2002. Following D’Andrea and colleagues’ report (1999),11 lamotrigine was chosen as the first-line treatment for prophylactic therapy provided there were no contraindications. Lamotrigine was commenced at 25 mg per day, increasing by 25 mg every 4–7 days until symptoms were controlled, adverse events were seen or a maximal dose of 600 mg was achieved. If symptoms were of such severity that activities of daily living were affected, subjects were hospitalised for a lignocaine infusion. Initially given via an intravenous route, after 2003 a subcutaneous route was used. Lignocaine (2 g reconstituted in normal saline to 100 mL) was infused subcutaneously into the anterior abdominal wall at a rate of 6 mL per hour, equivalent to 2 mg per minute. After 24–48 h the dose was adjusted according to the blood level of lignocaine. A level of 2–5 lg/mL was taken as therapeutic.21 An electrocardiogram was performed prior to the commencement of the infusion and again after 2 h. Vital signs were monitored at 30 min intervals for the first 2 h. Lignocaine was not given if there was a cardiac or other contraindication. Continuous cardiac monitoring was not performed unless there was a specific indication. Metoclopramide 10 mg orally was given prior to the start of the infusion and continued routinely at 10 mg four times a day throughout. Adverse events were recorded for all medications used. Response to medication was recorded using a simple 4-point scale (Table 1). 2.2. Statistical analysis All comparison statistics were made using odds ratios with 95% confidence intervals or p-values based on a v2 statistic and were performed using the Statistics Calculator v1.2 of the Toronto University Evidence Based Medicine website (www.cebm.utoronto.ca/practise/ca/statscal/; accessed 16 June 2006). In view of the relatively low subject numbers and on the assumption that the results would only be hypothesis-generating rather than definitive, adjusted figures have not been used. For incidence and prevalence
Table 1 Treatment response scale Scale
Response
Definition
– + ++
No response Mild– moderate Good
+++
Excellent
No change in headache frequency or severity <50% reduction in headache frequency and/or severity >50% reduction in headache frequency and/or severity >90% reduction in headache frequency and/or severity
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M.H. Williams, S.A. Broadley / Journal of Clinical Neuroscience 15 (2008) 526–534
data nominal 95% confidence intervals were calculated as per Altman.22 3. Results 3.1. Subjects During the 6-year study period, 24 cases of SUNCT or SUNA were identified. One subject was lost to follow-up and another died 9 months after SUNCT diagnosis from a carcinoma of the oesophagus. Age of onset varied from 17 to 65 years (mean 40 years). There were 14 females and 10 males, 23 Caucasians and 1 Asian. 3.2. Incidence and prevalence estimates In a 6-year period 24 patients were identified in a population of approximately 500 000. The authors are aware of three other cases, and direct questioning of all other neurological referral centres revealed the presence of eight additional cases. This suggests a conservative annual incidence estimate of 1.2/100 000 (95% CI: 0.2–2.0/100 000) for SUNCT/SUNA. Allowing for the death of one subject and another leaving the district the prevalence was approximately 6.6/100 000 (95% CI: 4.3–8.9/100 000). 3.3. Clinical features By definition all 24 subjects qualified for the diagnosis of SUNA, with 17 subjects meeting the more restrictive criteria for SUNCT. Five subjects were classified as SUNA as the attack duration exceeded 240 s on most occasions, whereas in two subjects the attacks varied between the SUNCT and SUNA ranges. The clinical features of the 24 patients are summarised in Table 2. The left side was affected in 13 patients, the right side in eight, the affected area changed sides in one, and two patients had varying attacks on either side. Symptom duration before diagnosis ranged from 1 month to 30 years. Individual attack duration varied from 1 s to 5 min, occurring at a frequency of 1 to 300 per day or night. Attacks of stabbing pain occurred in three distinct patterns: saw-toothed (eight subjects), grouped (nine subjects), and singly (seven subjects). Trigger factors were identified by 15/24 (63%) subjects. Twelve of 15 (80%) subjects with SUNCT had identifiable triggers versus 2/4 (50%) subjects with SUNA and 1/2 (50%) with both SUNCT and SUNA. In 8/11 (73%) episodic and 7/10 (70%) chronic subjects trigger factors were noted. The saw-toothed pattern had an increased frequency of trigger factors compared with the single stab group, 7/8 (87.5%) and 3/6 (50%) respectively. No subject noted a refractory period. Triggers in this series include a light touch to the face, a cool breeze, combing or brushing the hair, chewing, talking or teeth brushing. The cool breeze from air conditioning ducts was a common trigger. Subject 24, for example, had to have his hospital bed positioned away from the
air conditioning unit and would wear a bandage around his forehead for extra protection. Shaving was not noted as a trigger. Weight loss occurred in two subjects due to SUNCT being precipitated by chewing. Subject reporting of pain severity was variable but generally severe at the peak of an attack. The prominence of the autonomic features usually increased with the severity of the pain, but this was not always the case. Two subjects (subjects 3 and 11) occasionally had autonomic features without pain, in addition to more typical attacks. Fourteen subjects required admission to hospital because of severe pain and one subject felt suicidal because of the pain. Unusual clinical features were present in several subjects. An aura of tingling involving the ipsilateral cheek with a numb sensation inside the cheek was noted by subject 8 for 1–2 min prior to an attack whereas subject 5 knew an attack was imminent when tingling over the ipsilateral side of the nose and forehead developed. It was thought that these phenomena were possibly due to peripheral trigeminal nerve irritation. MRI in subject 8 showed arterial contact with the trigeminal nerve; however, no vessel contact was seen in subject 5. Subject 4 had right-sided SUNCT attacks with occasional independent attacks of typical cluster headache on the left side that responded to oxygen or intranasal sumatriptan. Migraine without aura also occurred frequently in this subject. Migraine was a co-morbidity in 7/24 (29%) subjects, one with visual aura. No subject had migraine features associated with their SUNCT or SUNA attacks. Subjects 5 and 11 were unusual in that the conjunctival injection and tearing were ipsilateral to the pain, whilst rhinorrhea occurred on the opposite side, with the ipsilateral nasal passage remaining clear during the attack. Subject 8 had conjunctival injection on the contralateral side to the SUNCT pain. 3.4. Episodic and chronic SUNCT/SUNA An episodic course was seen in 14 (58%) subjects and a chronic course in 10 (42%). In the episodic group there were seven males and seven females with an age of onset range of 17–64 years (median 37.1 years). The chronic group had seven females and four males with an age of onset range of 32–65 years (median 50.3 years). A comparison of clinical features in episodic and chronic cases is shown in Table 3. Subjects with episodic disease, three for more than 26 years, have maintained this pattern with remissions lasting up to 7 years and thus far have not evolved into the chronic form. In contrast, subjects with chronic disease have remained chronic from the onset, modified to some degree by medication. 3.5. MRI results MRI was not available for one subject lost to follow-up. Ischaemic changes were noted in four subjects, one with a
Table 2 Clinical features of 24 patients with SUNCT/SUNA Subject
Sex
Age at onset (years)
Age at diagnosis (years)
Duration of symptoms
Attack frequency (per day)
Duration of attacks (s)
Trigger factors
Episodic/ chronic
SUNCT/ SUNA
Attack pattern
Side
Previous diagnosis
MRI
Lignocaineb
Maximum dose (mg)
Effect
Route of infusion/ duration (days)
Effect
++ NA +++ NA NA NA +++ +++ ++ +++ +++ +++ +++ NA +++ NA +++ ++
1 2 3 4 5 6 7 8
M M F M F M F F
37 64 40 28 43 34 38 43
37 64 43 58 43 36 38 43
4 weeks 9 months 3 years 30 years 6 months 2 years 2 months 4 months
120 100 1–30 10 10–30 30–60 5 100–300
30 30 10–20 10–45 120–180 20–30 20 30–120
Yes Yes Yes No Yes Unknown Unknown Yes
Episodic Episodic Episodic Episodic Episodic Episodic Episodic Chronic
SUNCT SUNCT SUNCT SUNCT SUNCT SUNCT SUNCT SUNCT
ST ST SG SG SG SG SS ST
R L L R L R L R&L
CH CH TN CH Unknown TN Unknown CH
Normala Leukoariosisa Normala Normala Normala Not done Normal A both sides
150 100 400 200 400 NA NA 600
+++ +++ +++ ++ ++ NA NA ++
9 10
M F
53 46
56 46
3 years 5 months
20–30 90–120
30–120 3–10
None Yes
Chronic Chronic
SUNCT SUNCT
SG ST
L R
Migraine GCA
A and V A
400 600
+ +
11 12 13 14 15 16
F F F F F M
47 17 46 26 19 58
47 22 48 26 47 61
1 month 5 years 2 years 2 months 28 years 3 years
2–50 100–200 30–50 10 100–300 5–10
5–20 120 300 180–240 5–10 60–300
Yes Yes Yes Unknown None None
Chronic Episodic Chronic Episodic Episodic Chronic
SUNCT SUNCT SUNA SUNA SUNCT BOTH
SG ST SG SS ST SS
L/R L&R L L L R
Migraine PH PH TN CH TN
600 400 400 NA 50 200
+ +++ + NA +++ +
17 18
M M
19 55
47 56
26 years 1 year
8–10 20–30
20–180 120–300
Yes Yes
Episodic Chronic
SUNCT SUNA
SS SS
L R
CH Central pain
A both sides A both sides A and V Normal A A and V Lacunar infarcts A A
IV/5 Not used IV/6 Not used Not used Not used IV/6 SCI/9 SCI/7 SCI/7 SCI/5 SCI/5 SCI/5 Not used SCI/7 Not used SCI/5 SCI/7
100 400
+++ +
Not used SCI/7
NA +++
19
F
65
71
6 years
30–200
60–120
Yes
Chronic
SUNCT
ST
R
TN
400
+
SCI/8 SCI/14
+++ +++
20 21 22 23 24
M F F M M
58 47 32 54 54
58 49 34 54 54
6 2 2 1 3
7 2–6 20–40 15–20 100–300
120–300 300 2–10 1–300 30–90
None None Yes Yes Yes
Chronic Episodic Chronic Episodic Episodic
SUNA SUNA SUNCT BOTH SUNCT
SS SS SG SG ST
L L R L L
TN TN Unknown TN TN
A, Brainstem infarct A Normal A both sides A A
NA 200 200 NA 150
NA +++ ++ NA +++
Not used Not used SCI/7 Not used SCI/7
NA NA +++ NA +
months years years month months
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Lamotrigineb
(Short-lasting unilateral neuralgiform headache with conjunctival injection and tearing / Short-lasting unilateral neuralgiform headache with cranial autonomic symptoms). ST, saw-tooth; SG, stab groups; SS, single stabs; L, left; R, right; CH, cluster headache; TN, trigeminal neuralgia; GCA, giant cell arteritis; PH, paroxysmal hemicrania; NA, not applicable; LMCA, left middle cerebral artery; A, artery; V, vein; IV, intravenous; SCI, subcutaneous injection. a MRI performed without dedicated views of fifth nerve. b For definitions of treatment responses see Table 1.
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Table 3 Comparison of clinical features and response to treatment in episodic and chronic SUNCT/SUNA Clinical feature
Age >45 years Male Trigger factor present SUNCT syndrome Aberrant vessel Lamotrigine trialled Lamotrigine responsivea Lignocaine infusion used Lignocaine responsivea
Chronic
Episodic
n/N
%
n/N
%
8/10 4/10 7/10 7/10 10/10 9/10 1/9 9/10 9/9
(80) (40) (70) (70) (100) (90) (11) (90) (100)
4/14 7/14 8/14 12/14 5/13b 10/14 10/10 5/14 4/5
(29) (50) (57) (86) (38) (71) (100) (36) (80)
OR
95% CI
10.00 0.67 1.75 0.39 32.46 3.60 0.01 16.20 6.33
1.44–69.26 0.13–3.45 0.31–9.75 0.05–2.92 1.56–673.78 0.38–38.48 0–0.23 1.57–167.75 0.213–188.17
(Short-lasting unilateral neuralgiform headache with conjunctival injection and tearing / Short-lasting unilateral neuralgiform headache with cranial autonomic symptoms). OR, odds ratio; CI, confidence interval. a Good or excellent response (see Table 1 for definitions). b MRI not available in one subject.
left middle cerebral artery distribution infarction, lacunar infarcts in one, leukoariosis in one and one subject had a brain stem infarct. Of subjects who had dedicated views of the trigeminal nerve, 15/17 (88%) were positive for an aberrant arterial loop in contact with or deforming the trigeminal nerve. In three of these subjects, symptoms were bilateral and of the 20 symptomatic nerves 18 (90%) showed an aberrant vessel. In contrast an aberrant arterial loop was present in one of 14 (7%) of the asymptomatic nerves (p < 0.0001). No pituitary lesion was seen. 3.6. Response to treatment One subject had used verapamil without effect. One pregnant subject had a remission on carbamazepine but this was ineffective in seven other patients. Gabapentin appeared moderately effective in 1/8 cases only. Topiramate was moderately effective in one subject who was intolerant of lamotrigine but ineffective in five others. In the episodic group, 8/10 (80%) subjects had an excellent response to lamotrigine but 0/9 (0%) in the chronic group had this result (p = 0.004; Table 3). The other two episodic subjects had a moderate effect with lamotrigine. The majority of chronic subjects noted only a mild effect with lamotrigine. In responders the mean dose of lamotrigine required to achieve an excellent response was 194 mg whereas poor responders received an average of 429 mg/day. An effect was usually noted with a relatively low dose and in general there was little to be gained by pushing the dose above 400 mg/day. However, even subjects receiving higher doses, who felt that lamotrigine was ineffective, did notice an increase in symptoms on dose reduction. Drowsiness, fatigue and memory difficulties occasionally limited the dose (subjects 18, 19 and 22). A mild skin rash occurred in one subject while taking 50 mg of lamotrigine per day. This disappeared on cessation of the drug; however, her previously modified SUNCT increased in severity. Lamotrigine was reintroduced at 12.5 mg per day together with prednisone 50 mg per day. The rash did not return after the ste-
roid was tapered and the dose of lamotrigine was safely increased to 600 mg a day with a moderate effect on SUNCT symptoms. A lignocaine infusion was used on 17 occasions in 14 subjects, three by the intravenous route and 14 by subcutaneous infusion. Pain attacks were completely abolished on 13/17 (76%) occasions. The subcutaneous route was as effective as the intravenous route, 11/14 (79%) and 2/3 (67%) having an excellent result, respectively. Mild residual attacks persisted in three subjects and one subject noted only a minimal response. In episodic cases 5/14 (36%) required lignocaine for a mean infusion time of 6 days, whereas in the chronic group 9/10 (90%) required infusions for an average of 8 days, three needing a second admission. One patient felt somewhat depressed and three had vivid dreams. No adverse cardiac events occurred. A seizure occurred in subject 16, where there was a prior history of seizure disorder. Following appropriate adjustment of phenytoin dose the infusion was recommenced cautiously at a lower rate with partial control of SUNA symptoms and without any further adverse events. 4. Discussion Since Sjaasted and colleagues first described SUNCT in 1978,23 it has been considered a rare disorder. With increasing recognition more cases have been reported, for example Cohen et al. described 52 cases in 2005.24 Here we describe 24 cases and provide crude estimates for incidence and prevalence, which would suggest that SUNCT and SUNA are more common than previously thought. Although the typical presentation of SUNCT or SUNA is sufficiently dramatic to prompt neurological referral in the majority of cases, it seems likely that the syndromes are under diagnosed. Our incidence figures may be an overestimate due to the cohort effect that may occur when a new diagnosis emerges, but in fact the year by year incidence figures have not changed significantly over the 6 years of this study. In contrast to earlier reports that suggested that SUNCT
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syndrome is a male-dominant disease with a ratio of 17:2,25 this series shows a ratio of 7:5 in favour of females. The phenotypic expression of SUNCT is variable. Like Cohen et al., three basic patterns of attacks could be identified in the present study.24 The saw-toothed pattern was seen in one-third of subjects. Often these attacks would last up to 6 h, with mild background discomfort or pain punctuated by discrete short, usually severe, paroxysms of pain lasting for seconds or 1–2 min with a similar period of respite, the autonomic features waxing and waning with the pain. As this scenario would repeat itself several times a day or night, the actual number of individual stabs of pain could be up to 300 or more for a 24 h period. Spontaneously or with medication the pattern could change to stab groups or isolated stabs. Groups of stabs occurred in just over one-third of subjects. In this pattern, distinct paroxysms of SUNCT or SUNA may occur over a period of 5 to 15 min, with distinct groups repeating themselves several times a day or night. Single stabs occurred in the remainder. Usually the total number per 24 h period was less than the other two patterns but the intensity was no less severe. The saw-toothed pattern was frequently misdiagnosed as cluster headache. Accurate history taking, observing the subject during the attack and lack of response to oxygen and sumatriptan should alert the clinician. A diagnosis of paroxysmal hemicrania, episodic or chronic, was considered in some subjects, especially long SUNA and stab group subjects, but was discounted by the absolute failure of an indomethacin trial. Many subjects were referred because of a diagnosis of intractable trigeminal neuralgia. The ophthalmic distribution, the often longer duration of paroxysms, prominent autonomic features, the lack of a refractory period to trigger factors and the relative lack of response to carbamazepine assisted in establishing the diagnosis of SUNCT.6,7 In contrast to trigeminal neuralgia, no subject had a refractory period in the present series. This is one hallmark of SUNCT syndrome.6,7,26 Similar to trigeminal neuralgia, trigger factors were common in SUNCT, present in 80% of subjects but this was only noted in 50% of SUNA and SUNCT/SUNA subjects who had longer durations of individual attacks. Although not statistically significant, these findings are similar to those of Cohen et al.24 The distinctions between trigeminal neuralgia, SUNA and SUNCT are certainly blurred and there is potential for overlap. However, autonomic features in classical trigeminal neuralgia are rare and have distinct characteristics,27 which are unlikely to be included in the definition of autonomic features used for the present series. It is notable that in SUNA, in which there is greatest potential for overlap with trigeminal neuralgia, the incidence of trigger factors is lower than in SUNCT. The duration of episodes and very prominent early autonomic features in SUNCT are very unlikely to be confused with trigeminal neuralgia. The absence of a refractory period is less helpful, as the
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presence of this feature may not be noticed by subjects with classical trigeminal neuralgia. We identified two subjects with aura as part of the manifestation of their SUNCT attacks. Aura has been described in other trigeminal autonomic cephalgias including cluster headache,28,29 and chronic paroxysmal hemicrania,30 and more recently in SUNCT.20 Autonomic features without pain have been noted in the trigeminal autonomic cephalgias, notably cluster headache31 and chronic paroxysmal hemicrania.32 The mechanism of the autonomic features of SUNCT is presumably via the trigeminal autonomic reflex.33 The ipsilateral superior salivatory nucleus is stimulated via fibres from the nucleus caudalis, having been activated by the trigeminal nerve. Fibres from the superior salivatory nucleus travel initially in conjunction with the facial nerve and via the greater superficial petrosal nerve to terminate in the nasal mucosa, lacrimal apparatus and blood vessels. An internal trigger located in the ipsilateral hypothalamus is thought to activate the trigeminal autonomic reflex.34 May et al. demonstrated activation of the ipsilateral posterior hypothalamus in SUNCT syndrome.34 However, Sprenger and colleagues noted bilateral activation of a similar area of the hypothalamus.35 If the internal trigger can be bilateral in some patients then bilateral features could theoretically occur, a phenomenon which was observed in this series. The separation of the pain from the autonomic features suggests that the superior salivatory nucleus may be independently activated. In cluster headache a similar area in the hypothalamus appears to orchestrate attacks.16 More recently the contralateral hypothalamus has been shown to be involved in paroxysmal hemicrania36 and hemicrania continua,37 both indomethacin-responsive headaches. Stereotactic ablation of this area has resulted in complete relief of cluster headache in some patients, providing evidence that cluster headache is a primary headache disorder.38–40 Symptom control following deep brain stimulation of the appropriate area of the hypothalamus in a patient with SUNCT41 also suggests that SUNCT is a primary headache disorder with pathophysiology similar to cluster headache.16 Whether an aberrant vascular loop, potentially irritating the trigeminal nerve, may act as an additional trigger to attacks is open to speculation, but the present series would suggest that the finding of an aberrant vascular loop in close association with the ipsilateral fifth nerve is a common occurrence (88%). Previous literature on this association is restricted to isolated case reports.42 The authors are not aware of any prior systematic survey for aberrant vessels in SUNCT and SUNA. There have been anecdotal reports of successful treatment of SUNCT with microvascular decompression,43–46 but caution has been advised.47 Cases of symptomatic SUNCT have been reported, including vascular malformations,48–50 basilar impression,51 presumed brain stem infarction,52 a leiomyosarcoma of the cavernous sinus,53 craniosynostosis,54 prolactinoma55,56 and acromegaly.57
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The anecdotal effectiveness of verapamil,8 carbamazepine,58 gabapentin9,10 and topiramate14,15 were not confirmed in this study. However, verapamil was only used once and the doses of carbamazepine and gabapentin were possibly suboptimal, but in most cases were the maximum tolerated. It should be noted that topiramate was not used as first-line therapy but was given to subjects who had an incomplete response to lamotrigine. Topiramate was effective in one episodic SUNCT subject who had a skin rash attributed to lamotrigine. The separation of SUNCT or SUNA into episodic and chronic forms may have important therapeutic implications. Subjects with episodic SUNCT or SUNA were more responsive to lamotrigine than the chronic group (p = 0.001). In 80% of episodic subjects an excellent response was seen and in the other two a >50% reduction in symptomatology was noted. In the chronic group no subject had an excellent response to lamotrigine but two (22%) had a good response. The apparent effectiveness of lamotrigine in inducing remission in episodic subjects may be an overinterpretation, as spontaneous remission is part of the normal pattern of the disease. However, this seems unlikely as lamotrigine was frequently used after other trials of ineffective medication. Following initial success with an intravenous infusion of lignocaine in three subjects with SUNCT, subcutaneous lignocaine infusion was used on a further 14 occasions in 13 subjects. Complete control of symptoms often occurred within 4–5 days, but some required longer. On 76% of occasions complete control was achieved for both the pain and autonomic features. In the remainder there was either a marked reduction in frequency and severity of symptoms, or a transient improvement. Hospitalisation for a lignocaine infusion was required in 90% of chronic subjects compared with 36% of episodic subjects. Symptom control could usually be achieved in both groups. This period allowed for the introduction of prophylactic therapy and titration to an effective dose. Generally the effect of lignocaine is transient, with symptoms recurring within a day or two of ceasing the infusion. However, one subject with episodic SUNCT has remained in complete remission for 4 years following her subcutaneous infusion, without prophylactic medication. Adverse effects were minimal with subcutaneous lignocaine infusion. Nausea is common but is usually controlled with metoclopramide started prior to commencement of the infusion and continued on a regular basis. Neuropsychiatric effects were generally also mild.
SUNA, trigeminal neuralgia and other trigeminal autonomic cephalalgias. However, the present findings provide evidence for the usefulness in prognostic and therapeutic terms for the continued differentiation of these clinical entities, and we would recommend that, pending a definitive explanation of the underlying pathophysiology of these conditions, the strict diagnostic criteria of these clinical entities be adhered to. The most recent classification of the International Headache Society1 recommends that dual diagnoses be applied when features of trigeminal neuralgia and SUNCT coexist. However, in the present series that confusion was not apparent and we would suggest that the failure of SUNCT and SUNA to respond to carbamazepine is helpful in making the distinction between these two diagnoses and that a single diagnosis (usually SUNA) should be applied. We have identified episodic and chronic patterns for both SUNCT and SUNA, and this may have important aetiological, prognostic and therapeutic implications. In subjects with chronic SUNCT or SUNA an aberrant vessel impinging on the fifth nerve seems to occur more frequently, leading to the hypothesis that this is of aetiological significance and may account for the persistent nature of the attacks. At the present time it is not possible to comment on the implications with regard to treatment that this finding might have. Episodic and chronic forms appear to remain consistent with no changes in pattern being observed in this series. The chronic group tend to be more resistant to treatment and require more frequent admission to hospital. In this series 80% of patients with episodic SUNCT or SUNA had an excellent response to relatively low doses of lamotrigine, whereas patients with the chronic form usually require a higher dose and even then control is often suboptimal. This supports the use of lamotrigine as first-line therapy in SUNCT and SUNA. We have also demonstrated that lignocaine by subcutaneous infusion is as effective as the intravenous route in controlling severe exacerbations in the majority of cases, and allows time for the adjustment of prophylactic medication. It should be emphasised that this was an un-blinded, observational study, and that our findings should only be considered as hypothesis-generating. There is a need for a large-scale placebo-controlled trial of both lignocaine subcutaneous infusion for acute treatment in SUNCT/SUNA and for lamotrigine in the long-term management of this condition.
5. Conclusions
Thanks to Lyn Williams and Jan Neville for their assistance in preparing the manuscript.
In the Gold Coast region, SUNCT and SUNA were more common than has been previously recognised. A wide phenotypic expression of both pain pattern and autonomic features was seen. It is evident from this series and others that there is a degree of overlap in both the clinical features and proposed pathophysiological mechanisms for SUNCT,
Acknowledgements
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M.H. Williams, S.A. Broadley / Journal of Clinical Neuroscience 15 (2008) 526–534 2. Bouhassira D, Attal N, Esteve M, et al. ‘‘SUNCT” syndrome. A case of transformation from trigeminal neuralgia? Cephalalgia 1994;14:168–70. 3. Sesso RM. SUNCT syndrome or trigeminal neuralgia with lacrimation and conjunctival injection? Cephalalgia 2001;21:151–3. 4. Sjaastad O, Pareja JA, Zukerman E, et al. Trigeminal neuralgia. Clinical manifestations of first division involvement. Headache 1997;37:346–57. 5. Fromm GH. Trigeminal neuralgia and related disorders. Neurol Clin 1989;7:305–19. 6. Lain AH, Caminero AB, Pareja JA. SUNCT syndrome; absence of refractory periods and modulation of attack duration by lengthening of the trigger stimuli. Cephalalgia 2000;20:671–3. 7. Pareja JA, Kruszewski P, Sjaastad O. SUNCT syndrome: trials of drugs and anesthetic blockades. Headache 1995;35:138–42. 8. Narbone MC, Gangemi S, Abbate M. A case of SUNCT syndrome responsive to verapamil. Cephalalgia 2005;25:476–8. 9. Graff-Radford SB. SUNCT syndrome responsive to gabapentin (Neurontin). Cephalalgia 2000;20:515–7. 10. Porta-Etessam J, Benito-Leon J, Martinez-Salio A, et al. Gabapentin in the treatment of SUNCT syndrome. Headache 2002;42:523–4. 11. D’Andrea G, Granella F, Cadaldini M, et al. Possible usefulness of lamotrigine in the treatment of SUNCT syndrome. Neurology 1999;53:1609. 12. D’Andrea G, Granella F, Ghiotto N, et al. Lamotrigine in the treatment of SUNCT syndrome. Neurology 2001;57:1723–5. 13. Leone M, Rigamonti A, Usai S, et al. Two new SUNCT cases responsive to lamotrigine. Cephalalgia 2000;20:845–7. 14. Matharu MS, Boes CJ, Goadsby PJ. SUNCT syndrome: prolonged attacks, refractoriness and response to topiramate. Neurology 2002;58:1307. 15. Rossi P, Cesarino F, Faroni J, et al. SUNCT syndrome successfully treated with topiramate: case reports. Cephalalgia 2003;23:998–1000. 16. Matharu MS, Goadsby PJ. Trigeminal autonomic cephalgias. J Neurol Neurosurg Psychiatry 2002;72 (Suppl 2):ii19–=0?>ii26. 17. Hand PJ, Stark RJ. Intravenous lignocaine infusions for severe chronic daily headache. Med J Aust 2000;172:157–9. 18. Williams DR, Stark RJ. Intravenous lignocaine (lidocaine) infusion for the treatment of chronic daily headache with substantial medication overuse. Cephalalgia 2003;23:963–71. 19. Reutens DC, Fatovich DM, Stewart-Wynne EG, et al. Is intravenous lidocaine clinically effective in acute migraine? Cephalalgia 1991;11:245–7. 20. Matharu MS, Cohen AS, Goadsby PJ. SUNCT syndrome responsive to intravenous lidocaine. Cephalalgia 2004;24:985–92. 21. Brose WG, Cousins MJ. Subcutaneous lidocaine for treatment of neuropathic cancer pain. Pain 1991;45:145–8. 22. Altman DG. Practical Statistics for Medical Research. First ed. London: Chapman & Hall; 1991. 23. Sjaastad O, Russell D, Horven I, et al. Multiple neuralgiform, unilateral headache attacks associated with conjunctival injection and appearing in clusters. Proc Scand Migraine Soc 1978:31. 24. Cohen AS, Manjit S, Matharu MS, et al. Revisiting the International Headache Society criteria for SUNCT and SUNA: a case series of 52 patients. Cephalalgia 2005;25:1194. 25. Sjaastad O, Saunte C, Salvesen R, et al. Shortlasting unilateral neuralgiform headache attacks with conjunctival injection, tearing, sweating, and rhinorrhea. Cephalalgia 1989;9:147–56. 26. Pareja JA, Sjaastad O. SUNCT syndrome. A clinical review. Headache 1997;37:195–202. 27. Pareja JA, Baron M, Gili P, et al. Objective assessment of autonomic signs during triggered first division trigeminal neuralgia. Cephalalgia 2002;22:251–5. 28. Bahra A, May A, Goadsby PJ. Cluster headache: a prospective clinical study with diagnostic implications. Neurology 2002;58: 354–61. 29. Silberstein SD, Niknam R, Rozen TD, et al. Cluster headache with aura. Neurology 2000;54:219–21.
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30. Matharu MJ, Goadsby PJ. Post-traumatic chronic paroxysmal hemicrania (CPH) with aura. Neurology 2001;56:273–5. 31. Salvesen R. Cluster headache sine headache: case report. Neurology 2000;55:451. 32. Pareja JA. Chronic paroxysmal hemicrania: dissociation of the pain and autonomic features. Headache 1995;35:111–3. 33. Goadsby PJ, Lipton RB. A review of paroxysmal hemicranias, SUNCT syndrome and other short-lasting headaches with autonomic feature, including new cases. Brain 1997;120 (Pt 1):193–209. 34. May A, Bahra A, Buchel C, et al. Functional magnetic resonance imaging in spontaneous attacks of SUNCT: short-lasting neuralgiform headache with conjunctival injection and tearing. Ann Neurol 1999;46:791–4. 35. Sprenger T, Valet M, Platzer S, et al. SUNCT: bilateral hypothalamic activation during headache attacks and resolving of symptoms after trigeminal decompression. Pain 2005;113:422–6. 36. Matharu MS, Cohen AS, Frackowiak RS, et al. Posterior hypothalamic activation in paroxysmal hemicrania. Ann Neurol 2006;59:535–45. 37. Matharu MS, Cohen AS, McGonigle DJ, et al. Posterior hypothalamic and brainstem activation in hemicrania continua. Headache 2004;44:747–61. 38. Franzini A, Ferroli P, Leone M, et al. Stimulation of the posterior hypothalamus for treatment of chronic intractable cluster headaches: first reported series. Neurosurgery 2003;52:1095–9, discussion 9–101. 39. Leone M, Franzini A, Broggi G, et al. Long-term follow-up of bilateral hypothalamic stimulation for intractable cluster headache. Brain 2004;127:2259–64. 40. Schoenen J, Di Clemente L, Vandenheede M, et al. Hypothalamic stimulation in chronic cluster headache: a pilot study of efficacy and mode of action. Brain 2005;128:940–7. 41. Leone M, Franzini A, D’Andrea G, et al. Deep brain stimulation to relieve drug-resistant SUNCT. Ann Neurol 2005;57:924–7. 42. Zidverc-Trajkovic J, Mijajlovic M, Pavlovic AM, et al. Vertebral artery vascular loop in SUNCT and concomitant trigeminal neuralgia. Case report. Cephalalgia 2005;25:554–7. 43. Gardella L, Viruega A, Rojas H, et al. A case of a patient with SUNCT syndrome treated with Jannetta procedure. Cephalalgia 2001;21:996–9. 44. Hannerz J, Linderoth B. Neurosurgical treatment of short-lasting, unilateral, neuralgiform hemicrania with conjunctival injection and tearing. Br J Neurosurg 2002;16:55–8. 45. Lagares A, Gomez PA, Perez-Nunez A, et al. Short-lasting unilateral neuralgiform headache with conjunctival injection and tearing syndrome treated with microvascular decompression of the trigeminal nerve: case report. Neurosurgery 2005;56:E413, discussion E. 46. Lenaerts M, Diederich N, Phuoe D. A patient with SUNCT cured by the Jannetta procedure. Cephalalgia 1997;17:460. 47. Black DF, Dodick DW. Two cases of medically and surgically intractable SUNCT: a reason for caution and an argument for a central mechanism. Cephalalgia 2002;22:201–4. 48. Bussone G, Leone M, Dalla Volta G, et al. Short-lasting unilateral neuralgiform headache attacks with tearing and conjunctival injection: the first ‘‘symptomatic” case? Cephalalgia 1991;11:123–7. 49. De Benedittis G. SUNCT syndrome associated with cavernous angioma of the brain stem. Cephalalgia 1996;16:503–6. 50. Morales F, Mostacero E, Marta J, et al. Vascular malformation of the cerebellopontine angle associated with ‘‘SUNCT” syndrome. Cephalalgia 1994;14:301–2. 51. ter Berg JW, Goadsby PJ. Significance of atypical presentation of symptomatic SUNCT: a case report. J Neurol Neurosurg Psychiatry 2001;70:244–6. 52. Penart A, Firth M, Bowen JR. Short-lasting unilateral neuralgiform headache with conjunctival injection and tearing (SUNCT) following presumed dorsolateral brainstem infarction. Cephalalgia 2001;21: 236–9. 53. Kaphan E, Eusebio A, Donnet A, et al. Shortlasting, unilateral, neuralgiform headache attacks with conjunctival injection and tearing
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(SUNCT syndrome) and tumour of the cavernous sinus. Cephalalgia 2003;23:395–7. 54. Moris G, Ribacoba R, Solar DN, et al. SUNCT syndrome and seborrheic dermatitis associated with craniosynostosis. Cephalalgia 2001;21:157–9. 55. Massiou H, Launay JM, Levy C, et al. SUNCT syndrome in two patients with prolactinomas and bromocriptine-induced attacks. Neurology 2002;58:1698–9.
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Journal of Clinical Neuroscience 15 (2008) 526–534 www.elsevier.com/locate/jocn
Clinical Study
SUNCT and SUNA: Clinical features and medical treatment Max H. Williams a,*, Simon A. Broadley a,b a
Department of Neuroscience, Gold Coast Hospital, 108 Nerang Street, Southport, Queensland 4215, Australia b School of Medicine, Griffith University, Queensland, Australia Received 24 July 2006; accepted 12 September 2006
Abstract Short-lasting unilateral neuralgiform headache with conjunctival injection and tearing (SUNCT) and short-lasting unilateral neuralgiform headache attacks with cranial autonomic symptoms (SUNA) are considered to be rare primary headache disorders. The purpose of this study was to define the clinical features, response to prophylactic treatment and efficacy of lignocaine by subcutaneous infusion for periods of acute exacerbation requiring hospitalisation. Over a period of 6 years (March 2000–February 2006) all cases of SUNCT and SUNA in neurology clinics at the Gold Coast Hospital, Australia, were reviewed. International Headache Society diagnostic criteria were used. Clinical features and response to treatment were prospectively recorded using headache diaries and magnetic resonance imaging of the brain was carried out. Twenty-four subjects with SUNCT or SUNA were identified. The incidence of these conditions was 1.2/100,000 and the prevalence 6.6/100,000. An episodic disease course was evident in 14/24 (58%) cases, whereas 10/24 (42%) had a chronic course. An aberrant vessel in close association with the fifth cranial nerve was seen in 88% of cases. A good or excellent response to lamotrigine was seen in 11/19 (58%) and was more effective in the episodic group (100%). A subcutaneous infusion of lignocaine proved completely effective on 11/14 (78%) occasions. SUNCT and SUNA are not rare conditions. Characterisation into episodic and chronic disease course appears to be of prognostic and therapeutic importance. Lamotrigine is effective in the majority of cases and subcutaneous lignocaine is useful as acute treatment for severe recalcitrant attacks. Crown Copyright Ó 2007 Published by Elsevier Ltd. All rights reserved. Keywords: SUNCT; SUNA; Headache; Lamotrigine; Lignocaine
1. Introduction Short-lasting unilateral neuralgiform headache with conjunctival injection and tearing (SUNCT) is classified by the International Headache Society as a primary headache disorder.1 The hallmark of SUNCT syndrome is a tendency to recurrent attacks of moderate to severe stabbing pain around the eye or temple with associated autonomic features. The duration of the pain should be between 5 and 240 s with an attack frequency of 3 to 200 per day. Short-lasting unilateral neuralgiform headache attacks with cranial autonomic symptoms (SUNA) have similar features but there is a broader range of attack durations, between 2 s and 10 min, with an attack *
Corresponding author. Tel.: +61 7 5571 8161; fax: +61 7 5519 8613. E-mail address: [email protected] (M.H. Williams).
frequency of one or more per day.1 As for the other trigeminal autonomic cephalgias, cluster headache and paroxysmal hemicrania, episodic and chronic forms of SUNA, but not specifically SUNCT, are recognised by the International Headache Society.1 Trigeminal neuralgia usually involves the second or third division of the trigeminal nerve with brief shock-like pains lasting from a fraction of a second to 2 min, and has a refractory period to trigger factors.1 First division trigeminal neuralgia is uncommon, but can be associated with mild autonomic features and there have been reports of cases that appear to have evolved from this form of trigeminal neuralgia to SUNCT.2–4 Prominent autonomic features, attack duration, lack of refractory period to trigger factors and relative resistance to carbamazepine are cited as distinguishing features separating SUNCT from trigeminal neuralgia.4–7
0967-5868/$ - see front matter Crown Copyright Ó 2007 Published by Elsevier Ltd. All rights reserved. doi:10.1016/j.jocn.2006.09.006
M.H. Williams, S.A. Broadley / Journal of Clinical Neuroscience 15 (2008) 526–534
Medical treatment of SUNCT is frequently disappointing.7 There are anecdotal reports in the literature of various agents that have been effective in individual patients. These include verapamil,8 gabapentin,9,10 lamotrigine11–13 and topiramate.14,15 One difficulty in assessing medication response is that spontaneous remission may occur and can be prolonged.16 An intravenous infusion of lignocaine (known as lidocaine in the US) has been successful in controlling chronic daily headache17,18 but not acute migraine.19 A short infusion of 4 mg per min over 48 h with a 100 mg bolus of lignocaine was ineffective in two subjects with SUNCT syndrome.7 However, Matharu et al. found that an intravenous lignocaine infusion was at least temporarily effective in SUNCT syndrome, allowing time for the introduction of prophylactic medication in four subjects.20 Subcutaneous lignocaine infusion giving blood levels of 2 to 5 lg/mL has been shown to be effective in controlling neuropathic cancer pain.21 To our knowledge this mode of treatment has not been reported in cases of SUNCT. Here we describe a case series of SUNCT and SUNA identified at the Gold Coast Hospital over a 6-year period. The clinical features and response to medication for these cases are described. 2. Patients and methods 2.1. Study design Over a 6-year period (March 2000–February 2006) all subjects who met the International Headache Society criteria for SUNCT and SUNA were included. The subjects were seen in neurology clinics at the Gold Coast Hospital, Australia. Data were collected prospectively via a headache diary following the initial consultation. This included the site, severity, duration and pattern of pain and the presence or absence and duration of relapses and remissions. Subjects were instructed to note the presence and severity of autonomic features including conjunctival injection, tearing, eyelid oedema, ptosis, erythema, sweating, rhinorrhoea or nasal congestion. Retrospective information, based on subject or witness recall, was included where appropriate. Follow-up data were collected by chart review, direct re-interview or by telephone. Only subjects with prominent autonomic features were included. ‘Prominent’ was defined as conjunctival injection that was obvious to the subject or witness and was accompanied by lacrimation. If nasal congestion or rhinorrhea was associated with conjunctival injection and/or tearing this was also regarded as ‘prominent’. Thus subjects who had only conjunctival injection or tearing were excluded even though they may have met the International Headache Society criteria for SUNA. Episodic SUNCT or SUNA was defined according to the International Headache Society criteria for episodic SUNA1 as attacks lasting 7 days to 1 year, separated by a pain-free period lasting 1 month or longer. Chronic SUNCT or SUNA was defined as attacks occurring for
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more than 1 year without remission or with remission lasting less than 1 month. To exclude symptomatic SUNCT an MRI of the brain was carried out using a 1.5 T scanner. Dedicated views of the fifth cranial nerve were obtained in all subjects from 2002. Following D’Andrea and colleagues’ report (1999),11 lamotrigine was chosen as the first-line treatment for prophylactic therapy provided there were no contraindications. Lamotrigine was commenced at 25 mg per day, increasing by 25 mg every 4–7 days until symptoms were controlled, adverse events were seen or a maximal dose of 600 mg was achieved. If symptoms were of such severity that activities of daily living were affected, subjects were hospitalised for a lignocaine infusion. Initially given via an intravenous route, after 2003 a subcutaneous route was used. Lignocaine (2 g reconstituted in normal saline to 100 mL) was infused subcutaneously into the anterior abdominal wall at a rate of 6 mL per hour, equivalent to 2 mg per minute. After 24–48 h the dose was adjusted according to the blood level of lignocaine. A level of 2–5 lg/mL was taken as therapeutic.21 An electrocardiogram was performed prior to the commencement of the infusion and again after 2 h. Vital signs were monitored at 30 min intervals for the first 2 h. Lignocaine was not given if there was a cardiac or other contraindication. Continuous cardiac monitoring was not performed unless there was a specific indication. Metoclopramide 10 mg orally was given prior to the start of the infusion and continued routinely at 10 mg four times a day throughout. Adverse events were recorded for all medications used. Response to medication was recorded using a simple 4-point scale (Table 1). 2.2. Statistical analysis All comparison statistics were made using odds ratios with 95% confidence intervals or p-values based on a v2 statistic and were performed using the Statistics Calculator v1.2 of the Toronto University Evidence Based Medicine website (www.cebm.utoronto.ca/practise/ca/statscal/; accessed 16 June 2006). In view of the relatively low subject numbers and on the assumption that the results would only be hypothesis-generating rather than definitive, adjusted figures have not been used. For incidence and prevalence
Table 1 Treatment response scale Scale
Response
Definition
– + ++
No response Mild– moderate Good
+++
Excellent
No change in headache frequency or severity <50% reduction in headache frequency and/or severity >50% reduction in headache frequency and/or severity >90% reduction in headache frequency and/or severity
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M.H. Williams, S.A. Broadley / Journal of Clinical Neuroscience 15 (2008) 526–534
data nominal 95% confidence intervals were calculated as per Altman.22 3. Results 3.1. Subjects During the 6-year study period, 24 cases of SUNCT or SUNA were identified. One subject was lost to follow-up and another died 9 months after SUNCT diagnosis from a carcinoma of the oesophagus. Age of onset varied from 17 to 65 years (mean 40 years). There were 14 females and 10 males, 23 Caucasians and 1 Asian. 3.2. Incidence and prevalence estimates In a 6-year period 24 patients were identified in a population of approximately 500 000. The authors are aware of three other cases, and direct questioning of all other neurological referral centres revealed the presence of eight additional cases. This suggests a conservative annual incidence estimate of 1.2/100 000 (95% CI: 0.2–2.0/100 000) for SUNCT/SUNA. Allowing for the death of one subject and another leaving the district the prevalence was approximately 6.6/100 000 (95% CI: 4.3–8.9/100 000). 3.3. Clinical features By definition all 24 subjects qualified for the diagnosis of SUNA, with 17 subjects meeting the more restrictive criteria for SUNCT. Five subjects were classified as SUNA as the attack duration exceeded 240 s on most occasions, whereas in two subjects the attacks varied between the SUNCT and SUNA ranges. The clinical features of the 24 patients are summarised in Table 2. The left side was affected in 13 patients, the right side in eight, the affected area changed sides in one, and two patients had varying attacks on either side. Symptom duration before diagnosis ranged from 1 month to 30 years. Individual attack duration varied from 1 s to 5 min, occurring at a frequency of 1 to 300 per day or night. Attacks of stabbing pain occurred in three distinct patterns: saw-toothed (eight subjects), grouped (nine subjects), and singly (seven subjects). Trigger factors were identified by 15/24 (63%) subjects. Twelve of 15 (80%) subjects with SUNCT had identifiable triggers versus 2/4 (50%) subjects with SUNA and 1/2 (50%) with both SUNCT and SUNA. In 8/11 (73%) episodic and 7/10 (70%) chronic subjects trigger factors were noted. The saw-toothed pattern had an increased frequency of trigger factors compared with the single stab group, 7/8 (87.5%) and 3/6 (50%) respectively. No subject noted a refractory period. Triggers in this series include a light touch to the face, a cool breeze, combing or brushing the hair, chewing, talking or teeth brushing. The cool breeze from air conditioning ducts was a common trigger. Subject 24, for example, had to have his hospital bed positioned away from the
air conditioning unit and would wear a bandage around his forehead for extra protection. Shaving was not noted as a trigger. Weight loss occurred in two subjects due to SUNCT being precipitated by chewing. Subject reporting of pain severity was variable but generally severe at the peak of an attack. The prominence of the autonomic features usually increased with the severity of the pain, but this was not always the case. Two subjects (subjects 3 and 11) occasionally had autonomic features without pain, in addition to more typical attacks. Fourteen subjects required admission to hospital because of severe pain and one subject felt suicidal because of the pain. Unusual clinical features were present in several subjects. An aura of tingling involving the ipsilateral cheek with a numb sensation inside the cheek was noted by subject 8 for 1–2 min prior to an attack whereas subject 5 knew an attack was imminent when tingling over the ipsilateral side of the nose and forehead developed. It was thought that these phenomena were possibly due to peripheral trigeminal nerve irritation. MRI in subject 8 showed arterial contact with the trigeminal nerve; however, no vessel contact was seen in subject 5. Subject 4 had right-sided SUNCT attacks with occasional independent attacks of typical cluster headache on the left side that responded to oxygen or intranasal sumatriptan. Migraine without aura also occurred frequently in this subject. Migraine was a co-morbidity in 7/24 (29%) subjects, one with visual aura. No subject had migraine features associated with their SUNCT or SUNA attacks. Subjects 5 and 11 were unusual in that the conjunctival injection and tearing were ipsilateral to the pain, whilst rhinorrhea occurred on the opposite side, with the ipsilateral nasal passage remaining clear during the attack. Subject 8 had conjunctival injection on the contralateral side to the SUNCT pain. 3.4. Episodic and chronic SUNCT/SUNA An episodic course was seen in 14 (58%) subjects and a chronic course in 10 (42%). In the episodic group there were seven males and seven females with an age of onset range of 17–64 years (median 37.1 years). The chronic group had seven females and four males with an age of onset range of 32–65 years (median 50.3 years). A comparison of clinical features in episodic and chronic cases is shown in Table 3. Subjects with episodic disease, three for more than 26 years, have maintained this pattern with remissions lasting up to 7 years and thus far have not evolved into the chronic form. In contrast, subjects with chronic disease have remained chronic from the onset, modified to some degree by medication. 3.5. MRI results MRI was not available for one subject lost to follow-up. Ischaemic changes were noted in four subjects, one with a
Table 2 Clinical features of 24 patients with SUNCT/SUNA Subject
Sex
Age at onset (years)
Age at diagnosis (years)
Duration of symptoms
Attack frequency (per day)
Duration of attacks (s)
Trigger factors
Episodic/ chronic
SUNCT/ SUNA
Attack pattern
Side
Previous diagnosis
MRI
Lignocaineb
Maximum dose (mg)
Effect
Route of infusion/ duration (days)
Effect
++ NA +++ NA NA NA +++ +++ ++ +++ +++ +++ +++ NA +++ NA +++ ++
1 2 3 4 5 6 7 8
M M F M F M F F
37 64 40 28 43 34 38 43
37 64 43 58 43 36 38 43
4 weeks 9 months 3 years 30 years 6 months 2 years 2 months 4 months
120 100 1–30 10 10–30 30–60 5 100–300
30 30 10–20 10–45 120–180 20–30 20 30–120
Yes Yes Yes No Yes Unknown Unknown Yes
Episodic Episodic Episodic Episodic Episodic Episodic Episodic Chronic
SUNCT SUNCT SUNCT SUNCT SUNCT SUNCT SUNCT SUNCT
ST ST SG SG SG SG SS ST
R L L R L R L R&L
CH CH TN CH Unknown TN Unknown CH
Normala Leukoariosisa Normala Normala Normala Not done Normal A both sides
150 100 400 200 400 NA NA 600
+++ +++ +++ ++ ++ NA NA ++
9 10
M F
53 46
56 46
3 years 5 months
20–30 90–120
30–120 3–10
None Yes
Chronic Chronic
SUNCT SUNCT
SG ST
L R
Migraine GCA
A and V A
400 600
+ +
11 12 13 14 15 16
F F F F F M
47 17 46 26 19 58
47 22 48 26 47 61
1 month 5 years 2 years 2 months 28 years 3 years
2–50 100–200 30–50 10 100–300 5–10
5–20 120 300 180–240 5–10 60–300
Yes Yes Yes Unknown None None
Chronic Episodic Chronic Episodic Episodic Chronic
SUNCT SUNCT SUNA SUNA SUNCT BOTH
SG ST SG SS ST SS
L/R L&R L L L R
Migraine PH PH TN CH TN
600 400 400 NA 50 200
+ +++ + NA +++ +
17 18
M M
19 55
47 56
26 years 1 year
8–10 20–30
20–180 120–300
Yes Yes
Episodic Chronic
SUNCT SUNA
SS SS
L R
CH Central pain
A both sides A both sides A and V Normal A A and V Lacunar infarcts A A
IV/5 Not used IV/6 Not used Not used Not used IV/6 SCI/9 SCI/7 SCI/7 SCI/5 SCI/5 SCI/5 Not used SCI/7 Not used SCI/5 SCI/7
100 400
+++ +
Not used SCI/7
NA +++
19
F
65
71
6 years
30–200
60–120
Yes
Chronic
SUNCT
ST
R
TN
400
+
SCI/8 SCI/14
+++ +++
20 21 22 23 24
M F F M M
58 47 32 54 54
58 49 34 54 54
6 2 2 1 3
7 2–6 20–40 15–20 100–300
120–300 300 2–10 1–300 30–90
None None Yes Yes Yes
Chronic Episodic Chronic Episodic Episodic
SUNA SUNA SUNCT BOTH SUNCT
SS SS SG SG ST
L L R L L
TN TN Unknown TN TN
A, Brainstem infarct A Normal A both sides A A
NA 200 200 NA 150
NA +++ ++ NA +++
Not used Not used SCI/7 Not used SCI/7
NA NA +++ NA +
months years years month months
M.H. Williams, S.A. Broadley / Journal of Clinical Neuroscience 15 (2008) 526–534
Lamotrigineb
(Short-lasting unilateral neuralgiform headache with conjunctival injection and tearing / Short-lasting unilateral neuralgiform headache with cranial autonomic symptoms). ST, saw-tooth; SG, stab groups; SS, single stabs; L, left; R, right; CH, cluster headache; TN, trigeminal neuralgia; GCA, giant cell arteritis; PH, paroxysmal hemicrania; NA, not applicable; LMCA, left middle cerebral artery; A, artery; V, vein; IV, intravenous; SCI, subcutaneous injection. a MRI performed without dedicated views of fifth nerve. b For definitions of treatment responses see Table 1.
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Table 3 Comparison of clinical features and response to treatment in episodic and chronic SUNCT/SUNA Clinical feature
Age >45 years Male Trigger factor present SUNCT syndrome Aberrant vessel Lamotrigine trialled Lamotrigine responsivea Lignocaine infusion used Lignocaine responsivea
Chronic
Episodic
n/N
%
n/N
%
8/10 4/10 7/10 7/10 10/10 9/10 1/9 9/10 9/9
(80) (40) (70) (70) (100) (90) (11) (90) (100)
4/14 7/14 8/14 12/14 5/13b 10/14 10/10 5/14 4/5
(29) (50) (57) (86) (38) (71) (100) (36) (80)
OR
95% CI
10.00 0.67 1.75 0.39 32.46 3.60 0.01 16.20 6.33
1.44–69.26 0.13–3.45 0.31–9.75 0.05–2.92 1.56–673.78 0.38–38.48 0–0.23 1.57–167.75 0.213–188.17
(Short-lasting unilateral neuralgiform headache with conjunctival injection and tearing / Short-lasting unilateral neuralgiform headache with cranial autonomic symptoms). OR, odds ratio; CI, confidence interval. a Good or excellent response (see Table 1 for definitions). b MRI not available in one subject.
left middle cerebral artery distribution infarction, lacunar infarcts in one, leukoariosis in one and one subject had a brain stem infarct. Of subjects who had dedicated views of the trigeminal nerve, 15/17 (88%) were positive for an aberrant arterial loop in contact with or deforming the trigeminal nerve. In three of these subjects, symptoms were bilateral and of the 20 symptomatic nerves 18 (90%) showed an aberrant vessel. In contrast an aberrant arterial loop was present in one of 14 (7%) of the asymptomatic nerves (p < 0.0001). No pituitary lesion was seen. 3.6. Response to treatment One subject had used verapamil without effect. One pregnant subject had a remission on carbamazepine but this was ineffective in seven other patients. Gabapentin appeared moderately effective in 1/8 cases only. Topiramate was moderately effective in one subject who was intolerant of lamotrigine but ineffective in five others. In the episodic group, 8/10 (80%) subjects had an excellent response to lamotrigine but 0/9 (0%) in the chronic group had this result (p = 0.004; Table 3). The other two episodic subjects had a moderate effect with lamotrigine. The majority of chronic subjects noted only a mild effect with lamotrigine. In responders the mean dose of lamotrigine required to achieve an excellent response was 194 mg whereas poor responders received an average of 429 mg/day. An effect was usually noted with a relatively low dose and in general there was little to be gained by pushing the dose above 400 mg/day. However, even subjects receiving higher doses, who felt that lamotrigine was ineffective, did notice an increase in symptoms on dose reduction. Drowsiness, fatigue and memory difficulties occasionally limited the dose (subjects 18, 19 and 22). A mild skin rash occurred in one subject while taking 50 mg of lamotrigine per day. This disappeared on cessation of the drug; however, her previously modified SUNCT increased in severity. Lamotrigine was reintroduced at 12.5 mg per day together with prednisone 50 mg per day. The rash did not return after the ste-
roid was tapered and the dose of lamotrigine was safely increased to 600 mg a day with a moderate effect on SUNCT symptoms. A lignocaine infusion was used on 17 occasions in 14 subjects, three by the intravenous route and 14 by subcutaneous infusion. Pain attacks were completely abolished on 13/17 (76%) occasions. The subcutaneous route was as effective as the intravenous route, 11/14 (79%) and 2/3 (67%) having an excellent result, respectively. Mild residual attacks persisted in three subjects and one subject noted only a minimal response. In episodic cases 5/14 (36%) required lignocaine for a mean infusion time of 6 days, whereas in the chronic group 9/10 (90%) required infusions for an average of 8 days, three needing a second admission. One patient felt somewhat depressed and three had vivid dreams. No adverse cardiac events occurred. A seizure occurred in subject 16, where there was a prior history of seizure disorder. Following appropriate adjustment of phenytoin dose the infusion was recommenced cautiously at a lower rate with partial control of SUNA symptoms and without any further adverse events. 4. Discussion Since Sjaasted and colleagues first described SUNCT in 1978,23 it has been considered a rare disorder. With increasing recognition more cases have been reported, for example Cohen et al. described 52 cases in 2005.24 Here we describe 24 cases and provide crude estimates for incidence and prevalence, which would suggest that SUNCT and SUNA are more common than previously thought. Although the typical presentation of SUNCT or SUNA is sufficiently dramatic to prompt neurological referral in the majority of cases, it seems likely that the syndromes are under diagnosed. Our incidence figures may be an overestimate due to the cohort effect that may occur when a new diagnosis emerges, but in fact the year by year incidence figures have not changed significantly over the 6 years of this study. In contrast to earlier reports that suggested that SUNCT
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syndrome is a male-dominant disease with a ratio of 17:2,25 this series shows a ratio of 7:5 in favour of females. The phenotypic expression of SUNCT is variable. Like Cohen et al., three basic patterns of attacks could be identified in the present study.24 The saw-toothed pattern was seen in one-third of subjects. Often these attacks would last up to 6 h, with mild background discomfort or pain punctuated by discrete short, usually severe, paroxysms of pain lasting for seconds or 1–2 min with a similar period of respite, the autonomic features waxing and waning with the pain. As this scenario would repeat itself several times a day or night, the actual number of individual stabs of pain could be up to 300 or more for a 24 h period. Spontaneously or with medication the pattern could change to stab groups or isolated stabs. Groups of stabs occurred in just over one-third of subjects. In this pattern, distinct paroxysms of SUNCT or SUNA may occur over a period of 5 to 15 min, with distinct groups repeating themselves several times a day or night. Single stabs occurred in the remainder. Usually the total number per 24 h period was less than the other two patterns but the intensity was no less severe. The saw-toothed pattern was frequently misdiagnosed as cluster headache. Accurate history taking, observing the subject during the attack and lack of response to oxygen and sumatriptan should alert the clinician. A diagnosis of paroxysmal hemicrania, episodic or chronic, was considered in some subjects, especially long SUNA and stab group subjects, but was discounted by the absolute failure of an indomethacin trial. Many subjects were referred because of a diagnosis of intractable trigeminal neuralgia. The ophthalmic distribution, the often longer duration of paroxysms, prominent autonomic features, the lack of a refractory period to trigger factors and the relative lack of response to carbamazepine assisted in establishing the diagnosis of SUNCT.6,7 In contrast to trigeminal neuralgia, no subject had a refractory period in the present series. This is one hallmark of SUNCT syndrome.6,7,26 Similar to trigeminal neuralgia, trigger factors were common in SUNCT, present in 80% of subjects but this was only noted in 50% of SUNA and SUNCT/SUNA subjects who had longer durations of individual attacks. Although not statistically significant, these findings are similar to those of Cohen et al.24 The distinctions between trigeminal neuralgia, SUNA and SUNCT are certainly blurred and there is potential for overlap. However, autonomic features in classical trigeminal neuralgia are rare and have distinct characteristics,27 which are unlikely to be included in the definition of autonomic features used for the present series. It is notable that in SUNA, in which there is greatest potential for overlap with trigeminal neuralgia, the incidence of trigger factors is lower than in SUNCT. The duration of episodes and very prominent early autonomic features in SUNCT are very unlikely to be confused with trigeminal neuralgia. The absence of a refractory period is less helpful, as the
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presence of this feature may not be noticed by subjects with classical trigeminal neuralgia. We identified two subjects with aura as part of the manifestation of their SUNCT attacks. Aura has been described in other trigeminal autonomic cephalgias including cluster headache,28,29 and chronic paroxysmal hemicrania,30 and more recently in SUNCT.20 Autonomic features without pain have been noted in the trigeminal autonomic cephalgias, notably cluster headache31 and chronic paroxysmal hemicrania.32 The mechanism of the autonomic features of SUNCT is presumably via the trigeminal autonomic reflex.33 The ipsilateral superior salivatory nucleus is stimulated via fibres from the nucleus caudalis, having been activated by the trigeminal nerve. Fibres from the superior salivatory nucleus travel initially in conjunction with the facial nerve and via the greater superficial petrosal nerve to terminate in the nasal mucosa, lacrimal apparatus and blood vessels. An internal trigger located in the ipsilateral hypothalamus is thought to activate the trigeminal autonomic reflex.34 May et al. demonstrated activation of the ipsilateral posterior hypothalamus in SUNCT syndrome.34 However, Sprenger and colleagues noted bilateral activation of a similar area of the hypothalamus.35 If the internal trigger can be bilateral in some patients then bilateral features could theoretically occur, a phenomenon which was observed in this series. The separation of the pain from the autonomic features suggests that the superior salivatory nucleus may be independently activated. In cluster headache a similar area in the hypothalamus appears to orchestrate attacks.16 More recently the contralateral hypothalamus has been shown to be involved in paroxysmal hemicrania36 and hemicrania continua,37 both indomethacin-responsive headaches. Stereotactic ablation of this area has resulted in complete relief of cluster headache in some patients, providing evidence that cluster headache is a primary headache disorder.38–40 Symptom control following deep brain stimulation of the appropriate area of the hypothalamus in a patient with SUNCT41 also suggests that SUNCT is a primary headache disorder with pathophysiology similar to cluster headache.16 Whether an aberrant vascular loop, potentially irritating the trigeminal nerve, may act as an additional trigger to attacks is open to speculation, but the present series would suggest that the finding of an aberrant vascular loop in close association with the ipsilateral fifth nerve is a common occurrence (88%). Previous literature on this association is restricted to isolated case reports.42 The authors are not aware of any prior systematic survey for aberrant vessels in SUNCT and SUNA. There have been anecdotal reports of successful treatment of SUNCT with microvascular decompression,43–46 but caution has been advised.47 Cases of symptomatic SUNCT have been reported, including vascular malformations,48–50 basilar impression,51 presumed brain stem infarction,52 a leiomyosarcoma of the cavernous sinus,53 craniosynostosis,54 prolactinoma55,56 and acromegaly.57
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The anecdotal effectiveness of verapamil,8 carbamazepine,58 gabapentin9,10 and topiramate14,15 were not confirmed in this study. However, verapamil was only used once and the doses of carbamazepine and gabapentin were possibly suboptimal, but in most cases were the maximum tolerated. It should be noted that topiramate was not used as first-line therapy but was given to subjects who had an incomplete response to lamotrigine. Topiramate was effective in one episodic SUNCT subject who had a skin rash attributed to lamotrigine. The separation of SUNCT or SUNA into episodic and chronic forms may have important therapeutic implications. Subjects with episodic SUNCT or SUNA were more responsive to lamotrigine than the chronic group (p = 0.001). In 80% of episodic subjects an excellent response was seen and in the other two a >50% reduction in symptomatology was noted. In the chronic group no subject had an excellent response to lamotrigine but two (22%) had a good response. The apparent effectiveness of lamotrigine in inducing remission in episodic subjects may be an overinterpretation, as spontaneous remission is part of the normal pattern of the disease. However, this seems unlikely as lamotrigine was frequently used after other trials of ineffective medication. Following initial success with an intravenous infusion of lignocaine in three subjects with SUNCT, subcutaneous lignocaine infusion was used on a further 14 occasions in 13 subjects. Complete control of symptoms often occurred within 4–5 days, but some required longer. On 76% of occasions complete control was achieved for both the pain and autonomic features. In the remainder there was either a marked reduction in frequency and severity of symptoms, or a transient improvement. Hospitalisation for a lignocaine infusion was required in 90% of chronic subjects compared with 36% of episodic subjects. Symptom control could usually be achieved in both groups. This period allowed for the introduction of prophylactic therapy and titration to an effective dose. Generally the effect of lignocaine is transient, with symptoms recurring within a day or two of ceasing the infusion. However, one subject with episodic SUNCT has remained in complete remission for 4 years following her subcutaneous infusion, without prophylactic medication. Adverse effects were minimal with subcutaneous lignocaine infusion. Nausea is common but is usually controlled with metoclopramide started prior to commencement of the infusion and continued on a regular basis. Neuropsychiatric effects were generally also mild.
SUNA, trigeminal neuralgia and other trigeminal autonomic cephalalgias. However, the present findings provide evidence for the usefulness in prognostic and therapeutic terms for the continued differentiation of these clinical entities, and we would recommend that, pending a definitive explanation of the underlying pathophysiology of these conditions, the strict diagnostic criteria of these clinical entities be adhered to. The most recent classification of the International Headache Society1 recommends that dual diagnoses be applied when features of trigeminal neuralgia and SUNCT coexist. However, in the present series that confusion was not apparent and we would suggest that the failure of SUNCT and SUNA to respond to carbamazepine is helpful in making the distinction between these two diagnoses and that a single diagnosis (usually SUNA) should be applied. We have identified episodic and chronic patterns for both SUNCT and SUNA, and this may have important aetiological, prognostic and therapeutic implications. In subjects with chronic SUNCT or SUNA an aberrant vessel impinging on the fifth nerve seems to occur more frequently, leading to the hypothesis that this is of aetiological significance and may account for the persistent nature of the attacks. At the present time it is not possible to comment on the implications with regard to treatment that this finding might have. Episodic and chronic forms appear to remain consistent with no changes in pattern being observed in this series. The chronic group tend to be more resistant to treatment and require more frequent admission to hospital. In this series 80% of patients with episodic SUNCT or SUNA had an excellent response to relatively low doses of lamotrigine, whereas patients with the chronic form usually require a higher dose and even then control is often suboptimal. This supports the use of lamotrigine as first-line therapy in SUNCT and SUNA. We have also demonstrated that lignocaine by subcutaneous infusion is as effective as the intravenous route in controlling severe exacerbations in the majority of cases, and allows time for the adjustment of prophylactic medication. It should be emphasised that this was an un-blinded, observational study, and that our findings should only be considered as hypothesis-generating. There is a need for a large-scale placebo-controlled trial of both lignocaine subcutaneous infusion for acute treatment in SUNCT/SUNA and for lamotrigine in the long-term management of this condition.
5. Conclusions
Thanks to Lyn Williams and Jan Neville for their assistance in preparing the manuscript.
In the Gold Coast region, SUNCT and SUNA were more common than has been previously recognised. A wide phenotypic expression of both pain pattern and autonomic features was seen. It is evident from this series and others that there is a degree of overlap in both the clinical features and proposed pathophysiological mechanisms for SUNCT,
Acknowledgements
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