23 How Cluster Headache and Other Trigeminal Autonomic Cephalalgias Present

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1 23 How Cluster Headache and Other Trigeminal Autonomic Cephalalgias Present Henrik Winther Schytz 1. Cristina Tassorelli 2. Messoud Ashina 1 1 Glostrup Hospital, University of Copenhagen, Glostrup, Copenhagen, Denmark 2 University Consortium for Adaptive Disorders and Head Pain (UCADH), University of Pavia, Pavia, Italy Introduction Established Knowledge Cluster Headache Epidemiology Periodicity Attack Characteristics Autonomic Symptoms General Symptoms Premonitory and Prodromal Symptoms Neurological Examination Triggers Therapeutic Treatment Response Paroxysmal Hemicrania Epidemiology Attack Characteristics Autonomic Symptoms General Symptoms Neurologic Examination Triggers Therapeutic Treatment Response SUNCT (Short-Lasting Unilateral Neuralgiform Headache Attacks with Conjunctival Injection and Tearing) Epidemiology Attack Characteristics Autonomic Symptoms General Symptoms Neurological Examination Paolo Martelletti, Timothy J. Steiner (eds.), Handbook of Headache, DOI / _23, # Lifting The Burden 2011

2 How Cluster Headache and Other Trigeminal Autonomic Cephalalgias Present Triggers Therapeutic Treatment Response Differential Diagnosis of Trigeminal Autonomic Cephalalgias Current Research

3 How Cluster Headache and Other Trigeminal Autonomic Cephalalgias Present Abstract: The trigeminal autonomic cephalalgias (TACs) comprise of cluster headache (CH), paroxysmal hemicrania (PH), and short-lasting unilateral neuralgiform headache attacks with conjunctival injection and tearing (SUNCT). The TACs consist of severe headache attacks accompanied by prominent oculocephalic autonomic features. The TACs occur in both episodic and chronic forms, in which the episodic form is most frequent in CH compared to the predominance of chronic PH and chronic SUNCT. The three TACs can be differentiated from each other according to their attack duration, attack frequency, and therapeutic treatment response. CH has the longest duration of attacks with the lowest daily frequency. PH has an intermediate attack duration and frequency, whereas SUNCT has the shortest attack duration and highest daily attack frequency. CH is much more prevalent than PH and SUNCT, and is also characterized with more frequent nocturnal attacks as well as annual periodicity. CH may be triggered by alcohol and nitroglycerin during a cluster period. In contrast to CH and PH, SUNCT is very often triggered by cutaneous stimuli. A successful response oxygen treatment points to the CH diagnosis, a successful indomethacin-test strongly indicate PH, whereas negative responses following both treatments is likely to be seen in typical SUNCT patients. Introduction Cluster headache (CH), paroxysmal hemicrania (PH), and short-lasting unilateral neuralgiform headache attacks with conjunctival injection and tearing (SUNCT) are primary headaches with unilateral pain recently classified as trigeminal autonomic cephalalgias (TACs) (IHS 2004)(> Table 23.1). TACs can be very disabling conditions with a major impact on the patient s quality of life (May et al. 2006). TACs are accompanied by prominent oculocephalic autonomic features (mostly parasympathetic in nature), other primary headaches, such as migraine and hemicrania continua, may be accompanied by mild autonomic features. CH and PH exist in an episodic form characterized by attacks that recur in periods lasting 7 days to 1 year separated by pain-free periods lasting 1 month or longer, but also a chronic form occurring for more than 1 year or with short remissions lasting less than 1 month (IHS 2004). The 3 TAC entities can be differentiated from each other according to their attack duration, attack frequency, and therapeutic treatment response. Established Knowledge Cluster Headache Epidemiology CH is the most common TAC with a reported prevalence ranging from 0.06% to 0.3% (Tonon et al. 2002; Sjaastad and Bakketeig 2003; Torelli et al. 2005; Ekbom et al. 2006; Katsarava et al. 2007). CH mainly affects men with a female to male ratio of about 1:3 (Bahra et al. 2002; Ekbom et al. 2002), even though the number of female cluster headache patients seems to have increased over the years (Ekbom et al. 2002). In men with episodic and chronic CH and women with episodic CH, there is an onset peak at years of age. In women, particularly

4 How Cluster Headache and Other Trigeminal Autonomic Cephalalgias Present. Table 23.1 Diagnostic criteria for trigeminal autonomic cephalalgias from the International Classification of Headache Disorders (IHS 2004) Cluster headache At least five attacks of severe or very severe unilateral orbital, supraorbital, or temporal pain lasting min if untreated Headache accompanied by at least one of the following: Ipsilateral conjunctival infection or lacrimation Ipsilateral nasal congestion or rhinorrhea Ipsilateral eyelid edema Ipsilateral forehead and facial sweating Ipsilateral miosis or ptosis A sense of restlessness or agitation Attacks have a frequency from one every other day to eight per day Not attributed to another disorder Paroxysmal hemicrania At least 20 attacks of headache of severe, unilateral orbital, supraorbital, or temporal pain that lasts 2 30 min Headache associated with at least one of the following signs: Ipsilateral conjunctival injection or lacrimation Ipsilateral nasal congestion or rhinorrhea Ipsilateral eyelid edema Ipsilateral forehead or facial sweating Ipsilateral miosis or ptosis Attack frequency of more than five headaches daily for more than one half of the time, although periods with lower frequency may occur Attacks are completely prevented by therapeutic doses of indomethacin Not attributed to another disorder SUNCT 20 attacks of unilateral orbital, supraorbital, or temporal stabbing or pulsating pain lasting s Pain is accompanied by ipsilateral conjunctival injection and lacrimation Attacks occur with a frequency from 3 to 200 per day Not attributed to another disorder SUNCT short-lasting unilateral neuralgiform headache attacks with conjunctival injection and tearing the chronic cases, there is a more even distribution of the age at onset across life and relatively more chronic cases after 50 (Ekbom et al. 2002). Interestingly, CH patients are often smokers (85% men and 60% women) and consume more alcohol than the background population (Black et al. 2006). However, there exist no correlation between withdrawal from alcoholic drinks or smoking and changes in the course of CH, even though giving up drinking might favor the onset of remission period in some cases (Black et al. 2006).

5 How Cluster Headache and Other Trigeminal Autonomic Cephalalgias Present Periodicity One remarkable and fascinating aspect of CH is its periodic pattern, with attacks often occurring at almost the same time every day (Ekbom 1970). Besides the circadian (certain times of day) periodicity, episodic CH can also show a circannual (certain seasons of the year) periodicity (Kudrow 1980; Russell 1981). A well-known feature of CH is that 51% of cluster attacks occur during sleep, with a peak frequency from 4 to 10 AM (Russell 1981). These nocturnal circadian attacks occur during both REM (rapid eye movement) and non-rem sleep periods (Kudrow et al. 1984). Circannual cluster periods have been shown to peak in February and June, which may be related to peaks in the minimum and maximum light hours of the day (Kudrow 1980, 1987). Attack Characteristics Typically, a cluster headache attack rapidly increases within 10 min (Torelli and Manzoni 2003) to an excruciating pain, which usually lasts between 70 and 160 min, but may range from 15 min to 3 h (Bahra et al. 2002; IHS 2004). During an attack, the site of pain is predominantly retro-orbital (92%) and temporal (70%) (Bahra et al. 2002). Thus, the pain is predominantly located in areas under the distribution of the first division of the trigeminal nerve. However, the pain might be experienced over a wide area including the forehead, jaw, cheek, upper and lower teeth, and, less commonly, the ear, nose, neck, shoulder (Bahra et al. 2002). Pain is strictly unilateral, indeed only 1% of patients experience a shift of the pain during an attack. However, it must be noted that 18% of CH subjects have reported pain side shift within one cluster period and from one period to the other (Bahra et al. 2002). The pain during cluster headache attacks is extremely intense, boring, pressing, or burning pain (Torelli and Manzoni 2005) and is described as one of the worst known pain experience (Blau 1993). CH patients are restless in up to 93% of cases (Bahra et al. 2002), which therefore has been considered a sensitive and specific parameter of CH. During attacks, patients tend to walk around, sit (or kneel), rock, and clutch the affected side of the head (Blau 1993). Patients may also, in order to alleviate or cope with the excruciating pain, rub their head, apply cold substances to the site of pain, or seek a dark room (Russell 1981). During the active periods, CH attacks tend to recur several times per day (Bahra et al. 2002), but a high variability exists and therefore the criterion regarding attacks frequency of the IHS classification allows from one every second day to eight per day (IHS 2004). The volcano effect of episodic CH is well known, in which attacks are substantially shorter and less severe in the beginning and end of a cluster period than in the middle (Kudrow 1980). Interictal pain has also been reported in up to 50% during active cluster periods (Marmura et al. 2010). Episodic CH is the most frequent form of CH, whereas chronic CH occurs in 10 15% of cases (IHS 2004). However, CH may transform from the episodic to the chronic form (Torelli and Manzoni 2002), even though chronic CH may also occur de novo (primary) (Torelli et al. 2000). Most CH patients experience one cluster period per year lasting a mean of 9 weeks (Bahra et al. 2002), and it has been documented that 67% of CH patients have remissions lasting 1 year or less and 81% have remissions lasting 2 years or less (Kudrow 1980). CH, and likely the other TACs, may remain unrecognized due to a diagnostic delay with a median time between the first episode and the diagnosis of up to 3 years (Van Vliet et al. 2003).

6 How Cluster Headache and Other Trigeminal Autonomic Cephalalgias Present Autonomic Symptoms During a CH attack, the most frequent autonomic symptom is lacrimation (91%), followed by conjunctival injection (77%), nasal congestion (75%), ptosis or eyelid swelling (74%), and rhinorrhea (72%) (Bahra et al. 2002). Sweating seems to occur only in a minority of attacks (26%) and is difficult to assess clinically (Sjaastad et al. 1981). It has been reported that 3% of patients lack autonomic symptoms (Ekbom 1990), but this can still lead to a CH diagnosis, if a sense of restlessness and agitation is present during a CH attack (IHS 2004). General Symptoms Nausea, photophobia, and phonophobia, can be present in CH patients. In a large cohort, 50% of cluster patients reported nausea during an acute attack, and a similar percentage reported at least one episode of photophobia (56%) and phonophobia (43%), which remarkably could be lateralized (Bahra et al. 2002). Moreover, 6% of CH patients have reported typical migraine aura with their cluster headache, in which 36% had a personal history of migraine (Silberstein et al. 2000; Bahra et al. 2002). Premonitory and Prodromal Symptoms It has been reported that 8% of CH patients have premonitory symptoms from 1 day to 8 weeks before the onset of a cluster period, which can consist of changes in skin sensation, paresthesia, lethargy, and euphoria (Blau and Engel 1998). More frequently (61% of cases), CH patients are reported to experience prodromal symptoms only minutes before pain, such as mood alterations and sensations (tingling, pulsation) in the area of subsequent pain (Blau and Engel 1998). Thus, the identification of prodromal symptoms in a CH patient might be important for establishing early treatment of an attack. Neurological Examination Neurological examination of a CH patient may reveal mild ptosis and miosis on the side of the head, especially during or immediately following the attack, and from time to time impaired trigeminal sensation, although the latter will trigger a search for a lesion. Ipsilateral tenderness of the carotid artery, periorbital swelling, and congestion of the conjunctiva are also noted. During a cluster period, a mild, partial Horner syndrome ipsilateral to the pain is often present. Triggers CH attacks may be triggered by alcohol, nitroglycerin, and histamine during cluster periods (Ekbom 1968; Black et al. 2006).

7 How Cluster Headache and Other Trigeminal Autonomic Cephalalgias Present Therapeutic Treatment Response CH is the only primary headache responding to oxygen therapy. Inhaled oxygen at 100%, 12 L/min, delivered by non-rebreathing face mask at symptom is more likely to result in being pain-free at 15 min than compared to placebo (high-flow air) (78% versus 20%) (Cohen et al. 2009). In addition, CH attacks respond promptly, within 15 min, to 6 mg subcutaneous for a median of 96% of attacks treated (Ekbom et al. 1995). Verapamil in a daily dose of mg is the drug of first choice in the prophylaxis of episodic and chronic cluster headache (Evers 2010), whereas chronic CH patients may also respond to prophylactic treatment with lithium (Halker et al. 2010). Controlled trials comparing verapamil and lithium with placebo show efficacy of both substances, with a more rapid action of verapamil (Evers 2010). Treatment of the TACs will be presented in detail in > Chap. 25 Treatment of Cluster Headache and Other Trigeminal Autonomic Cephalalgias. Paroxysmal Hemicrania Epidemiology PH is a rare condition with a prevalence estimated to be about 0.02% (Antonaci and Sjaastad 1989) and compromise only 3 6% of all TACs (May et al. 2006). The female to male ratio in PH has been reported to be 2.4:1 (Antonaci and Sjaastad 1989), which is in contrast to the male preponderance in CH. The mean age of onset is reported to be 37 years with a wide range from 5 to 68 (Cittadini et al. 2008). So far no evidence of genetic etiology exists in PH. Attack Characteristics The pain during PH attacks is very severe and most frequently described as sharp (51% of cases) and stabbing (49%), although throbbing (32%) and other qualities have been reported (Cittadini et al. 2008). The pain is usually located in the temporal region and orbital region (77% of cases), but also in the retro-orbital region (61%) (Cittadini et al. 2008). It occurs less frequently in other areas of the head and neck (Cittadini et al. 2008). Unilaterality of pain is a defining criteria of PH and found in 97% of cases (Cittadini et al. 2008). The mean length of the PH attacks is 17 min, and even though the IHS criterion regarding the length of attacks identifies a range between 2 and 30 min, more than half of the patients have the longest attacks lasting more than 30 min (Cittadini et al. 2008). The mean attack frequency per day is 11 with a range of 2 50 per day (Cittadini et al. 2008). As agitation is considered a hallmark of CH, it is interesting that 80% of PH patients are found to be agitated or restless (Cittadini et al. 2008). Furthermore, up to 58% of patients are reported to have mild interictal background, which can make differentiation from hemicrania continua difficult, but is usually attributed to co-occurrence of migraine, medication overuse (Cittadini et al. 2008). In contrast to CH, PH patients do not appear to have any circadian or circannual periodicity (Cittadini et al. 2008). PH may show a chronic and an episodic pattern, but in contrast to CH, most PH patients (80%) suffer from the chronic form (Antonaci and Sjaastad 1989). In episodic PH, the duration of the headache phase ranges from 2 weeks to 5 months, with remission phases from 1 to 36 months (Newman and Lipton 1997).

8 How Cluster Headache and Other Trigeminal Autonomic Cephalalgias Present Autonomic Symptoms Lacrimation is the most frequent autonomic feature (87% of cases) during attacks, followed by conjunctival injection (68%), rhinorrhea (58%), nasal congestion (55%), ptosis (55%), eyelid edema (42%), forehead and facial sweating (32%), and miosis (10%). In addition, facial flushing is reported by 55% of patients (Cittadini et al. 2008). General Symptoms Up to 39% of PH patients report nausea and/or vomiting during the attacks (Cittadini et al. 2008). Furthermore, 65% of the patients have phonophobia, which is unilateral in 25% of cases (Cittadini et al. 2008). Photophobia is present in 65% of patients, being unilateral in 40% of cases (Cittadini et al. 2008). Interestingly, more than half of the PH patients have a personal history of migraine (Cittadini et al. 2008). Neurologic Examination Neurologic examination of a PH patient is most often normal after the cessation of an attack, even though trigeminal sensation might be impaired in some patients (Cittadini et al. 2008). Triggers PH attacks are not easily triggered, but stress (26%), nitroglycerin (25%), exercise (23%), alcohol (19%), and neck movement (19%) represent the most frequent known triggers (Antonaci and Sjaastad 1989; Cittadini et al. 2008). Therapeutic Treatment Response The IHS criteria require an absolute response to indomethacin in PH (IHS 2004) and therefore an INDO-test is a valid diagnostic tool, as CH and SUNCT are not responsive to this test (Antonaci et al. 2003; Cohen 2007). To rule out incomplete response, an INDO-test should be used in a dose of 150 mg daily orally or rectally, or 100 mg by injection, but for maintenance, smaller doses are often sufficient (IHS 2004). Furthermore, PH patients usually show no response to oxygen therapy or triptans, in contrast to CH patients (Cittadini et al. 2008). SUNCT (Short-Lasting Unilateral Neuralgiform Headache Attacks with Conjunctival Injection and Tearing) Epidemiology The prevalence of SUNCT is unknown, but the low number of reported cases suggests that it is very rare. In 2006, the National Hospital for Neurology and Neurosurgery in the UK had

9 How Cluster Headache and Other Trigeminal Autonomic Cephalalgias Present collected 43 SUNCT cases, which were referred from all over the UK with a population of 59.6 million (Cohen et al. 2006). The female to male ratio has been reported to range 1:1.3 2 (Matharu et al. 2003; Cohen et al. 2006). The mean age at onset of SUNCT has been reported to be 48 (range=19 75) (Cohen et al. 2006). There is only one reported case in the literature of a family history of SUNCT (Gantenbein and Goadsby 2005). Attack Characteristics SUNCT patients present with attacks that appear in one or more of the following three patterns: single stabs, a group of stabs, or a long attack with a sawtooth pattern of stabs in which the pain never returns to baseline (Cohen et al. 2006). Mean duration of attack seems to depend on the attack pattern with single stabs lasting 58 s, group of stabs 390 s and sawtooth stabs 1,270 s (Cohen 2007). Thus, some attacks appear to be longer than the diagnostic criteria for SUNCT (IHS 2004). The mean attack frequency per day is 57, but it may range from 2 to 600 (Cohen 2007). Most patients describe the pain during attack as stab-like (67%), but some also describe it as an electric shock, with sharp or shooting quality (Cohen et al. 2006). The majority of SUNCT patients (67%) experience pain located in the eye, but it may also be located in the retro-orbital region (56%), forehead region (37%), or even in other regions of the face (Cohen et al. 2006). One patient in a series of 43 patients has been reported to have atypical bilateral attacks (Cohen et al. 2006). Up to 62% of SUNCT patients are agitated during the attacks (Cohen et al. 2006); therefore, agitation appears to be a general feature of all the TACs. SUNCT patients might have interparoxysmal pain after attacks, especially when having a personal or family history of migraine (Cohen et al. 2006). SUNCT can occur at any time of the day, and unlike cluster headache, it does not show any striking circadian rhythm; only 7% of SUNCT sufferers have nocturnal episodes (Cohen et al. 2006). However, 40% of SUNCT patients have attacks that occur during sleep or wakefulness (Cohen et al. 2006), but this might be triggered by naturally occurring cutaneous stimuli in the face. SUNCT patients might have seasonal variations of their attacks (Irimia et al. 2008b). The International Headache Classification did not identify an episodic and a chronic form for SUNCT (IHS 2004); however, a recent prospective study conducted on 43 SUNCT patients shows that 30% of them had an episodic SUNCT (Cohen et al. 2006) and that some SUNCT patients might switch from an episodic form into a secondary chronic SUNCT (Cohen et al. 2006). Autonomic Symptoms Besides the obligate ipsilateral conjunctival injection and lacrimation associated with SUNCT attacks, 53% of patients show ipsilateral rhinorrhea, 51% ipsilateral ptosis, and 40% nasal blockage (Cohen et al. 2006). General Symptoms Nausea, vomiting, photophobia, and phonophobia are not normally associated with SUNCT, although they can be present, especially in patients with a previous or family history of

10 How Cluster Headache and Other Trigeminal Autonomic Cephalalgias Present migraine, reported in about half of SUNCT patients (Cohen et al. 2006). The photophobia and phonophobia are usually ipsilateral in SUNCT, as compared to bilateral in migraine (Irimia et al. 2008a). Neurological Examination Neurologic examination is often normal in SUNCT patients during and between attacks, except for the documented autonomic signs, which quickly abate when the attack ends. Yet, in a cohort of patients, 30% of SUNCT had abnormal examinations; generally these were sensory abnormalities at the site of attacks, either reduction of sensation or hyperesthesia to pinprick (Cohen et al. 2006). It is important to note that although SUNCT is by definition an idiopathic disorder, patients can present with symptomatic SUNCT caused by various intracranial abnormalities (Cohen et al. 2006) and therefore neuroimaging is very important in order to exclude secondary causes of SUNCT. Triggers Most SUNCT patients (74%) report triggerability of attacks from cutaneous stimuli such as touching the face, cold wind on the face, chewing, talking, or other stimuli such as movement of the neck or bright lights (Cohen et al. 2006). Therapeutic Treatment Response Interestingly, it has been reported that intravenous lidocaine seems highly effective for shortterm prevention, although the effects can last up to 6 months after infusion (Cohen 2007). Lamotrigine up to 400 mg daily has also shown potential as a possible preventive treatment for SUNCT (Cohen et al. 2006). In addition, topiramate and gabapentin have also been suggested to be useful in the treatment of SUNCT (Goadsby et al. 2010). Differential Diagnosis of Trigeminal Autonomic Cephalalgias The three TACs can be differentiated from each other according to their attack duration, attack frequency, and therapeutic treatment response (> Table 23.2). Yet, there is an overlap in attack duration (> Fig. 23.1) as well as frequency between the three TACs. Furthermore, both SUNCT and PH might have longer attacks than presently stated in the IHS criteria. To differentiate between the TACs, it is necessary to compare all aspects of each headache spectrum to reach a conclusive diagnosis. It is also important to notice that there are case stories of patients with coexisting CH and PH (Shah and Prakash 2009). There are certain characteristics that are helpful when differentiating between the three TACs. CH has the longest duration of attacks with the lowest daily frequency. PH has an intermediate attack duration and frequency, whereas SUNCT has the shortest attack duration and highest daily attack frequency. Both CH and SUNCT have a male preponderance in contrast to PH, even though this might be of little help in a daily clinical situation. In CH,

11 How Cluster Headache and Other Trigeminal Autonomic Cephalalgias Present Table 23.2 Characteristics of trigeminal autonomic cephalalgias Cluster headache Paroxysmal hemicrania SUNCT Prevalence % 0.02% Very rare Sex ratio F/M 1:3 2.4:1 1:1.3 2 Mean age at onset Attack duration (mean) min ( min) 2 30 min (17 min) 5 s to 4 min (58 s) Attack frequency (mean) 1 8 day (5) 5 40 day (11) day (59) Chronic/episodic Episodic (85%) Chronic (80%) Chronic (70%) Pain quality Boring, pressing, burning Sharp, stabbing, throbbing Stabbing, electric shock, sharp Pain location Retro-orbital, temporal Temporal, orbital Eye, retro-orbital Triggers Alcohol, nitroglycerin Usually not Cutaneous stimuli triggered Autonomic features Yes Yes Yes (CI & T) Migrainers features Yes Yes No Indomethacin effects ++ Abortive treatment Oxygen Sumatriptan s.c. Indomethacin Lidocain i.v. Prophylactic treatment Verapamil lithium Lidocain i.v. Lamotrigine SUNCT short-lasting unilateral neuralgiform headache attacks with conjunctival injection and tearing, s.c. subcutaneous, i.v. intravenous, CI conjunctival injection, T tearing SUNCT Paroxysmal hemicrania Cluster headache 5 s 4 min 2 30 min min Overlap between duration Overlap between duration. Fig Overlap between attack duration in trigeminal autonomic cephalalgias. The duration of each trigeminal autonomic cephalalgia is specified by the International Classification of Headache Disorders (IHS 2004). SUNCT short-lasting unilateral neuralgiform headache attacks with conjunctival injection and tearing (Adapted from Leone and Bussone 2009) the episodic form is most frequent compared to the predominance of chronic PH and chronic SUNCT. CH also seems to have an earlier age onset compared to PH and SUNCT, although the age variation is large. CH is much more prevalent than PH and SUNCT, and is also characterized with more frequent nocturnal attacks as well as annual periodicity. CH may be triggered by alcohol and nitroglycerin during a cluster period, whereas PH is not very easily triggered.

12 How Cluster Headache and Other Trigeminal Autonomic Cephalalgias Present In contrast to CH and PH, SUNCT is very often triggered by cutaneous stimuli. In all TACs, the pain intensity is severe to very severe and patients are often agitated, even though it is less frequent in SUNCT as compared to CH. CH pain is often located retro-orbitally, whereas SUNCT pain is more often reported in the eye. General symptoms are usually most prominent amongst CH and PH patients as compared to SUNCT. A headache patient might present with a spectrum of head pain symptoms, which do not allow the headache to be classified into one particular TAC entity. In such a case, therapeutic medication trials can be most helpful in establishing a diagnosis. Especially an indomethacin-test and/or oxygen treatment would be highly important as diagnostic tools. Ideally, successful oxygen treatment would point to CH, whereas a successful indomethacin-test would strongly indicate PH, and negative responses following both treatments is likely to be seen in typical SUNCT patients. Almost half of TAC patients have a history of migraine. For this reason, a headache patient might well have migraine attacks coexistent with their TAC. Furthermore, migraine attacks can resemble TAC features, since 27 73% of migraine patients have been reported to show autonomic symptoms, such as rhinorrhea, lacrimation, and flushing during attacks (Gupta and Bhatia 2007; Obermann et al. 2007). Yet, differentiation of migraine from PH and SUNCT is usually not a diagnostic problem considering that the latter two present with very short attacks of pain associated with prominent autonomic features. CH can be distinguished from migraine due to cluster periods with shorter and often nocturnal attacks associated with agitation a migraine patient will typically prefer to lie still in bed instead of pacing around as typically seen during a CH attack. Lateralization of photophobia and phonophobia might be helpful in establishing a diagnosis, as these are more prominent features in TACs and relatively uncommon in migraine (Irimia et al. 2008a). Therapeutic intervention might also be helpful, even though a positive treatment response to sumatriptan and indomethacin is expected during a genuine migraine attack (Mett and Tfelt-Hansen 2008). Trigeminal neuralgia (TN) is a unilateral disorder characterized by brief electric shock like pains (IHS 2004), which can be challenging to differentiate from SUNCT. Both syndromes are short lasting, might have a high frequency of attacks, can be precipitated by cutaneous stimuli and have a usual onset during middle or old age. However, TN affects the first division of the trigeminal nerve in <5% of cases (IHS 2004), which is the region that most often affects SUNCT patients. TN also often has very short attack duration, less than 5 s, compared to SUNCT. In contrast to SUNCT, TN patients usually have a refractory period, following a painful attack, in which pain cannot be triggered. TN patients can have autonomic symptoms, but these are rare compared to the prominent autonomic symptoms in SUNCT (Matharu et al. 2003). Finally, TN has a female preponderance, which is the opposite in SUNCT (Manzoni and Torelli 2005; Cohen et al. 2006). There are other primary headaches that might resemble TACs. Primary stabbing headache consists of a single stab or a series of stabs in the distribution of the first division of the trigeminal nerve, which can be misinterpreted as SUNCT (IHS 2004). However, the stabbing attacks last only a few seconds and there are usually no autonomic symptoms. Hemicrania continua is an indomethacin-responsive primary headache with autonomic symptoms characterized by daily and continuous pain without pain-free intervals (IHS 2004). The continuous pain is moderate, but might show exacerbations of severe pain. Thus, hemicrania continua differs from PH because of the continuous pain, and from migraine due to the absolute response on therapeutic doses of endomethacin (IHS 2004). Patients presenting with symptoms resembling CH and other TACs might have intracranial abnormalities causing these pain syndromes. Thus, neuroimaging is an essential part of diagnosing the TACs correctly.

13 How Cluster Headache and Other Trigeminal Autonomic Cephalalgias Present Current Research With the exeption of CH, the TACs were first officially classified by the International Headache Society in 2004 and based on their low frequency in the general population, there is an ongoing demand for research exploring the epidemiology and symptomatology of these disorders. As an example, short-lasting unilateral neuralgiform headache attacks with cranial autonomic symptoms (SUNA) are classified in the appendix of the ICHD-II (IHS 2004). SUNCT might be a subform of SUNA, which could become established as a TAC in the future headache classification. However, SUNA has rarely been reported (Cohen et al. 2006) and might need to be described in more detail before becoming validated as a TAC in the future classification of headache. An emerging interest in the clinical presentation of the TACs is the lateralization of symptoms (Goadsby et al. 2010). Thus, when present, photophobia and phonophobia are usually ipsilateral in SUNCT (Cohen et al. 2006) and PH (Cittadini et al. 2008), as compared to bilateral in migraine. Furthermore, the cranial autonomic symptoms in CH are also more likely to be lateralized in comparison to migraine patients where symptoms are more often bilateral (Lai et al. 2009). Interestingly, neuroimaging studies have shown hypothalamic activation ipsilateral to the pain in CH; ipsilateral, contralateral, bilateral, or absent in SUNCT; and contralateral in PH (Leone and Bussone 2009). Based on the neuroimaging findings of TAC patients, deep brain stimulation (DBS) has been explored as a possible novel treatment approach. Recently, a prospective crossover, double-blind, multicenter study assessed the efficacy of unilateral hypothalamic DBS in 11 patients with severe refractory chronic CH (Fontaine et al. 2010). Randomized phase findings of this study did not support the efficacy of DBS in refractory CCH, but open phase findings suggested long-term efficacy in more than 50% patients (Fontaine et al. 2010). Furthermore, DBS has also been successfully reported in some patients with PH and SUNCT (Leone and Bussone 2009). Percutaneous radiofrequency ablation of the sphenopalatine ganglion has also been attempted as treatment strategy as the parasympathetic nervous system is likely to be activated during cluster headache attacks. This strategy has been shown to be effective in reducing attack frequency in chronic cluster headache (Narouze et al. 2009). The importance of the parasympathetic nervous system was recently explored in a novel animal model of cluster headache (Akerman et al. 2009). The study demonstrated how oxygen can act specifically on parasympathetic nerve projections to the cranial vasculature to inhibit both evoked trigeminovascular activation and activation of the autonomic pathway, which might occur during cluster headache attacks. Thus, current research on pathophysiology and treatment are all linked to the anatomy and clinical presentation of the TAC, which needs to be explored further in future studies. References Akerman S, Holland PR et al (2009) Oxygen inhibits neuronal activation in the trigeminocervical complex after stimulation of trigeminal autonomic reflex, but not during direct dural activation of trigeminal afferents. Headache 49: Antonaci F, Sjaastad O (1989) Chronic paroxysmal hemicrania (CPH): a review of the clinical manifestations. Headache 29(10): Antonaci F, Costa A et al (2003) Parenteral indomethacin (the INDOTEST) in cluster headache. Cephalalgia 23(3): Bahra A, May A et al (2002) Cluster headache: a prospective clinical study with diagnostic implications. Neurology 58(3): Black DF, Bordini CA et al (2006) Symptomatology of cluster headaches. In: The headaches. Lippincott Williams & Wilkins, Philadelphia, pp

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