Journal of Neurology

, Volume 253, Issue 12, pp 1525–1532

Update on the diagnosis and management of Trigemino-Autonomic Headaches

Authors

    • Dept. of Systems NeuroscienceUniversitäts-Krankenhaus Eppendorf (UKE)
REVIEW

DOI: 10.1007/s00415-006-0303-2

Cite this article as:
May, A. J Neurol (2006) 253: 1525. doi:10.1007/s00415-006-0303-2

Abstract

Severe shortlasting headaches are rare but very disabling conditions with a major impact on the patients’ quality of life. Following the IHS criteria, these headaches broadly divide themselves into those associated with autonomic symptoms, so called trigeminal autonomic cephalgias (TACs), and those with few autonomic symptoms. The trigeminal-autonomic cephalgias include cluster headache, paroxysmal hemicranias, and a syndrome called SUNCT (short lasting unilateral neuralgic cephalgias with conjunctival injection and tearing). In all of these syndromes, hemispheric head pain and cranial autonomic symptoms are prominent. The paroxysmal hemicranias have, unlike cluster headaches, a very robust response to indomethacin, leading to a notion of indomethacin-sensitive headaches. Although TACs are, in comparison with migraine, quite rare, it is nevertheless very important to consider the clinical factor that they are easy to diagnose and the treatment is very effective in most patients.

Keywords

trigemino-autonomic headacheTACcluster headacheSUNCTdiagnosistherapy

Introduction

The classification

Trigeminal autonomic cephalgia (TAC) is a relatively new term [16], first proposed by Goadsby and Lipton [14] for a group of primary headaches with pain and autonomic involvement in the facial area of the trigeminal nerve. All these headache syndromes have two features in common: short-lasting, unilateral, severe headache attacks and accompainment of typical autonomic symptoms. To date, the following syndromes belong to the TACs:
  • episodic and chronic cluster headache (CH)

  • episodic and chronic paroxysmal hemicrania (PH)

  • short-lasting unilateral neuralgiform headache with conjunctival injection and tearing (SUNCT-syndrome)

Why is it important to know and recognize all the different types of TAC, given that they are relatively rare? First of all, these disabling conditions are easy to recognize. Secondly, in most cases, a subclassification is possible and reasonable, as therapeutic regimen and response differ. For neurologists, despite the diagnostic challenges, the short-lasting primary headaches [16] are important to recognize because of their excellent, but highly selective response to treatment. In 1997, Peter Goadsby and Richard Lipton documented a nosological analysis and definition of a group of short-lasting headache syndromes [14]. These paroxysmal hemicranias are characterized by frequent, short-lasting attacks of unilateral pain usually in the orbital, supraorbital or temporal region. The pain is severe and associated with autonomic symptoms such as conjunctival injection, lacrimation, nasal congestion, rhinorrhoea, ptosis and eyelid oedema. Table 1,2,3,4,5
Table 1

Diagnostic criteria of cluster headache

A. At least 5 attacks fulfilling criteria B-D

B. Severe or very severe unilateral orbital, supraorbital and/or temporal pain lasting 15–180 minutes if untreated

C. Headache is accompanied by at least one of the following:

1. ipisilateral conjunctival injection and/or lacrimation

2. ipsilateral nasal congestion and/or rh3. inorrhea

3. ipsilateral eyelid oedema

4. ipsilateral forehead and facial sweating

5. ipsilateral miosis and/or ptosis

sense of restlessness or agitation

D. Attacks have a frequency from one every other day to 8 per day

E. Not attributed to another disorder

Table 2

Treatment of the acute attack of cluster headache

Name

Efficacy

Dosage

Inhalation of 100% oxygen

Effective in up to 60% of patients

>7–10 litres 100%igen O2 using a facial mask for 15–20 min in a upright sitting position

Nasal instillation of Lidocain

Effective in 25–30% of patients

patients with contraindications for triptans

1 ml of 4% Lidocain-Lsg. ipsilateral to the pain. The head should be reclined at a 45° and rotated to the affected side by 30° to 40°

Subcutaneous injection of Sumatriptan

Treatment of choice

Effective in >75% of patients within 5–20 min

6 mg s.c.

Nasal instillation of Suma- or Zolmitriptan

Nearly as fast as the subcutaneous application. Best for patients with moderate, longlasting attacks

Nasal Spray, contralateral to the pain

Intramuscular DHE

Due to side effects: treatment of third choice

2 mg

Table 3

Preventive medication in cluster headache

Name

Efficacy

Dosage

Verapamil

Treatment of choice

Effective in up to 70% of patients

The full efficacy of Verapamil can be expected within 2 to 3 weeks

240–360 mg/d

An increase of 80 mg every three days is recommended.

Rarely, a daily dose of more than 720 mg may be necessary (ECG)

Lithiumcarbonate

Efficacy ranges between 20% and 73%

it may be more effective in episodic cluster headache

The plasma level should be monitored and maintained between 0.3 and 1.2 mmol/l

Cortico-steroids

Effective in > 80% of patients

Usually used as the initial prophylactic option and for the moment required until the increasing dosages of verapamil take effect

Prednisone 60 to 100 mg given once a day for at least 5 days is recommended, then decreasing the dosage by 10 mg every day

Methysergide

Studies ranged between 20% and 73%

The continuous use of methysergide is limited to three or four months

Initial 1 mg/die

Very often 4–8 mg/die effective

Sometimes up to 12 mg/die necessary

Topiramate

Only case series and open studies

Clinically effective in >50%

At least 100 mg per day

The starting dose should be 25 mg

Valproicacid

Three open trials with inconsistent results

Third resort after verapamil, lithium. methysergide and topiramate

Initial 5–10 mg/kg bodyweight,

Up to 1200 mg/die

Gabapentin

Only open trials and case reports

1800–2400 mg per day

Table 4

Diagnostic criteria of paroxysmal hemicrania

A At least 20 attacks fulfilling criteria B-D

B Attacks of severe unilateral orbital, supraorbital or temporal pain lasting 2–30 minutes

C Headache is accompanied by at least one of the following:

1 ipisilateral conjunctival injection and/or lacrimation

2 ipsilateral nasal congestion and/or rhinorrhoea

3 ipsilateral eyelid oedema

4 ipsilateral forehead and facial sweating

5 ipsilateral miosis and/or ptosis

D Attacks have a frequency above 5 per day for more than half the time, although periods with lower frequency may occur

E Attacks are prevented completely by therapeutic doses of indomethacin

F Not attributed to another disorder

Table 5

Diagnostic criteria of SUNCT syndrome

A At least 5 attacks fulfilling criteria B-D

B Attacks of unilateral orbital, supraorbital or temporal stabbing or pulsating pain lasting 5–240 seconds

C Pain is accompanied by ipsilateral conjunctival injection and lacrimation

D Attacks occur with a frequency from 3 to 200 per day

E Not attributed to another disorder

Goadsby and Lipton divided these short-lasting primary headache syndromes into those exhibiting marked autonomic activation and those without autonomic activation. Table 6 summarizes a list of short-lasting headaches with autonomic symptomes. The former group comprise chronic and episodic paroxysmal hemicrania, short-lasting unilateral neuralgiform headache with conjunctival injection and tearing (SUNCT syndrome) and cluster headache [16]. These headache syndromes are compared with other short-lasting headache disorders, such as hypnic headache, and a chronic headache syndrome with milder autonomic features such as hemicrania continua. Recent imaging data, however, place hemicrania continua nearer to the TACs [28] and future work will probably do the same with hypnic headache. Idiopathic stabbing headache, cough headache, exertional headache, sexual headache and trigeminal neuralgia are not part of these syndromes as these short-lasting disorders have no autonomic component [16, 38].
Table 6

Comparison of trigemino-autonomic headache syndromes

 

Cluster Headache

Paroxysmal Hemicrania

SUNCT Syndrome

Pain

-Quality

pungent, throbbing

twinging

stabbing

-Intensity

extremly high

high

moderate to high

-Localisation

periorbital

orbital, temporal

orbital, temporal

- Duration of attack

15 –120 min

2–45 min

5–250 sec

- Frequency of attack

1–8/d

1–40/d

1/d bis 30/h

Autonomic symptoms

++

++

+

Circadian rhythmicity

+

(−)

Therapy:

acute:

acute:

acute:

- treatment of choice

100% oxygen, 15l/min intranasal Lidocain Sumatriptan s.c.

Acetylsalicylic acid (naproxen and diclofenac)

None

preventative:

preventative:

preventative:

Verapamil, Lithium carbonate Corticosteroids, Topiramate Methysergide,

Indomethacin

Lamotrigen

SUNCT = short-lasting unilateral neuralgiform pain with conjunctival injection and tearing; min = minutes; sec = seconds; h = hours; d = day, Yrs = years. * modified from [31]

Cluster Headache

Cluster headache is certainly the most prominent and most common of the TACs. Despite the fact, that the clinical picture of cluster headache is characteristic, making it probably the easiest idiopathic headache syndrome to diagnose, patients are often misdiagnosed and undertreated [31]. Cluster headache is characterized by recurrent, strictly unilateral attacks of headaches of great intensity and brief duration. The pain of cluster headache is perhaps the most severe known to humans, with female patients describing each attack as being worse than childbirth. The pain attacks are accompanied by local (ipsilateral) signs of autonomic dysfunction, such as ipsilateral parasympathetic (rhinorrhoea, lacrimation, impaired sweating) and sympathetic (miosis, ptosis) symptoms [42].

The prevalence is approximately 0.1 % and mostly affects men. The attacks occur regularly and their timing seems to be related to the sleep-wake cycle. Attacks most commonly appear in cluster periods (episodic cluster headache) lasting from a week to several months. The periods are separated by clinical remissions of at least 2 weeks. About 15–20% of patients suffer from chronic symptoms (without remissions = chronic cluster headache). The most salient feature of cluster headache is the reported seasonal variation and the clockwise regularity of the headache attacks [50]. Consequently, a whole range of circadian irregularities in hormone levels have been reported in cluster headache patients [12, 22]. Melatonin in particular is a marker of the circadian system and a blunted nocturnal peak melatonin level and complete loss of circadian rhythm have been reported in cluster headache patients [51]. The medical treatment of cluster headache includes both acute therapy aimed at aborting individual attacks and prophylactic therapy aimed at preventing recurrent attacks during the cluster period [31].

Treatment

The treatment of cluster headache is based on empirical data rather than on a pathophysiological concept of the disease [5, 32]. Although the headache attacks are ususally excrutiating, drug treatment in cluster headache shows a placebo rate similar to that observed in migraine treatment [37], which appears to be as high as 30%. In general, cluster headache treatment can be divided into acute therapy aimed at aborting individual attacks and prophylactic therapy aimed at preventing recurrent attacks during the cluster period [21, 26]. Non-drug treatment is ineffective in nearly all patients.

Acute therapy

Because of the rapid onset and short time to peak intensity of cluster headache pain, fast-acting symptomatic therapy is needed. Oxygen (15 min, 100%, 15 L/min), subcutaneous sumatriptan (6 mg), and intramuscular dihydroergotamine (2 mg) provide the most rapid, effective, and reliable relief for cluster headache attacks. In recent open and double-blind, placebo-controlled trials, sumatriptan nasal spray 20 mg [41, 49] and oral zolmitriptan 10 mg [1] were also effective within 30 minutes. The preemptive use of 5-HT1B/D agonists (triptans) for cluster headache remains controversial.

Preventive therapy

The importance of an effective preventive regimen during cluster periods cannot be overstated. During cluster periods, individual cluster attacks often occur daily for several weeks to months. Since many patients have more than one attack a day (up to eight), treating only the acute pain may result in overmedication or toxicity, and may unnecessarily prolong suffering. The primary goal of the preventive therapy is to produce a suppression of attacks and to maintain remission through the expected cluster period.

Corticosteroids (prednisone and dexamethasone) are the fastest-acting preventive agents. Treatment is usually initiated with 60–80 mg of prednisone per day for 2–3 days followed by 10 mg decrements every 2–3 days. Dexamethasone at a dose of 4 mg twice a day for 2 weeks followed by 4 mg a day for 1 week has also been shown to be effective. Corticosteroids are quite useful for inducing a rapid remission in patients with episodic cluster headache, but long-term use of corticosteroids must be resisted.

Verapamil is often used as the first preventive therapy for both episodic and chronic cluster headache. In doses of up to 360 mg, it is generally well tolerated and can be used safely in conjunction with sumatriptan, ergotamine, corticosteroids, and other preventive agents. The initial starting daily dosage is 80 mg three times a day or 240 mg of sustained release a day. Doses range from 240 g to 720 g a day divided into separate allotments. Lithium carbonate therapy is effective for cluster headache, based mainly on open clinical trials. The initial starting daily dosage is either 300 mg three times a day or 450 mg sustained release. Most patients will benefit from dosages between 600 g and 900 mg a day.

Methysergide is an effective preventive drug for the treatment of cluster headache. The daily dose is usually 2 mg in three separate dosages, but up to 12 mg may be used if tolerated. Methysergide should be stopped after a treatment period of 4–6 months.

Topiramate and Gabapentin have been associated with rapid improvement in recent studies.

Prioritization of therapy

Because of the rapid onset and short time to peak intensity of cluster headache pain, subcutaneous sumatriptan is the treatment of choice. The absorption and pharmacological actions of oral medications are usually too slow. Oxygen is the other standart treatment besides sumatriptan. Patients with chronic and relatively long-lasting active periods of episodic cluster headache should be primarily treated with verapamil. Corticosteroids, ergotamine or even triptans with a long half life may be used as an effective initial prophylactic option until verapamil takes effect,. Methysergide or corticosteroids are the medication of choice in relatively short lasting active cluster periods (less than 2 months). Lithium and valproic acid are considered helpful but second line therapy. There will be evidence-based European guidelines for the treatment of cluster headache and related headaches published shortly [35].

Operative procedures

Surgical procedures should be considered with great caution because no reliable long term observational data are available and because they can induce trigeminal neuralgia or anaesthesia dolorosa. There are reports of the complete inefficacy of surgical treatment in cluster headache and related syndromes [2, 7, 18, 29]. Given that trigeminal destructive procedures have significant morbidity [18] and that nerve root section has a well described morbidity, these procedures have to be considered with great caution [29]. Very recently, deep brain stimulation of the posterior inferior hypothalamus has been shown to be effective in the majority of a sample of patients with intractable cluster headache [11, 23, 40]. Recently, a protocol of recommendations for the selection of patients for this procedure has been published [24]. It has to be pointed out, however, that the method of hypothalamic deep brain stimulation is still highly experimental and it is not understood how stimulation of an area which is thought to act as a pace-maker for acute cluster attacks is able to prevent these attacks [36]. In summary, surgical procedures are not indicated in most of the patients with cluster headache. Patients with intractable chronic cluster headache should be referred to centres with expertise in both destructive and neuromodulatory procedures to be offered all reasonable alternatives before a definitive procedure are conducted.

Paroxysmal Hemicrania

Paroxysmal hemicrania was first described by Sjaastad [44] (for a recent review see Dodick, 2004 [6]) and is characterized by short bouts of severe unilateral pain in the orbital and temporal area. The typical attack frequency is >5 per day, but there are reports of between 1 and 40 attacks per day. The age of onset is usually in the twenties, with a 3:1 female to male ratio. Similar to cluster headache, a chronic and an episodic form have been described and the syndrome also has a distinctive temporal pattern [43]. The pain is associated with at least one autonomic symptom, such as ipsilateral conjunctival injection and tearing with nasal congestion and rhinorrhea.

Treatment

There is no drug that comes anywhere near the efficacy of indomethacin for the treatment of paroxysmal hemicrania. Almost all reported cases responded to treatment with indomethacin, but responded poorly to other treatments, including other nonsteroidal anti-inflammatory drugs. In fact, the IHS criteria require, that the attacks should rapidly resolve following treatment with indomethacin. The dose can extend to 150 mg/day orally and a response usually occurs within days of initiating an adequate dose. The standard treatment for CPH is indomethacin at a dose of 25 mg t.d.s., increasing to 50 mg t.d.s. after a week if there is no response. Occasional patients require higher doses or slow-release indomethacin preparations at night to treat break-through headaches. In some patients, gastrointestinal side-effects require treatment with gastro-protective agents, such a histamine−2 or proton pump blockers. If indomethacin is not tolerated, it may be useful to try verapamil, acetazolamide or piroxicam and acetylsalicylic acid. Interestingly, subcutaneous sumatriptan is ineffective.

SUNCT-Syndrome

Short-lasting unilateral neuralgiform headache with conjunctival injection and tearing (SUNCT) is among the rarest idiopathic headache syndromes and is characterized by an extremly high frequency of attacks (up to 200 attacks/day) with less severe pain but marked autonomic activation during attacks. Even though there are distinct clinical differences - such as the frequency and duration of attacks and the different approach to treatment - many of the basic features of SUNCT - such as episodicity, autonomic symptoms and unilaterality - are shared by other headache types, including cluster headache and CPH. This suggests a pathophysiological similarity to those syndromes and prompted the suggestion to unify them on clinical grounds as trigeminal-autonomic cephalgias (TACs). The paroxysms of pain usually last between 5 and 250 s, although longer, duller interictal pains have been reported. Patients can have up to 30 episodes per hour, although it is more usual to have 5–6 per hour. The frequency may also vary in bouts. The conjunctival injection seen with SUNCT is often the most prominent autonomic feature and tearing may also be very obvious.

Treatment

Unfortunately, SUNCT syndrome does usually not respond to therapy. Unlike CPH and EPH, which are highly responsive to indomethacin, SUNCT is remarkably intractable. However, recent reports suggest a good response to lamotrigine [27, 39]. Other treatment options include gabapentin, topiramate, intravenous lidocaine, and intravenous phenytoin. These drugs were often applied in combination. In the author’s opinion lamotrigene should be tried first, leaving gabapentin and topiramate as treatments of second choice. Intravenous treatments may have long lasting effects but are often not feasable in clinical practice. No evidence-based recommendations can be given [35]. However, because of the extreme burden caused by this disorder, all reasonable treatment options should be tried.

The pathophysiological puzzle

Although these syndromes are well defined from a clinical point of view [15] and have been recognised for more than two centuries [17], their pathophysiology is still poorly understood. However, the last decade has seen remarkable progress in unraveling the pathophysiological puzzle [12]. The vascular theory has been superseded by the realisation that neurovascular phenomena may be more important. The excruciatingly severe unilateral pain is likely to be mediated by activation of the first (ophthalmic) division of the trigeminal nerve, while the autonomic symptoms are due to activation of the cranial parasympathetic outflow from the VIIth cranial nerve [13]. This trigeminal–autonomic reflex evolves from a brainstem connection between the trigeminal nerve and facial (VIIth cranial nerve) para- sympathetic outflow. However, a clinical challenge to the model arises from the variation in patterns of autonomic symptoms from syndrome to syndrome as well as differences in treatment. The relapsing-remitting course [20], its seasonal variation [20] and the clockwise regularity [8] of single attacks are characteristic and suggest an involvement of the biological clock, namely the hypothalamus, in the origin of the illness [9, 19, 48]. Significantly lowered levels of plasma testosterone in male cluster headache patients during cluster periods provided the first evidence of hypothalamic involvement in cluster headache. This was further supported by a reduced response to thyrotropin-releasing hormone [25] and a range of other circadian irregularities in hormone levels that have been reported in cluster headache [3, 10, 48]. Melatonin in particular is a marker of the circadian system and a blunted nocturnal peak melatonin level and complete loss of circadian rhythm have been reported in cluster headache patients [51]. Recently, using functional and structural imaging, a significant structural difference in grey matter density, a ‘lesion’ coinciding with the inferior posterior hypothalamus, was found in cluster headache [33, 45] and Hemicrania continua [28], but not in migraine patients [30] when compared to healthy controls. Given that many of the basic features of SUNCT are shared by cluster headache and paroxysmal hemicrania, the question arises whether a shared pathophysiological basis exists, which could possibly be visualized through similar cerebral activation patterns. Indeed, several independant studies uniformly found an activation next to the hypothalamic area activated in cluster headache [4, 34, 47]. Even in a patient suffering from excrutiating trigemino-autonomic headache attacks, in whom frequency, duration and therapeutic response allowed no clear-cut classification to one of the subtypes of trigeminal autonomic cephalgia, the same prominent activation in the hypothalamic grey matter was found [46]. If this biological model is correct, the underlying cause for trigeminal autonomic cephalagias may indeed be similar and the variation in duration and frequency might be generally dependant on a different disorder of the inferior posterior hypothalamic neurons, perhaps a modulation of neuronal activity or a different involvement of the trigeminovascular system, explaining the relativly different phenotypes of these related syndromes. In any case, these case studies underline the conceptual value of the term “TAC” for the group of headaches focussed around the trigeminal-autonomic reflex and, moreover, emphasize the importance of the hypothalamus as a key region in the pathophysiological process of these disorders.

Summary and Conclusion

The last three years have seen remarkable progress in understanding the pathophysiology of circadian headache syndromes and have brought exciting news. The vascular theory has been superseded by recognition that neurovascular phenomena seem to be more important. In a recent Update, the International Headache Society has recognised a group of circadian headaches, the “trigeminal-autonomic cephalalgias”, in which head pain and cranial autonomic symptoms are prominent and, despite their clinical similarities, show a highly selective response to treatment (table 6). Scientific work has broadened our pathophysiological view and has consequently led to successfull deep brain stimulation of the hypothalamus in cluster headache and SUNCT-syndrome. Further research in this field is urgently needed and the time has come to use the evidence for a disorder of circadian rhythm in these syndromes to further development of chronobiotics in the treatment of these disorders.

Acknowledgments

The author wish to thank E. Schoell for editing the manuscript. AM is supported by a grant of the Deutsche Forschungsgemeinschaft (MA 1862/2) and by a grant of the BMBF (project no. 371 57 01).

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© Steinkopff Verlag Darmstadt 2006