What is cluster headache?Cluster headache is a primary headache disorder classified with similar conditions known as trigeminal autonomic cephalalgias (table⇓).3 These conditions are typified by recurrent attacks of unilateral pain, which are very severe and usually involve the orbital or periorbital region innervated by the first (ophthalmic) division of the trigeminal nerve. Characteristic signs and symptoms of activation of the cranial autonomic pathways accompany the pain on the same side: lacrimation, conjunctival injection, nasal congestion or rhinorrhoea (or both), ptosis or miosis (or both), and periorbital oedema (box 1; fig 1⇓).Box 1 Cranial autonomic features of cluster headache attacks4 5* Ipsilateral lacrimation (91%) Ipsilateral conjunctival injection (77%) Ipsilateral nasal congestion or rhinorrhoea (75%/72%) Ipsilateral ptosis† (74%) Ipsilateral oedema of the eyelid or the face (or both) (74%) Ipsilateral sweating of the forehead or the face (or both) (38%) Ipsilateral miosis† (29%) *Features are ipsilateral to the side of pain; not all features need to be present †A partial Horner’s syndrome may persist to a lesser degree between attacks. View larger version: In this window In a new window Fig 1 Cranial autonomic features during a cluster headache attack. This photograph was taken during an attack and clearly shows characteristic left periorbital oedema and left partial ptosis, with left conjunctival injection and tear formation. These signs reverted to normal when the attack stoppedView this table: In this window In a new window Comparison of the trigeminal autonomic cephalalgias based on cohorts studied,4 6 7 the international classification of headache disorders,3 and patients seen in practice*The term cluster headache originates from the tendency of attacks to cluster together into bouts that last several weeks. In the episodic form of the disorder, the bouts can occur at certain times of year, often with a seasonal predilection.4 They are separated by periods of remission, which last at least a month (box 2).3 However, about 10% of patients have the chronic form of the disorder and have continuous attacks with no respite.Box 2 Diagnostic criteria for cluster headache3 A) At least five attacks fulfilling criteria B-D B) Severe or very severe unilateral orbital, supraorbital, or temporal pain that lasts for 15-180 minutes if untreated C) Headache accompanied by at least one of the following: Ipsilateral conjunctival injection or lacrimation (or both) Ipsilateral nasal congestion or rhinorrhoea (or both) Ipsilateral eyelid oedema Ipsilateral forehead and facial sweating Ipsilateral miosis or ptosis (or both) Restlessness or agitation D) Attacks have a frequency of one every other day to eight each day E) Not attributed to another disorder Episodic cluster headache: Attacks occurring in periods that last seven days to one year separated by pain-free periods that last one month or longer Chronic cluster headache: Attacks that occur for more than one year without remission or with remissions that last less than one month A well described physiological reflex arc, the trigeminovascular reflex, potentiates the trigeminal pain and cranial autonomic features of cluster headache by positive feedback mechanisms (fig 2⇓).8View larger version: In this window In a new window Fig 2 The trigeminovascular reflex. Nerve endings containing pain receptors innervate structures of the face and cranial vault, particularly the pain producing dura mater and cerebral blood vessels (the durovascular complex). This nociceptive information is carried to the brainstem in the trigeminal nerve, via the trigeminal ganglion. Within the brainstem, trigeminal fibres synapse in an area known as the trigeminocervical complex (TCC). From here, information ascends to the hypothalamus, thalamus, and cortex via pain processing pathways. In addition, the afferent trigeminal signals arriving at the TCC also stimulate the cranial parasympathetic system via the superior salivatory nucleus. This results in increased firing of parasympathetic fibres carried from the brainstem in the facial nerve and then greater superficial petrosal nerve, which synapse at the sphenopalatine ganglion. These fibres innervate facial structures (including the lacrimal gland and nasal mucosa, thus causing the lacrimation and rhinorrhoea seen with attacks) and the durovascular complex. Neurotransmitter release at these parasympathetic terminals (vasoactive intestinal polypeptide) causes further irritation of trigeminal sensory nerve endings and release of calcitonin gene related peptide, which potentiates the trigeminovascular reflex arc. It is this reflex that is responsible for the pain and facial parasympathetic signs of cluster headache attacks.9 The ptosis and miosis seen with attacks arise from interruption of the oculosympathetic fibres that run with the internal carotid artery and through the cavernous sinus, where they are thought to be affected by local vascular distension.10 The posterior hypothalamus, which shows a strong activation signal in functional imaging studies during attacks (insert), may modulate signalling through the TCC, perhaps providing a breaking mechanism to regulate the trigeminovascular reflex9Functional imaging studies have detected activation ipsilateral to the pain in the region of the posterior hypothalamus (fig 2), which may have a pivotal role in integrating the pain, cranial autonomic features, and unique timing of cluster headache.11