Acute Abortive Therapies:—
Most of the current treatment options for TACs are empirical, and little is known about the mechanisms of action of pharmacological agents in TACs. For example, CH is triggered by nitric oxide donors such as GTN and alcohol. These are thought to increase the cell's requirement for oxygen for cellular respiration.9 It is speculated that oxygen may work in CH by reducing oxidative stress and promoting cellular respiration. Furthermore, it has been postulated that during the cluster bout, hypothalamic dysfunction causes changes in the parasympathetic system,92 which would impair the activity of the chemoreceptors in the carotid body. Therefore, the nocturnal hypoxic episodes would precipitate an attack in an already physiologically compromised system.93 However, good controlled clinical evidence for the use of oxygen in CH is lacking, and future studies may assess the efficacy of high-dose oxygen as compared to either low-flow or placebo.
Triptans, either as subcutaneous or intranasal preparations, are effective in aborting acute attacks of CH, although there are problems of tachyphylaxis, and limits to the number of daily doses. However, they remain the most practical of treatments in terms of ease of administration and portability, and are therefore likely to remain the mainstay of abortive therapy.
Topiramate has a good effect in many headache syndromes including migraine in controlled trials.94,95 Its efficacy has been shown in open-label trials in CH,96–99 and in case reports in hemicrania continua100 and PH.62,101
Topiramate has been reported to be effective in 6 SUNCT patients at doses up to 300 mg daily,65,74,75,102 and in 52% of SUNCT in a recent series (although ineffective in 1 SUNA patient).50 Topiramate is also used in the treatment of other painful conditions, including painful diabetic neuropathy.103,104 It has a wide range of mechanisms of action.105 Future controlled studies of topiramate in all 3 TACs will be very useful in ascertaining its effectiveness in these syndromes, although its mechanism of action specifically in each syndrome may not directly reflect the pathophysiology of the diseases.
The effectiveness of intravenous lidocaine has been demonstrated in SUNCT.50 Intravenous lidocaine has been demonstrated to provide effective analgesia in a variety of acute and chronic pain states.106,107 It has been reported to be effective in several headache syndromes including trigeminal neuralgia,108 chronic migraine,109 and CH.110 It has been proposed as treatment for chronic daily headache including analgesic rebound headache,111 and was found to be helpful in 2 retrospective series of 71 patients112 and 12 patients,113 most of whom had chronic migraine, and in case reports of CH and SUNCT.114 The phenomenon that the attacks of SUNCT and SUNA were abolished for up to 6 months after the infusion50 has been noted in animal models with prolonged reduction of tactile allodynia far beyond the pharmacological half-life of lidocaine.115,116
The advantage is that this allows a period of time where the patient can be drug-free for many weeks, or for titration of preventive medications. A disadvantage is that lidocaine has to be given as a continuous intravenous infusion, with cardiac monitoring for the development of arrhythmias.65 Therefore, future studies might concentrate on its derivative, mexiletine, which can be taken as an oral preparation.
The work done by Leone and Schoenen's groups43,91,117 has demonstrated the efficacy of deep brain stimulation in the region of the posterior hypothalamus in CH and SUNCT, which correlates with functional imaging results of activation in this region in CH,118 PH,119 SUNCT,89 and also in hemicrania continua, which is not a TAC but shared some clinical aspects with the TACs.120 However, these procedures are not without risk,43 and currently these procedures are reserved for those patients who are refractory to other forms of treatment.
Other forms of neuromodulation such as electrical occipital nerve stimulators have had a good effect in CH and hemicrania continua.48,121 A series of 8 patients with chronic migraine reported a beneficial effect with suboccipital stimulators, with changes on PET imaging in the brainstem and “pain matrix.”44 This suggests that suboccipital stimulators are capable of central neuromodulation. In future these may be a more attractive form of neuromodulation than the deep brain stimulation, due to the reduction of risk of side effects.
Injections of a combination of steroid and local anesthetic in the region of the GON have been effective in primary headache syndromes including migraine, CH, PH, HC, and SUNCT,24,25,86 with tenderness over the GON being a strong predictor of a good outcome.25 The advantage that the attacks may be abolished for several days after the injection allow the introduction or dose increase of preventive drugs, and may prove a valuable clinical intervention in the future.
TACs and the Hypothalamus:—
The activation of the hypothalamus in all TACs has come from functional imaging studies in CH,118,122 PH,123 and SUNCT.73,89,124 Deep brain hypothalamic stimulation has had a good effect in a series of 16 CH patients,117,125 and in a single case of SUNCT;117 thus adding further evidence for the role of the hypothalamus in these syndromes.
Furthermore, PH, which is another TAC, and hemicrania continua, which is not a TAC but shares some characteristics, both have activation in the posterior hypothalamus and also the ventral midbrain.120,123 As both of these syndromes respond absolutely to indomethacin, it is tempting to speculate that indomethacin may have an action at the ventral midbrain.
There is also biochemical evidence for hypothalamic activity in TACs.
Melatonin production is reduced in CH patients.126–129 Melatonin therapy is presumed to act in CH by supplementing the reduced melatonin secretion by a malfunctioning pineal system, and has been linked to the diurnal hypothalamic rhythm found in CH, by preventing both the nocturnal and daytime attacks.130 However, it is also reported to be beneficial in open-label trials in other headache syndromes such as migraine and hemicrania continua, and has been suggested to have many mechanisms of action, such as an anti-inflammatory effect, free radical scavenging, and membrane stabilization.131
The apparent discrepancies between the TACs may be reflected in their responses to medications; for instance oxygen an acute abortive therapy in CH may possibly act either on abnormal mitochondrial energy metabolism132 or in nocturnal CH attacks, which are possibly due to hypoxia in an already physiologically compromised hypothalamus.13,92,93 The lack of response to oxygen in PH and SUNCT may be because the attacks are too short for an abortive to have a meaningful effect, or because the pathophysiology of these syndromes is different.
It is interesting to observe that the clinical feature that is common to the 4 primary headache syndromes in which posterior hypothalamic activation has been reported (ie, PH, CH, SUNCT, and HC) is prominent cranial autonomic features in association with the headache. It has been suggested that the pathophysiology of these syndromes revolves around the trigeminal-autonomic reflex.1 There is considerable experimental animal literature to document that stimulation of trigeminal efferents can result in cranial autonomic outflow, the trigeminal-autonomic reflex.133 In fact, some degree of cranial autonomic symptomatology is a normal physiologic response to cranial nociceptive input134,135 and patients with other headache syndromes, such as migraine, may report these symptoms.136,137 Moreover, the known physiology predicts bilateral cranial parasympathetic outflow with unilateral activation, with the predominant manifestations ipsilateral to stimulation.133 Thus it is no surprise that subclinical conjunctival changes have been recently reported in CH that are contralateral to the pain.138 It has been suggested that the cranial autonomic symptoms may be prominent in these syndromes due to a central disinhibition of the trigeminal-autonomic reflex by the hypothalamus.139 Indeed, there are direct hypothalamic-trigeminal connections,140 and the hypothalamus is known to have a modulatory role on the nociceptive and autonomic pathways, specifically trigeminovascular nociceptive pathways.141
The current classification of primary headache syndromes in general, and TACs in particular, is based largely on clinical phenotype, with response to indomethacin in PH and HC.3 It is possible that HC and PH have a different pathophysiology to CH and SUNCT, which is why they respond to indomethacin, and CH and SUNCT do not. The hypothalamus is suggested to be the mediator of the attacks in TACs on clinical grounds largely due to evidence gathered from CH, such as biochemical abnormalities and the diurnal and seasonal variations in CH.13 The act of including PH and SUNCT/SUNA as TACs from a phenotypic basis stems from the fact that they are all unilateral, relatively short-lasting attacks of severe orbital, retro-orbital or temporal pain, with ipsilateral cranial autonomic symptoms.3 The agitation and restlessness stated in CH has also been shown in this series of SUNCT patients. The differences between the syndromes lie not only in the duration and frequency of the attacks, but also in their response to medications, such that CH responds well to oxygen19,142 and sumatriptan;143-145 PH to indomethacin;146 and SUNCT/SUNA to intravenous lidocaine.50 Other differences include the ability to trigger SUNCT/SUNA attacks by cutaneous stimuli, which is generally not the case in other TACs.
In summary, each of the TACs has its own clinical characteristics, which have been observed and classified,3 and specific treatments such as oxygen and verapamil in CH, indomethacin in PH, and intravenous lidocaine or lamotrigine in SUNCT. Certain medications, such as topiramate, appear to have an effect in all the TACs, as well as in migraine and other pain syndromes. Still, the finding of hypothalamic activation on functional imaging studies in all of these syndromes clearly points to the hypothalamus both as a generator or facilitator of these attacks, and therefore as a target for treatment. Future work may concentrate on neuromodulatory or pharmacological treatments directed toward the hypothalamus, or more peripheral neuromodulatory treatments such as occipital nerve stimulators, which are effective in TACs as well as in other headache syndromes.
Conflict of Interest: None