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Keywords:

  • trigeminal autonomic cephalalgias;
  • cluster headache;
  • paroxysmal hemicrania;
  • SUNCT;
  • treatment

Abstract

  1. Top of page
  2. Abstract
  3. CLUSTER HEADACHE
  4. MANAGEMENT
  5. MANAGEMENT
  6. SHORT-LASTING UNILATERAL NEURALGIFORM HEADACHE ATTACKS WITH CONJUNCTIVAL INJECTION AND TEARING
  7. MANAGEMENT OF SUNCT/SUNA
  8. THE FUTURE FOR TREATMENT OF TACS
  9. References

The trigeminal autonomic cephalgias include cluster headache, paroxysmal hemicrania, and short-lasting unilateral neuralgiform headache attacks with conjunctival injection and tearing (SUNCT). The evidence for the current treatment options for each of these syndromes is considered, including oxygen, sumatriptan, and verapamil in cluster headache, indomethacin in paroxysmal hemicrania, and intravenous lidocaine and lamotrigine in SUNCT. Some treatments such as topiramate have an effect in all of these, as well as in migraine and other pain syndromes. The involvement of the hypothalamus in functional imaging studies implies that this may be a substrate for targeting treatment options in the future.

The trigeminal autonomic cephalalgias (TACs) are a group of primary headache disorders characterized by unilateral head pain that occurs in association with ipsilateral cranial autonomic features.1,2 The TACs include cluster headache (CH), paroxysmal hemicrania (PH), and short-lasting unilateral neuralgiform headache attacks with conjunctival injection and tearing (SUNCT). These headaches are grouped into section 3 of the revised International Classification of Headache Disorders (ICHD-II).3 The TACs differ in attack duration and frequency as well as the response to therapy. CH has the longest attack duration and relatively low attack frequency. PH has intermediate duration and intermediate attack frequency. SUNCT has the shortest attack duration and the highest attack frequency (Table 1). The importance of recognizing these syndromes resides in their excellent but highly selective response to treatment.

Table 1.—.  Clinical Features of the Trigeminal Autonomic Cephalalgias
 Cluster HeadacheParoxysmal HemicraniaSUNCT
  1. *Migrainous features such as nausea, photophobia, and phonophobia.

  2. SUNCT = short-lasting unilateral neuralgiform headache attacks with conjunctival injection and tearing.

  3. ++= absolute response to indomethacin; −= no effect with indomethacin.

Sex F:M1:3.5 to 72.13 to 2.36:11:1.2
Pain 
 TypeStabbing, boringThrobbing, boring, stabbingBurning, stabbing, sharp
 SeverityExcruciatingExcruciatingSevere to excruciating
 SiteOrbit, templeOrbit, templePeriorbital
Attack frequency1/alternate day –8/day1 to 40/day (>5/day for more than half the time)3 to 200/day
Duration of attack15 to 180 minutes2 to –30 minutes5 to 240 seconds
Autonomic featuresYesYesYes (prominent conjunctival injection and lacrimation)
Migrainous features*YesYesVery rarely
Alcohol triggerYesOccasionalNo
Cutaneous triggersNoNoYes
Indomethacin effect++
Abortive treatmentSumatriptan injection or nasal sprayNilNil
Oxygen 
Prophylactic treatmentVerapamilIndomethacinLamotrigine
Methysergide Topiramate
Lithium Gabapentin

CLUSTER HEADACHE

  1. Top of page
  2. Abstract
  3. CLUSTER HEADACHE
  4. MANAGEMENT
  5. MANAGEMENT
  6. SHORT-LASTING UNILATERAL NEURALGIFORM HEADACHE ATTACKS WITH CONJUNCTIVAL INJECTION AND TEARING
  7. MANAGEMENT OF SUNCT/SUNA
  8. THE FUTURE FOR TREATMENT OF TACS
  9. References

Cluster headache is a strictly unilateral headache that occurs in association with cranial autonomic features. It is an excruciating syndrome and is probably one of the most painful conditions known to humans with female patients describing each attack as being worse than childbirth. It is located mainly around the orbital and temporal regions though any part of the head can be affected. The headache usually lasts 45 to 90 minutes but can range from 15 minutes to 3 hours. In most patients, it has a striking circannual and circadian periodicity. It is not uncommon by neurological standards at about 1 patient per 1,000 of the population.

About 80% to 90% of patients have episodic cluster headache (ECH), which consists of recurrent bouts or cluster periods, each with a duration of more than a week and separated by remissions lasting more than 4 weeks. The cluster periods occur typically once or twice a year. The remaining 10% to 20% of patients have chronic cluster headache (CCH) in which either no remission occurs within 1 year or the remissions last less than 1 month.3

Triggers.—CH attacks are typically triggered by alcohol, with 90% of patients reporting sensitivity to alcohol during their cluster bout.4 Anecdotal evidence suggests that volatile substances, such as solvents and oil-based paints, can also trigger attacks. These may act as nitric oxide donors, as it is well established that migraine and CH attacks are inducible by nitric oxide donors such as nitroglycerin.5–7 Nitric oxide is thought to act as an inhibitor of cytochrome oxidase,8 and increases the cell's requirement for oxygen for cellular respiration.9

Other triggers for CH attacks include sleep. About 75% of CH attacks occur between 9 pm and 10 am.10 Attacks usually occur about 90 minutes after the patient falls asleep, which coincides with the first REM sleep,11 although this is less apparent in chronic CH.12 It has been observed that cluster periods may be triggered by traveling through different time zones, which may reflect hypothalamic activity and diurnal variation in CH.13

MANAGEMENT

  1. Top of page
  2. Abstract
  3. CLUSTER HEADACHE
  4. MANAGEMENT
  5. MANAGEMENT
  6. SHORT-LASTING UNILATERAL NEURALGIFORM HEADACHE ATTACKS WITH CONJUNCTIVAL INJECTION AND TEARING
  7. MANAGEMENT OF SUNCT/SUNA
  8. THE FUTURE FOR TREATMENT OF TACS
  9. References

General Measures and Patient Education.—

Patients should be advised to abstain from taking alcohol during the cluster period. Otherwise, dietary factors seem to have little importance. Anecdotal evidence suggests that patients should be cautioned against prolonged exposure to volatile substances, such as solvents and oil based paints. Patients should be advised to avoid afternoon naps as sleeping can precipitate attacks in some patients

Abortive Agents.—

Because the pain of CH builds up so rapidly the most efficacious abortive agents are those that involve parenteral or pulmonary administration (Table 2).

Table 2.—.  Abortive Management of Cluster Headache
Good efficacyOxygen 100% at 7 to 12 L/min for 15 to 30 minutes
Sumatriptan subcutaneous injection 6 mg (maximum twice daily for the duration of the cluster period)
Moderate efficacySumatriptan nasal spray 20 mg or Zolmitriptan 5 mg (maximum thrice daily for the duration of the cluster bout)
Octreotide subcutaneous injection 100 μg
Poor efficacy or unprovenErgotamine tablets or suppository
Intranasal lidocaine

Triptans.— Subcutaneous sumatriptan 6 mg is the drug of choice in abortive treatment of a cluster attack. It has a rapid effect and high response rate. In CH, unlike in migraine, subcutaneous sumatriptan can be prescribed at a frequency of twice daily, on a long-term basis if necessary without risk of tachyphylaxis or rebound.14 Sumatriptan 20 mg nasal spray15 and zolmitriptan 5 mg nasal spray16 are both more effective than placebo, although clinical experience suggests that they are less likely to work than the injection. Sumatriptan 100 mg 3 times daily taken prior to an anticipated onset of an attack or at regular times does not prevent the attack,17 and regular oral triptans may induce medication overuse headache in susceptible patients,18 so that this approach is generally not recommended. Clinical trials are under way to assess the efficacy of sumatriptan 4 mg subcutaneously, which may allow for thrice daily dosing (http://www.clinicaltrials.gov/show/NCT00399243).

Oxygen.— Inhalation of 100% oxygen, at 7 to 12 L/min, is rapidly effective in relieving pain in the majority of sufferers.19 It should be inhaled continuously for 15 to 20 minutes via a nonrebreathing facial mask.

Octreotide.— Subcutaneous octreotide 100 μg has recently been demonstrated to be moderately effective in the treatment of acute CH attacks.20 In clinical practice, octreotide may have a particular utility in patients who are unresponsive to or intolerant of triptans and oxygen.

Lidocaine.— Lignocaine solution 20 to 60 mg, given as nasal drops (4% to 6% lidocaine solution) or a spray deep in the nostril on the painful side, results in mild to moderate relief in most patients, though only a few patients obtain complete pain relief.21 Intranasal lidocaine serves as a useful adjunct to other abortive treatments but is rarely adequate on its own.

Other Drugs.— Oral or rectal ergotamine is generally too slow in onset to provide meaningful relief in a timely manner. Opiates, nonsteroidal anti-inflammatory drugs (NSAIDs) and combination analgesics have no role in the acute management of CH.

Preventive Treatments.—

The aim of preventive therapy is to produce a rapid suppression of attacks and to maintain that remission with minimal side effects until the cluster bout is over, or for a longer period in patients with CCH (Table 3).

Table 3.—.  Preventive Management of Cluster Headache
Short-Term Prevention (for Episodic Cluster Headache)Long-Term Prevention (for Prolonged Bouts of Episodic Cluster Headache or Chronic Cluster Headache)
  1. *Patients with predictable nocturnal headaches only.

  2. Unproven but promising.

  3. Limited data or negative data.

Prednisolone/prednisone (transitional only)Verapamil
MethysergideLithium
VerapamilMethysergide
Daily (nocturnal) ergotamine*Topiramate
TopiramateGabapentin
Valproate (divalproex)Valproate‡
PizotifenPizotifen‡

Short-Term Prevention.—

Patients with either short bouts, perhaps in weeks, or in whom one wishes to quickly control the attack frequency, can benefit from short-term prevention. These medicines are distinguished by the fact that they cannot be used in the long-term and thus may require replacement by long-term agents in many patients.

Corticosteroids.— Corticosteroids are highly efficacious and the most rapid-acting of the preventative agents.22 Treatment should be limited to a short intensive course of 2 to 3 weeks in tapering doses because of the potential for side effects. The authors start patients on oral prednisolone 1 mg/kg to a maximum of 60 mg once daily for 5 days and thereafter decrease the dose by 10 mg every 3 days, to 0 at 21 days. In this way the risk of side effects due to long-term steroid use (diabetes, hypertension, avascular necrosis of femoral heads) is minimized. Unfortunately, relapse almost invariably occurs as the dose is tapered. For this reason, corticosteroids are used as an initial therapy in conjunction with preventives, until the latter are effective.

Methysergide.— Methysergide is a potent prophylactic agent for the treatment of CH.23 It is an ideal choice in patients with short cluster periods that last less than 4 to 5 months. Doses up to 12 mg daily can be used if tolerated. Prolonged treatment has been associated with rare fibrotic reactions (retroperitoneal, pulmonary, pleural, and cardiac). We advise a 1-month holiday every 6 months of methysergide treatment and check for evidence of pulmonary, cardiac, renal, or abdominal pathology yearly in patients on prolonged methysergide therapy. Methysergide is now no longer available in the USA.

Greater Occipital Nerve (GON) Injection.— Injection of local anesthetic and corticosteroid around the GON on the affected side can abort a bout of CH.24 This is an excellent short-term strategy,25,26 with only very modest, infrequent side effects.27

Long-Term Prevention.—

Verapamil.— Verapamil is the preventive drug of choice in both episodic and chronic CH.28–30 Clinical experience has demonstrated that higher doses than those used in cardiological indications are needed. Dosages commonly employed range from 240 to 960 mg daily in divided doses. Verapamil can cause heart block by slowing conduction in the atrioventricular node. Observing for PR interval prolongation on ECG can monitor potential development of heart block. After performing a baseline ECG, patients are usually started on 80 mg 3 times daily and thereafter the total daily dose is increased in increments of 80 mg every 10 to 14 days. An ECG is performed prior to each increment. The dose is increased until the cluster attacks are suppressed, side effects intervene or the maximum dose of 960 mg daily is achieved. About 20% of CH patients on verapamil have cardiac conduction problems and these can develop after months of stable dosing and are not dose-dependent.31 We thus perform ECGs every 6 months with long-term therapy. Verapamil is more useful in patients with longer cluster bouts (at least 6 to 8 weeks), as the authors find that the time taken to achieve the required dose and relief of symptoms, may approach or even exceed the length of shorter bouts.

Lithium.— Lithium is an effective agent for CH prophylaxis, though the response is less robust in ECH than CCH.29,32 Renal and thyroid function tests are performed prior to initiation of therapy. Patients are then started on 300 mg twice daily and the dose titrated aiming for a serum lithium level in the upper part of the therapeutic range (0.8 to 1.1 μmol/L). Most patients will benefit from dosages between 600 to 1,200 mg daily. The concomitant use of NSAIDs, diuretics, and carbamazepine is contra-indicated, as they can increase the toxicity of lithium. Lithium and verapamil may be used concomitantly, but with care for increased neurotoxicity.33

Other Drugs.— Topiramate, valproate, pizotifen, and gabapentin are used without clear clinical trials. We would be most interested in a clinical trial of topiramate in CH.

Surgery.— This is a last-resort measure in treatment-resistant patients.34 Procedures such as radiofrequency blockade of the sphenopalatine ganglion35 and percutaneous radiofrequency rhizotomy36 have had variable effects ranging from no relief to pain-free at 20 years follow-up. Destructive procedures such as trigeminal nerve section has also had variable results, ranging from no effect to pain-free at 19 years.37,38 Occasionally complete trigeminal anesthesia is achieved, with subsequent risk of corneal injury.37,38 Gamma knife radiosurgery has also been used in CH, although with high morbidity and lower efficacy.39 Destructive surgery in order to block trigeminal sensory or autonomic pathways should only be considered in patients with strictly unilateral attacks, as those whose attacks alternate sides may find an upsurgence of attacks on the side contralateral to surgery.38In one devastating case the CH attacks persisted even after complete destruction of the trigeminal sensory pathway.40

Functional imaging data has suggested the hypothalamus to be the origin for CH (reviewed in ref. [41]). There have been recent successes with abolition of attacks by the insertion of deep brain stimulators to the posterior hypothalamus in CH,42,43 and this clearly may prove a viable option in the future, for patients with otherwise refractory CCH. A less invasive procedure such as occipital nerve stimulation has been reported as effective in patients with migraine,44 occipital neuralgia,45 CH,46,47 and in 1 case each of CH and hemicrania continua.48 This approach is very promising and offers a more acceptable side effect profile than destructive and invasive procedures.

Paroxysmal Hemicrania (PH).—

PH is a rare syndrome that responds in a dramatic and absolute fashion to indomethacin, thereby underlining the importance of distinguishing it from CH and SUNCT, which are not responsive to indomethacin.49,50

The clinical phenotype of PH is highly characteristic.51,52 Patients typically have unilateral, relatively brief, severe attacks of pain associated with cranial autonomic features that recur several times per day. The pain is certainly reported in the ophthalmic trigeminal distribution, although it also often involves other parts of the head. The headache usually lasts 2 to 30 minutes, though can go on for up to 4 hours. The headache has an abrupt onset and cessation. Interictal discomfort or pain is present in up to 60% of patients, and restlessness or agitation in 85%.53 The frequency of attacks in PH is high ranging from 1 to 40 daily, with mean attack frequency of 11 to 14 daily (range 2 to 40).51–53 The attacks occur regularly throughout the 24-hour period without a preponderance of nocturnal attacks as in CH.

Triggers.— While the majority of attacks are spontaneous, approximately 10% of attacks may be precipitated mechanically, either by bending or by rotating the head. Attacks may also be provoked by external pressure against the transverse processes of C4-5, C2 root, or the GON. Alcohol ingestion triggers headaches in only 7% of patients.51 In our clinical experience cutaneous triggering, such as touching the skin, chewing, or talking, is not a feature of PH.

Periodicity.— PH is classified depending on the presence of a remission period. About 20% of patients have episodic paroxysmal hemicrania (EPH), which is diagnosed when they experience recurrent bouts, each with a duration of more than a week and separated by remissions lasting 1 month or longer. The remaining 80% of patients have chronic paroxysmal hemicrania (CPH), in which either no remission occurs within 1 year or the remissions last less than 1 month. Notably, in PH the chronic form dominates the clinical presentation, in contrast to CH in which the episodic form prevails.

MANAGEMENT

  1. Top of page
  2. Abstract
  3. CLUSTER HEADACHE
  4. MANAGEMENT
  5. MANAGEMENT
  6. SHORT-LASTING UNILATERAL NEURALGIFORM HEADACHE ATTACKS WITH CONJUNCTIVAL INJECTION AND TEARING
  7. MANAGEMENT OF SUNCT/SUNA
  8. THE FUTURE FOR TREATMENT OF TACS
  9. References

The treatment of PH is entirely prophylactic, as attacks are too short and intense for any acute oral treatment to be effective. Indomethacin is the treatment of choice.

Indomethacin.—

Complete resolution of the headache is prompt, usually occurring within 1 to 2 days of initiating the effective dose. The typical maintenance dose ranges from 25 to 100 mg daily but may vary inter- and intra-individually between 12.5 and 300 mg daily, depending on the fluctuation in attack severity.54 Hence, dosage adjustments may be necessary to address the clinical fluctuations seen in PH. On discontinuation, symptoms usually appear within 12 hours to 2 weeks though during active headache cycles, skipping or even delaying doses may result in the prompt reoccurrence of the headache. In patients with EPH, indomethacin should be given for slightly longer than the typical headache bout and then gradually tapered. In patients with CPH, long-term treatment is usually necessary; however, long-lasting remissions have been reported in rare patients following cessation of indomethacin hence drug withdrawal should be advised at least once every 6 months.

The most common serious side effect of indomethacin is the development of peptic ulcers. Gastrointestinal side effect secondary to indomethacin may be treated with antacids, misoprostol, histamine H2 receptor antagonists, or proton pump inhibitors and should always be considered for patients who require long-term treatment. Indomethacin suppositories are occasionally helpful if gastric intolerance is a major problem, or when high doses, such as 300 mg daily, are required.

In patients who do not respond to indomethacin, the diagnosis should be reconsidered, and we are reluctant to make it. Patients who need escalating doses of indomethacin to suppress the symptoms, become refractory to treatment with indomethacin, or require a continuous, high dosage of indomethacin may have underlying pathology and need careful diagnostic evaluation for symptomatic causes.

For patients who cannot tolerate indomethacin one faces a difficult challenge. No other drug is consistently effective in PH. Some response is seen with a range of other NSAIDs; however, this is usually not helpful.

Cyclooxygenase-2 Inhibitors.—

There has been some limited success in treatment of PH with cyclooxygenase-2 (COX-2) inhibitors, rofecoxib,55 and celecoxib.56,57 However, prolonged use of both of these agents has recently been linked with an increased risk of myocardial infarctions and strokes, and this culminated in the withdrawal of rofecoxib from the market worldwide.58 In view of this, the available COX-2 inhibitors should be prescribed only with great caution in PH.

Other Drugs.— There are several case reports of a partial or complete response to verapamil.59,60 Indeed, prior to the introduction of COX-2 inhibitors, verapamil was considered the more successful alternative drug treatment to indomethacin.59 Other calcium channel antagonists that have been reported to be effective in PH include flunarizine59,61 and nicardipine.61 This is not our experience. Topiramate may be helpful in PH.62

Local Nerve Injections.— Local anesthetic blockades of pericranial nerves, including the GON, supraorbital nerve, and lesser occipital nerve, have generally been reported to be ineffectual as have stellate ganglion blocks, sphenopalatine ganglion blocks, and cervical sympathetic blocks.51,63 Our experience is that GON injection with local anesthetic and depo-corticosteroid is helpful.25 We have no long-term experience with invasive procedures.

SHORT-LASTING UNILATERAL NEURALGIFORM HEADACHE ATTACKS WITH CONJUNCTIVAL INJECTION AND TEARING

  1. Top of page
  2. Abstract
  3. CLUSTER HEADACHE
  4. MANAGEMENT
  5. MANAGEMENT
  6. SHORT-LASTING UNILATERAL NEURALGIFORM HEADACHE ATTACKS WITH CONJUNCTIVAL INJECTION AND TEARING
  7. MANAGEMENT OF SUNCT/SUNA
  8. THE FUTURE FOR TREATMENT OF TACS
  9. References

SUNCT is a rare primary headache syndrome, characterized by unilateral orbital or temporal pain, which is stabbing or throbbing in quality and is severe. There should be at least 20 attacks, lasting for 5 to 240 seconds and ipsilateral conjunctival injection and lacrimation should be present.3 In recognition of the possibility that all patients with generically the same condition might not have both conjunctival injection and tearing, the classification committee considered that SUNCT syndrome may be a subset of SUNA, Short-lasting unilateral neuralgiform headache attacks with cranial autonomic features, including the latter in the appendix. In SUNA there may be cranial autonomic symptoms other than conjunctival injection and lacrimation, or indeed only one of those symptoms may be present.

Diagnosis.—

The International Headache Society describes the site of pain in SUNCT as unilateral orbital, supraorbital, or temporal pain,3 although it is clear from a large series that the pain may be experienced anywhere in the head.64 Clinical experience demonstrates that attacks may take on different characters; single stabs, which are usually short-lived, groups of stabs, or a longer attack comprised of many stabs between which the pain does not resolve to normal, thus giving a “saw-tooth” phenomenon with attacks lasting many minutes.64

Important clinical characteristics that lead to the suspicion of a diagnosis of SUNCT are the cutaneous (or other) triggerability of attacks, a lack of refractory period to triggering between attacks, and the lack of a response to indomethacin. In our cohort, oxygen was unhelpful in 100% of patients, and the indomethacin test showed no distinction between indomethacin and saline placebo in all patients.50 Apart from trigeminal sensory disturbance the neurological examination is normal in primary SUNCT.

Secondary (Symptomatic) SUNCT.— Secondary SUNCT is mainly seen with either posterior fossa or pituitary gland lesions, although other sites have been documented. It is recommendation that a brain MRI with pituitary views and pituitary function tests should be a minimal work-up for SUNCT/SUNA. The diagnosis of SUNCT is often confused with trigeminal neuralgia (TN) particularly in first division TN. Minimal or no cranial autonomic symptoms and a clear refractory period to triggering are useful pointers to a diagnosis of TN compared to SUNCT/SUNA.

MANAGEMENT OF SUNCT/SUNA

  1. Top of page
  2. Abstract
  3. CLUSTER HEADACHE
  4. MANAGEMENT
  5. MANAGEMENT
  6. SHORT-LASTING UNILATERAL NEURALGIFORM HEADACHE ATTACKS WITH CONJUNCTIVAL INJECTION AND TEARING
  7. MANAGEMENT OF SUNCT/SUNA
  8. THE FUTURE FOR TREATMENT OF TACS
  9. References

Attack Therapy.—

Since the attacks are so short, attack therapy is not a useful concept in SUNCT/SUNA. One can use short-term prevention in hospital with lidocaine, which arrests the problem and long-term prevention to minimize disability out of hospital.

Short-Term Prevention.—

Lidocaine.— Intravenous lidocaine has been reported previously in 4 patients with SUNCT, providing them with pain-free times of up to 12 hours.65 A recent trial of intravenous lidocaine in 11 patients reported some relief to total abolition of their symptoms, the longest pain-free period being 3 weeks in a patient with chronic SUNCT, 12 weeks pain-free in chronic SUNA, and 6 months pain-free in a patient with episodic SUNCT.66 A trial of intravenous lidocaine is thus warranted for both diagnostic and therapeutic purposes.

Long-Term Prevention.—

Lamotrigine.— Lamotrigine given in an open-label manner at doses up to 300 mg daily was reported as highly efficacious in 10 patients,67–71 although it was ineffective in 4 patients.65,72,73 Lamotrigine had a moderate to good effect in 68% SUNCT and 25% SUNA patients in a recent open label study.50 Problems with lamotrigine include a skin reaction, which may progress to Stevens–Johnson syndrome, and this necessitated the cessation of lamotrigine in at least 1 patient in the literature.74

Topiramate.— Topiramate has been reported to be effective in 5 patients at doses up to 300 mg daily,65,74,75 although not in all cases.72,76 Problems with topiramate include side effects, which sometimes necessitated the cessation of the drug. Recently 52% of SUNCT patients had a good response to topiramate in an open-label study, although the response in SUNA was less clear.50 As SUNCT has until recently been thought of as an untreatable condition, and with a 52% success rate in an open-label study, the use of topiramate is still advised in SUNCT. Patients with a previous history of renal stones, glaucoma, depression, and those who are underweight, should not be offered topiramate as a first-choice agent, in case of developing known side effects.

Gabapentin.— SUNCT has been shown to respond to gabapentin, with complete suppression of attacks in 3 of 9 patients treated with 800 to 2,700 mg daily,77–79 and minimally effective in 1 patient with SUNA at an unknown dose.80 Interestingly it was effective in 60% of SUNA but only 45% of SUNCT in an open-label trial.13 It is therefore suggested for use in SUNA, and as a second-line agent in SUNCT.

Carbamazepine.— Carbamazepine has been a mainstay of treatment in trigeminal neuralgia,81 and has also been reported as having a good or partial effect in SUNCT at doses up to 900 mg a day,65,82 especially when used in combination with prednisolone83–85 or topiramate.65 However, it was effective in only 39% of our series of SUNCT patients,86 and thus is used less frequently than other preventives.

Surgery.—

Jannetta Procedure.— Two patients have been reported who have been treated with the Jannetta procedure (microvascular decompression of the trigeminal nerve) with good effect,84,87 although in 1 patient it made the symptoms worse.65 In 2 further patients it was unhelpful, as were glycerol rhizotomy and γ knife radiosurgery, and in fact the patients suffered postsurgical side effects, which were anesthesia dolorosa, unilateral deafness, chronic vertigo, and disequilibrium.72 The latter is in line with our experience, that microvascular decompression is either of no value or harmful in SUNCT/SUNA.

GON Injections.— Two patients with SUNCT and 6 patients with PH underwent lidocaine blockades of the GON with no benefit.63,88 A combination of lidocaine and a steroid was beneficial in 9 out of 14 CH patients,26 and a moderate to good effect was demonstrated in 5 out of 8 SUNCT patients.86 GON injections may render the patient pain-free for weeks or months, which would allow for the introduction and dose escalation of preventive medications.

Hypothalamic Deep Brain Stimulation.— Functional imaging work has shown that activation of the posterior hypothalamus is linked to attacks of SUNCT.73,89,90 One patient with intractable SUNCT has been reported to have had a good response to deep brain stimulation in the region of the posterior hypothalamus.91 More information is required before it could be routinely recommended.

THE FUTURE FOR TREATMENT OF TACS

  1. Top of page
  2. Abstract
  3. CLUSTER HEADACHE
  4. MANAGEMENT
  5. MANAGEMENT
  6. SHORT-LASTING UNILATERAL NEURALGIFORM HEADACHE ATTACKS WITH CONJUNCTIVAL INJECTION AND TEARING
  7. MANAGEMENT OF SUNCT/SUNA
  8. THE FUTURE FOR TREATMENT OF TACS
  9. References

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.

Preventive Medications:—

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.

Neuromodulatory Procedures:—

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

References

  1. Top of page
  2. Abstract
  3. CLUSTER HEADACHE
  4. MANAGEMENT
  5. MANAGEMENT
  6. SHORT-LASTING UNILATERAL NEURALGIFORM HEADACHE ATTACKS WITH CONJUNCTIVAL INJECTION AND TEARING
  7. MANAGEMENT OF SUNCT/SUNA
  8. THE FUTURE FOR TREATMENT OF TACS
  9. References