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Cluster headacheacute and prophylactic therapy

Published by Wiley Periodicals, Inc.
Cluster Headache—Acute and Prophylactic Therapyhead_1830272.286
Cluster headache (CH) pain is the most severe of the primary headache syndromes. It is characterized by periodic attacks
of strictly unilateral pain associated with ipsilateral cranial autonomic symptoms. The majority of patients have episodic CH,
with cluster periods that typically occur in a circannual rhythm, while 10% suffer from the chronic form, with no significant
remissions between cluster periods. Sumatriptan injection or oxygen inhalation is the first-line therapy for acute CH attacks,
with the majority of patients responding to either treatment. The calcium channel blocker verapamil is the drug of choice for
CH prevention. Other drugs that may be used for this purpose include lithium carbonate, topiramate, valproic acid, gabapentin,
and baclofen. Transitional prophylaxis, most commonly using corticosteroids, helps to control the attacks at the beginning of a
cluster period. Peripheral neural blockade is effective for short-term pain control. Recently, the therapeutic options for
refractory CH patients have expanded with the emergence of both peripheral (mostly occipital nerve) and central (hypotha-
lamic) neurostimulation. With the emergence of these novel treatments, the role of ablative surgery in CH has declined.

Key words: cluster headache, acute therapy, prophylactic therapy
Abbreviations: AEs adverse effects, CCH chronic cluster headache, CH cluster headache, DHE Dihydroergotamine, ECH
episodic cluster headache, GON greater occipital nerve, HBO hyperbaric oxygen, HS hypothalamic stimula-
tion, NBO normobaric oxygen, ONS occipital nerve stimulation, SPG sphenopalatine ganglion

Cluster headache (CH) pain is considered the ipsilateral to the pain. Patients typically pace rest- most severe of the primary headache syndromes and lessly during an acute attack. The hallmark of CH is is arguably one of the most severe pain syndromes the circadian periodicity of the attacks. Also, in epi- that afflict humans.1 The disorder is characterized by sodic CH (ECH), the cluster periods often occur at attacks of severe, strictly unilateral pain, typically in predictable times of the year (circannual periodicity).
the retro-orbital and fronto-temporal areas, associ- Recent imaging studies confirm activation of the ated with symptoms and signs of cranial autonomic hypothalamus during CH attacks.2 These findings may explain the characteristic periodicity of CH. Activa- rhinorrhea/nasal congestion, and Horner’s syndrome) tion of the trigeminovascular system has also beenshown during acute attacks.
From the The Neurologic Group of Bucks/Montgomery
The management of CH includes: (1) patient edu- County—Neurology, Doylestown, PA, USA (A. Ashkenazi);
cation about the nature of the disorder; (2) advice on Washington University School of Medicine—Neurology, St.
Louis, MO, USA (T. Schwedt).

lifestyle changes (eg, avoiding alcohol during anactive cluster period); (3) prompt treatment of the Address all correspondence to A. Ashkenazi, The Neurologic
Group of Bucks/Montgomery County, 800 West State Street,

acute attack; and (4) prophylactic treatment. Most Suite 101, Doylestown, PA 18901, USA.
patients can be managed with medical therapy.
Accepted for publication November 13, 2010.
Rarely, surgical treatment is indicated. Recently, neu- limit our search to a specific time period. We focused rostimulation has emerged as a therapeutic option for on clinical efficacy and tolerability of the various drugs and procedures based on data from human We performed a PubMed search of the English studies. We included the best available studies for literature to find studies on the acute and prophylac- each discussed drug or procedure. These ranged from tic treatment of CH. Search terms were CH and each randomized controlled trials for some treatments, to of the following: acute treatment, prophylactic (or preventive) treatment, triptans, oxygen, ergotamine,dihydroergotamine, lidocaine, somatostatin, oct-reotide, verapamil, lithium, topiramate, valproic acid, TREATMENT OF THE ACUTE ATTACK
methysergide, gabapentin, baclofen, melatonin, botu- (TABLE 1)
linum toxin, corticosteroids, neurostimulation, occipi- Because the pain of acute CH attacks evolves tal nerve block/stimulation, sphenopalatine ganglion rapidly, oral medications are usually not as effective block/stimulation, hypothalamic stimulation, radio- for this purpose as they are for migraine attacks. For rapid and effective pain control, the therapeutic agent surgery, microvascular decompression. We did not Table 1.—Drugs for the Acute Treatment of Cluster Headache
daily during a clusterperiod; contraindicated inpatients with CV diseases contraindicated in patientswith CV diseases contraindicated in patientswith CV diseases contraindicated in patientswith CV diseases; cannotbe used with triptans *See Appendix for detailed guidelines.
AEs = adverse effects; CV = cardiovascular; EFNS = European Federation of Neurological Societies; IM = intramuscular;IN = intranasal; IV = intravenous; L/min = liters per minute; SC = subcutaneous.
TRIPTANS
repeated use. The response to treatment of patients The 5-HT1B/1D agonists (known as triptans), in an who had chronic CH (CCH) was somewhat less injectable or intranasal preparation, are a mainstay of robust, and slower to occur, as compared with that of ECH patients. Adverse effects were reported by 62% Sumatriptan.—Sumatriptan, injected subcutane-
of patients. Withdrawal rate was 33%, with 4 (8%) ously, is the drug of choice for acute CH attacks.1 The patients withdrawing because of AEs.
efficacy of the drug for this indication was examined The efficacy of intranasal sumatriptan in the in a number of well-designed studies.4-7 In 1 random- treatment of acute CH attacks was examined in 1 ized, placebo-controlled study the efficacy of subcu- placebo controlled study.8 Patients with ECH or taneous sumatriptan (6 mg) for acute CH treatment CCH, whose attacks lasted at least 45 minutes, were was examined.4 Data from 39 patients were evalu- given intranasal sumatriptan 20 mg, or placebo. Data ated. Headache severity decreased within 15 minutes from 154 attacks, experienced by 118 patients, were in a significantly higher proportion of sumatriptan- analyzed. At 30 minutes after treatment, headache treated, as compared with placebo-treated, attacks (74% vs 26 %). Also, a significantly higher proportion sumatriptan- compared with placebo-treated attacks of sumatriptan-treated patients were pain free 15 (57% vs 26%). The corresponding pain-free rates at minutes after injection, as compared with those who that time were 47% and 18%. The drug was well received placebo (46% vs 10%). Sumatriptan was tolerated. Another study, that was open label, well tolerated. In another controlled study, subcuta- reported on lower efficacy of intranasal, as compared neous sumatriptan at a dose of either 6 mg or 12 mg, with subcutaneous sumatriptan, in acute CH treat- or placebo, was given to 134 CH patients.5 Fifteen ment.9 A limitation of that study, in addition to its minutes after injection, the proportion of patients open-label design, was the fact that treatment out- who experienced headache relief was 80%, 75% and comes were evaluated at a relatively early time point 35% for sumatriptan 12 mg, sumatriptan 6 mg, and placebo, respectively. The higher dose of sumatriptan In summary, injectable sumatriptan is effective was not significantly superior to the lower dose, and and well tolerated for the majority of CH patients.
was associated with more adverse effects (AEs). In an The drug has a rapid onset of action. It remains well open-label study from the same group, the long-term tolerated and effective even when taken frequently safety and efficacy of subcutaneous sumatriptan was (up to twice daily) during a cluster period. The rec- examined in 138 CH patients.6 Each patient treated a ommended dose is 6 mg, although lower doses maximum of 2 attacks per day with a single injection (2-3 mg) may be effective in some patients.10 Intrana- per attack. A total of 6353 attacks, that occurred over sal sumatriptan appears to be less effective, and to 3 months, were evaluated. Headache relief was have a slower onset of action than the injectable obtained in 96% of attacks. There was no evidence for decreased efficacy of the drug with continued use.
patients with coronary artery disease or cerebrovas- Sumatriptan was well tolerated, and there was no cular disease. Because CH typically afflicts middle increase in AEs with higher frequency of using the aged men, many of whom smoke, a clinical evalua- drug. In another open-label study, the efficacy and tion, oriented toward the risk of vascular diseases, tolerability of sumatriptan in CH treatment were needs to be done before prescribing the drug.
evaluated over a period of up to 1 year.7 The Zolmitriptan.—The efficacy of intranasal zolmi-
maximum daily dose of sumatriptan was 12 mg. A triptan for acute CH attacks has been studied in 2 total of 2031 attacks, experienced by 52 patients, were controlled trials.11,12 In 1 study, 92 patients received evaluated. In 88% of the attacks, treatment was effec- either intranasal zolmitriptan (5 mg or 10 mg) or tive within 15 minutes after injection, and 57% of placebo, for acute attacks.11 Thirty minutes after treat- patients were pain free at that time point. There was ment, headache relief rates were significantly higher no significant change in the efficacy of the drug with for zolmitriptan compared with placebo (62%, 40%, and 21% for zolmitriptan 10 mg, zolmitriptan 5 mg, patients experienced significant pain relief within 15 and placebo, respectively). Patients with ECH had minutes. The best response was observed in younger higher response rates to zolmitriptan (and to (<50 years old) patients who had ECH. Fogan exam- placebo) compared with those who had CCH. Zolmi- ined the efficacy of oxygen for acute CH in a double triptan was well tolerated. In a similarly designed blind crossover study.18 Nineteen men were treated study, 52 CH patients treated 151 attacks with intra- with either oxygen, or air inhalation, at a rate of nasal zolmitriptan (10 mg or 5 mg) or placebo.12 6 L/min. After treatment, average pain relief score Zolmitriptan, at both doses, was superior to placebo was significantly higher for oxygen, as compared with with regards to headache relief at 30 minutes (63%, air. Rozen examined the effect of high flow oxygen on 50% and 30% for zolmitriptan 10 mg, zolmitriptan CH pain in 3 patients who had been refractory to 5 mg, and placebo, respectively). The corresponding oxygen given at the standard flow rate of 7-10 L/ pain-free rates at that time point were 47%, 39%, and min.19 All 3 patients (2 with CCH and 1 with ECH) 20%. Zolmitriptan, at both doses, was well tolerated.
had complete or near-complete headache response Oral zolmitriptan was evaluated as an acute after inhaling 100% oxygen at a rate of 14-15 L/min.
treatment for CH attacks in a randomized controlled Two of the patients were heavy smokers. The author study.13 The drug was found to be superior to placebo suggested that patients who fail to respond to oxygen in ECH, but not CCH, patients. Thirty minutes after at the standard flow rate should be tried on higher treatment, headache response rates in ECH patients flow. In a recent large controlled trial, Cohen et al were 47% and 29%, for zolmitriptan 10 mg and examined the efficacy of high flow oxygen in the treat- ment of acute CH attacks.20 A total of 109 patients In summary, intranasal zolmitriptan may be used treated 4 CH attacks with either oxygen (12 L/min) or for the acute treatment of CH, with comparable effi- inhaled air, given via a facial mask for 15 minutes.
cacy to that of intranasal sumatriptan. Oral zolmitrip- Oxygen was significantly superior to placebo with tan has only limited efficacy for this purpose. As with regards to the primary end point (elimination of pain or “adequate pain relief” at 15 minutes—78% vs patients with a history of cardiovascular or cere- 20%, with oxygen and air, respectively).
Hyperbaric oxygen (HBO) has also been studied as a treatment for acute CH attacks.21,22 Weiss et al treated a CH patient with hyperbaric (2 atmospheres) Oxygen inhalation has been used for the treat- 100% oxygen, after she had been refractory to con- ment of acute CH attacks for decades.1 The major ventional oxygen therapy.21 Two attacks were treated advantage of oxygen is the virtual lack of AEs. As with HBO, with prompt and complete pain relief. Di opposed to triptans, oxygen can be given to patients Sabato et al treated 7 ECH patients with HBO in a with a history of cardiovascular or cerebrovascular placebo controlled study.22 Six patients responded disease. The mechanism of action of oxygen on CH well to treatment, with interruption of their attack.
has long been related to its vasoconstrictive effect.14 Moreover, in 3 of the responders the CH period More recently, however, it has been shown that ended after HBO treatment. Placebo treatment had oxygen inhibits neuronal activation in the trigeminal nucleus caudalis when this activation is initiated by In summary, normobaric oxygen is an effective stimulation of the parasympathetic outflow through treatment of acute CH attacks in the majority of the facial nerve.15 Oxygen has been evaluated as an patients. It is well tolerated and has virtually no AEs.
acute treatment of CH in a number of studies.16 In an As opposed to triptans, there is no limitation to the open study, Kudrow examined the efficacy of oxygen number of times per day it can be used. A proper for acute CH attacks in 52 patients.17 Oxygen 100% technique of use is crucial for good results with was inhaled via a facial mask at a rate of 7 liters/ oxygen therapy. The patient should be instructed to minute (L/min) for 15 minutes. Thirty-nine (75%) use the oxygen via a non-rebreathable mask, at a rate of 7-10 L/min, in a sitting position, for at least 15-20 studies that compared the various routes of adminis- minutes. Patients may increase the flow rate up to tration of the drug for CH. The efficacy and tolerabil- 15 L/min if needed. The optimal flow rate should be ity of intranasal DHE (1 mg) in the treatment of determined individually for each patient. The major acute CH was examined in a controlled study of 25 disadvantage of oxygen therapy is its inconvenience patients.24 Intranasal DHE decreased the intensity, of use, particularly when the patient is out of home.
but not the duration, of the attacks, and was well Portable oxygen tanks are available for patients who tolerated. The authors suggested that the moderate wish to use it in these circumstances. Oxygen therapy efficacy of the drug in their study may have been for CH should be used with caution, or even avoided, related to the dose they used. They recommended in patients with chronic obstructive pulmonary that the drug be examined at a higher dose in future disease, because of the risk of respiratory depression.
trials (the maximal recommended dose of intranasal HBO may be considered for refractory CH patients.
DHE for acute headache treatment in adults is 2 mg).
However, because this is not a readily available In summary, because of the moderate efficacy of therapy, and there is no evidence for a sustained effect most ergot preparations and the difficulty of receiving of it on CH,23 the majority of patients are not likely to intravenous DHE (probably the most effective preparation for this purpose) in a timely manner, therole of ergots in the acute treatment of CH is limited.
ERGOTAMINE AND
DIHYDROERGOTAMINE

LIDOCAINE
Ergot derivatives were among the first agents to Data on the efficacy of locally applied lidocaine be used in CH treatment. Reports on the efficacy of on acute CH attacks are derived from several non- ergotamine for this indication date back to the 1940s controlled studies and 1 randomized controlled and 1950s.1 These data, however, were based on small, trial.25-28 Kittrelle et al examined the effect of open-label studies and on case reports. The drug has lidocaine, applied topically to the sphenopalatine not been evaluated in controlled studies for this indi- fossa, on acute CH attacks.25 Four of the 5 treated cation. Kudrow compared the efficacy of sublingual patients experienced rapid relief from pain and asso- ergotamine with that of oxygen in 50 patients with ciated symptoms of nitrate-induced CH attacks. The CH.17 The response rate to ergotamine was 70%, as treatment was also effective for spontaneous attacks.
compared with 82% for oxygen (with no significant In another study, Hardebo and Elner examined the between-group difference). Oxygen was better toler- effect of lidocaine 4%, self-applied using a nasal ated than ergotamine; however, the latter was more dropper through the nostril ipsilateral to the pain, on convenient to use. Because of limited availability and CH pain and associated symptoms.26 Twenty-four potentially serious AEs, most notably those related to patients were studied, with moderately positive the drug’s vasoconstrictive effect, ergotamine is cur- results. Robbins examined the effect of intranasal lidocaine, administered through a spray bottle, on Dihydroergotamine (DHE) is available in inject- pain in 30 men with ECH.27 Patients treated 2 con- able (intravenous, intramuscular, or subcutaneous) secutive CH attacks. Results were modest, with 27% and intranasal formulations. Although no data from reporting on “moderate relief,” 27% on “mild relief,” controlled trials are available, clinical experience sug- and 46% on no relief. In a placebo-controlled study, gests efficacy of intravenous DHE for acute CH. This Costa et al examined the efficacy of lidocaine 10%, treatment, however, is not practical for the majority applied bilaterally to the sphenopalatine fossa via of patients because of the difficulty in receiving it promptly with attack onset. Based on our clinical nitroglycerin-induced CH attacks.28 Lidocaine appli- experience, intramuscular and subcutaneous DHE cation resulted in elimination of pain in all (15) injections are not as effective as the intravenous patients. However, there was a considerable delay (of route, although, to our knowledge there are no 37 minutes on average) between the time of lidocaine application and pain relief (the corresponding time is alcohol. Patients should be advised to avoid alco- interval for placebo was 59 minutes).
holic beverages during a cluster period (or, in the case In summary, intranasal lidocaine is at best mod- erately effective in the treatment of acute CH attacks.
It should not be used as a first-line therapy for this PROPHYLACTIC THERAPY
indication. This treatment may be used as adjunctive Prophylactic therapy for CH is divided into main- therapy in some patients whose attacks do not com- tenance prophylaxis and transitional prophylaxis.
pletely respond to other, more effective, therapies.
throughout the entire course of the cluster period SOMATOSTATIN AND OCTREOTIDE
with the intent of reducing the frequency and severity Sicuteri et al conducted a controlled study to of cluster attacks. When treating ECH, maintenance examine the efficacy of intravenous somatostatin for prophylactics are generally discontinued after resolu- acute CH attacks.29 Seventy-two attacks, experienced tion of the cluster period and then restarted at the by 8 men, were studied. Somatostatin infusion was onset of the next cluster period. Although mainte- superior to placebo, and comparable to intramuscular nance prophylaxis monotherapy is optimal, some ergotamine, in relieving CH pain. Matharu et al patients will require a combination of maintenance evaluated the efficacy of octreotide, a somatostatin medications for adequate control of CH. However, analog that can be given subcutaneously, for acute care must be taken to avoid potentially negative drug CH.30 Octreotide 100 mg was significantly superior to interactions. Transitional prophylactics are adminis- placebo with regard to headache response rates (52% tered for short durations as adjunctive therapies to maintenance prophylactics in an attempt to abort the An important advantage of these drugs is their cluster period or to further reduce the frequency and lack of vasoconstrictive effect, making them a viable severity of cluster attacks. They are often begun treatment option for patients who cannot use triptans simultaneously with initiation of maintenance pro- phylaxis because they tend to work more quickly andthus provide control of CH until the maintenance SUMMARY—TREATMENT OF THE
ACUTE ATTACK
In summary, injectable sumatriptan and inhaled MAINTENANCE PROPHYLAXIS (TABLE 2)
oxygen are both a first-line therapy for acute CH. The First-Line Therapy.—Verapamil, a calcium-channel
decision on which of these options to use should be blocker, is the first-line maintenance prophylactic made after considering the patient’s medical comor- medication for CH. Verapamil is considered first-line bidities and personal preference. In patients who do therapy because of its efficacy, relative safety, and the not respond well to these treatments (or in those who ability to coadminister symptomatic and transitional cannot use triptans), somatostatin or its analogs therapies with less concern about drug interactions appear to be a promising therapeutic option. Intrana- compared with some of the other maintenance pro- sal lidocaine may be tried as adjunctive therapy in phylactic medications (eg, lithium carbonate). In open-label studies, approximately 70% of ECH and There are little data with regard to clinical CCH patients have substantial improvement with parameters that may predict response to the various verapamil therapy.32 In a double-blind placebo- acute CH treatments. In a prospective study of 246 controlled trial of verapamil for maintenance prophy- CH patients, older age was a predictor for decreased laxis of ECH, 15 patients were randomized to 120 mg response to triptans, whereas nausea, vomiting, and of verapamil 3 times daily while 15 subjects were restlessness predicted decreased response to oxy- randomized to placebo.33 During 2 weeks of treat- gen.31 As opposed to migraine, there are few known ment, 80% of patients receiving verapamil had a triggers to the acute CH attack, most notable of which greater than 50% reduction in headache frequency, Table 2.—Maintenance Prophylactic Therapy for Cluster Headache
cognitive dysfunction, fatigue,dizziness, taste alteration *See Appendix for detailed guidelines.
AEs = adverse including 4 patients who became attack free. Vera- Target dosages of verapamil ranging from 200 mg pamil took effect quickly, with one-half of responders to 960 mg per day in divided doses are typically used having substantial improvement within the first week for cluster prophylaxis.35 Most patients will respond and the other one-half responding during the second to doses of 200 mg to 480 mg per day.36 Immediate or week. Meanwhile, zero patients receiving placebo had extended release formulations may be used. Slow a greater than 50% reduction in headache frequency.
titrations up to the target dose may reduce AEs Adverse effects due to verapamil were mild, with con- including hypotension, constipation, and peripheral stipation being the most common and most bother- edema. A method of titrating and tapering verapamil some. A double-blind, crossover study of verapamil vs dosage in 40 mg intervals is described in a paper by lithium carbonate for CCH suggests that verapamil is Blau and Engel.36 EKG monitoring is necessary a superior treatment.34 In this randomized trial, each during verapamil therapy because of the risk of heart of the 24 subjects received verapamil 360 mg per day block and bradycardia, AEs that can develop with or lithium carbonate 300 mg 3 times daily for 8 weeks, initiation of therapy, increases in dose, and even and then following a 2 week washout period was during continued stable dose therapy.37 In our prac- switched to the other therapy for an additional 8 tice, we obtain a baseline EKG before initiating vera- weeks. Verapamil and lithium both provided similar pamil therapy, repeat EKG with each increase in dose reductions in both headache index and analgesic con- of at least 80 mg, and an EKG each 3 months if the sumption. However, verapamil worked more quickly, dose has been unchanged. Patients should be with over 50% of patients having significant improve- informed of the possibility of developing gingival ment in headache index within the first week com- hyperplasia because of long-term use of verapamil.
pared with 37% of those taking lithium. Furthermore, Second-Line Therapy.—Lithium carbonate is a
only 12% of those taking verapamil reported AEs second-line therapy for maintenance prophylaxis of compared with 29% of those taking lithium.
CH. We consider lithium as a second-line therapy because of its potential for causing numerous AEs, studies only.43,44 A double-blind placebo-controlled the need for blood test monitoring during therapy, study of sodium valproate did not support its efficacy; and its potential for causing several drug interactions.
however, this may have been due to an exceedingly Nonetheless, lithium carbonate has been demon- high response rate of 62% in the placebo group.45 strated to provide significant benefit in the treatment Effective doses range from 500 mg to 2000 mg daily in of CCH. Its efficacy for treating CCH has been dem- divided doses. Common AEs include weight gain, onstrated in the investigation discussed in “First-Line fatigue, tremor, hair loss, and nausea. Monitoring with Therapy” and in a study of 8 additional CCH complete blood counts and liver function tests are patients.34,38 In the latter study, all 8 patients had at necessary during valproic acid therapy. Limited evi- least a 75% improvement within the first 2 weeks of dence supports the use of melatonin for cluster pro- therapy. However, only 1 of 3 who were followed phylaxis. In a double-blind, placebo-controlled trial of long-term had continued improvement after 18 10 mg melatonin, 5 of 10 subjects randomized to months of therapy. The evidence for the utility of melatonin had cluster remission within 5 days while lithium carbonate for the treatment of ECH is less none of the 10 subjects taking placebo went into clear, with generally small studies providing contra- remission.46 Open-label studies of gabapentin suggest dictory results.34,38,39 Lithium carbonate doses of its value in maintenance prophylaxis of CH in doses 600 mg to 900 mg per day are typically needed to ranging from 800 mg to 3600 mg per day.47,48 Gaba- obtain target therapeutic serum lithium levels of 0.4 pentin is typically a well-tolerated medication but to 0.8 mEq/L. Lithium serum levels, renal function, more common AEs include somnolence and fatigue, and thyroid function should be monitored during dizziness, weight gain, peripheral edema, and ataxia.
lithium therapy. Common AEs to lithium include In a small open-label study of baclofen 10 mg 3 times diarrhea, tremor and polyuria. Symptoms and signs of daily, 6 of 9 subjects went into remission within 1 toxicity include nausea, vomiting, diarrhea, confusion, week and an additional 1 subject had improvement nystagmus, extrapyramidal signs, ataxia, and seizures.
followed by remission at week 2.49 Although adverse Topiramate, in doses ranging from 50 mg to events were not reported by subjects in this study, 200 mg per day, is considered second-line therapy for more common AEs to baclofen include drowsiness, CH prophylaxis. Although we have designated topi- dizziness, ataxia, and muscle weakness. Clonidine, ramate as second-line therapy, consistent with the given as a 5 mg to 7.5 mg transdermal patch (that Grade B recommendation in the European Federa- delivers the drug at a rate of 0.2-0.3 mg daily for tion of Neurological Societies guidelines, topiramate 1 week), has been studied in 2 small open-label use for CH prophylaxis has been investigated in studies.50,51 In the first, which included 8 ECH and 5 open-label studies only.40-42 Common AEs to topira- CCH patients, there were significant reductions in mate include cognitive dysfunction, paresthesias, mean attack frequency, pain intensity, and attack alteration in taste, weight loss, fatigue, and dizziness.
duration.50 However, a second study including 16 Patients with a history of nephrolithiasis should not ECH patients failed to confirm these positive receive topiramate because of an increased risk of results.51 Tiredness and reduction in blood pressure recurrent stones while taking this medication.
were AEs noted in these studies. An open-label study Third-Line Therapy.—Other therapies that may be
of botulinum toxin type A as add-on therapy in 3 effective for maintenance cluster prophylaxis include ECH and 9 CCH patients had mixed results.52 Fifty methysergide, valproic acid, melatonin, gabapentin, units injected ipsilateral to the headache resulted in baclofen, clonidine, and botulinum toxin. Although headache remission in 1 CCH patient, improvement methysergide is likely effective for preventing CH, it in attack frequency and severity in an additional 2 is not available in the USA and long-term use is asso- CCH patients, improvement in a continuous baseline ciated with fibrotic complications. Thus, we cannot headache with no change in superimposed cluster recommend its use. Valproic acid has been shown to attacks in an additional 1 CCH patient, and no benefit provide benefit in open-label and retrospective in the remaining 8 patients. More common AEs to botulinum toxin therapy include weakness of injected trate, 3-4 mg per day in divided doses, may be admin- muscles and pain at injection sites.
prophylaxis.58,61 Administration just before bedtime TRANSITIONAL PROPHYLAXIS
may help to prevent nighttime attacks.
Corticosteroids are often prescribed concurrent with initiation of maintenance prophylaxis in order to INVASIVE PROCEDURES FOR CLUSTER
quickly obtain cluster control. Oral and intravenous HEADACHE TREATMENT
corticosteroids may both provide benefit. Varying With an individually tailored pharmacologic doses of oral prednisone, ranging from 10 mg/day to treatment plan, the majority of CH patients will 80 mg/day, were evaluated in a study of 9 episodic and achieve satisfactory results. For those who remain 10 chronic cluster patients.53 Peak prednisone dose refractory to medical treatment, a number of invasive was given for 3 to 10 days and tapered over 10 to 30 procedures are available. These include peripheral days. Complete relief from CH was seen in 11 nerve blocks, peripheral or central neurostimulation patients, 3 had 50-99% relief, 3 had 25-50% relief, and and, as a last resort, ablative surgery. Peripheral nerve 2 patients had no benefit. The ECH and CCH patients block, mostly targeting the greater occipital nerve had similar responses. Investigators observed that (GON), may also be used in less refractory patients, prednisone doses of 40 mg or higher were needed for as an adjunct to pharmacologic therapy.
benefit. Headache recurrence was common duringthe prednisone taper. Other studies of oral pred- PERIPHERAL NERVE AND
nisone have had similar results.54,55 Intravenous corti- SPHENOPALATINE GANGLION BLOCK
costeroids, sometimes followed by oral steroids, Efficacy of GON block in CH treatment was sug- may also provide benefit for transitional cluster gested by Anthony in the 1980s.62 More recently, the therapy.56,57 A single high dose of intravenous meth- procedure was investigated as CH treatment in a ylprednisolone (30 mg/kg body weight over 3 hours) number of studies, with the majority showing positive delivered on the eighth day of an active cluster period results.63-66 Peres et al evaluated the effect of GON provided 10 of 13 treated patients with 2 or more days block in 14 patients with CH.63 Patients received of attack cessation.56 The mean interval between GON block ipsilateral to the head pain using steroid treatment and attack recurrence was 3.8 days.
lidocaine 1% and triamcinolone 40 mg. Patients were Three patients had complete cluster remission.
evaluated before and 1 week after the block. Nine Although adequate trials supporting their use are (64%) patients had good or moderate response. The lacking, ergotamine tartrate and DHE may be used procedure was well tolerated. Ambrosini et al evalu- for transitional prophylaxis.58,59 In an open-label ated the effect of suboccipital injection of lidocaine study, 23 ECH and 31 CCH patients were admitted to 2% with betamethasone, compared with lidocaine the hospital for treatment with repetitive intravenous and saline, in 23 CH patients in a randomized, con- DHE.60 All patients became headache free while trolled study.64 The CH attacks disappeared within 72 being treated with IV DHE: 10 patients (16%) after hours in 85% of the lidocaine + betamethasone group the first dose, an additional 12 (19%) during the first (with 61% remaining attack free for 4 weeks) com- day of hospitalization, and 22 (34%) more became pared with none in the lidocaine + saline group. Injec- headache free by the second day of hospitalization.
tions were well tolerated. Afridi et al examined the By day 3, greater than 90% of patients were headache efficacy of GON block, using lidocaine 2% and meth- free and by day 5 all were headache free. At 3 months ylprednisolone, in patients with refractory chronic after discharge, >90% of ECH patients and 44% of daily headache.65 Their sample included 19 patients CCH patients remained headache free. Approxi- with CH who received 22 injections. Thirteen of the mately 83% of patients reported no AEs from IV injections (59%) resulted in a complete or partial DHE. Reported AEs included nausea, non-cardiac response, with a median duration of 12 and 21 days, chest tightness, and a metallic taste. Ergotamine tar- for complete and partial response, respectively. In contrast to these results, Busch et al reported on only patients. Complications/AEs included lead migration, minor headache improvement in 60% of 15 CH painful paresthesias, muscle recruitment, neck stiff- patients who received GON block using prilocaine.66 ness, skin pain, and infection. Mean battery life was Endoscopically guided sphenopalatine ganglion (SPG) blockade has been evaluated by Felisati et al The SPG stimulation may also be an effective for CH treatment.67 Of 20 refractory CCH patients treatment for refractory CH. Five patients with CCH, who underwent the procedure, 11 experienced signifi- refractory to more conventional therapies, were cant, albeit temporary, symptom relief.
treated with SPG stimulation during 18 acute clusterattacks.71 Stimulation resulted in complete attack PERIPHERAL NERVE AND
resolution for 11 of the attacks, greater than 50% SPHENOPALATINE GANGLION
reduction in pain severity without complete resolu- STIMULATION
tion for 3 attacks, and minimal to no relief for 4 Peripheral nerve stimulation may be effective attacks. Benefits from stimulation were noted within 1 and indicated for the prophylactic therapy of CCH minute to 3 minutes of treatment initiation. Stimula- patients who are refractory or intolerant to medica- tion was well tolerated with only mild AEs from tion therapy. Several small studies have now shown stimulator placement, including transient epistaxis occipital nerve stimulation (ONS) to be a promising and transient mild facial pain. Further investigations therapy for such patients. Eight patients with drug- of SPG stimulation for the acute and prophylactic resistant CCH, treated with unilateral ONS, were fol- lowed for an average of 15.1 months.68 At the time oflast follow-up, 2 of 8 patients were pain free, 3 had a DEEP BRAIN (HYPOTHALAMIC)
~90% reduction in headache frequency, 2 had ~40% STIMULATION
reduction, and 1 patient derived no benefit. Two Leone et al reported in 2001 on a 39-year-old patients had side-shift of their cluster attacks requir- man with intractable CH whose attacks improved sig- ing treatment with suboccipital steroid injection.
nificantly after implantation of a stimulating elec- Complications included electrode migration (n = 1), trode to the posterior hypothalamus, ipsilateral to the lead displacement after a fall (n = 1), and thoracic pain.72 Since this first report, several studies have discomfort or tingling (n = 2). Bilateral ONS was been published on the efficacy and tolerability of investigated in 8 patients with medically intractable hypothalamic stimulation (HS) for CH.73-75 Schoenen CH.69 At median follow-up of 20 months, subjective et al examined the effect of unilateral HS in 6 refrac- self-assessment of benefit was graded as substantial tory CCH patients.73 Three patients had “excellent” (Ն90%) in 2 patients, moderate (Ն40%) in 3, mild results, while another had only a transient remission.
(Ն25%) in 1, and nil in 2 patients. Six patients In 1 patient treatment had to be stopped because of reported that they would recommend the use of ONS AEs (autonomic disturbances and panic attacks), and to other similar cluster patients. Complications, affect- 1 died of intracerebral hemorrhage shortly after the ing 4 of the patients, included: excessive pain at inci- procedure. Leone et al reported on the long-term sion site (n = 1), electrode migration (n = 3), electrode results of 16 previously refractory CCH patients who fracture (n = 1), and shock-like sensation because of had HS.74 At a mean follow-up of 23 months, major kinking of wires (n = 1). In 2009, results from improvement in pain, or complete pain elimination, extended follow-up of these 8 patients and an addi- was obtained in 13 (81%) patients. The mean time to tional 6 patients treated with bilateral ONS were headache benefit was 42 days. Overall, the procedure reported.70 At a median follow-up of 17.5 months, 10 was well tolerated. No hormonal, affective or sleep- of 14 patients reported improvement, including 3 with related abnormalities were observed. One patient >90% improvement, 3 with 40–60% improvement, had an asymptomatic intracerebral hemorrhage that and 4 with 20–30% improvement. Nine patients subsequently resolved. Transient diplopia was a stated that they would recommend ONS to other common AE with high amplitude stimulation.
Bartsch et al reported on 6 CCH patients who under- intermedius, has shown some efficacy in refractory went HS.75 At a mean follow-up of 17 months, 3 CCH; however, response rate decreased over time.81 patients responded well to treatment, being almost Gamma knife radiosurgery is a relatively recent attack free, while 3 patients failed to respond. The therapeutic approach for CH.82,83 Despite early procedure was well tolerated. The authors concluded encouraging results,82 more recent data showed only that HS is effective in a subset of refractory CCH modest long-term pain relief and high rate of AEs, patients. Interestingly, in another study, HS was not effective in the majority of patients when used as an Another surgical approach for CH targets the acute CH treatment, suggesting that this treatment parasympathetic component of the disease, typically affects CH through more complex pain modulating by blocking or ablating the SPG.67,84,85 In 1 study, radiofrequency blockade of the SPG was performed In summary, HS is an emerging viable treatment in 66 CH patients.84 Complete pain relief was for refractory CCH. It appears to be effective in some, achieved in 61% and 30% of ECH and CCH patients, but not all, patients. Although the treatment is gener- respectively. In a more recent study, 15 refractory ally well tolerated, the risk of intraceberal hemor- CCH patients were treated with radiofrequency abla- rhage, and even death, should be kept in mind when tion of the SPG.85 The treatment decreased signifi- cantly the mean attack frequency, mean pain intensityand pain-related disability, and these effects lasted for12-18 months.
ABLATIVE SURGICAL PROCEDURES
In summary, ablative surgical procedures should With the emergence of a variety of pharmaco- be reserved as the last resort for refractory CH logic and non-pharmacologic therapies for CH, the patients. The procedures that appear to be more role of ablative surgery in this disease has declined.1 effective in the long-term management of the disease Candidates for surgery should have strictly unilateral, are radiofrequency trigeminal ganglion ablation and side-locked, CH attacks. A number of procedures trigeminal rhizotomy. It should be noted, however, have been used with some success for this indication, that CH attacks have been shown to persist after including radiofrequency ablation of the trigeminal trigeminal root section in a case report of man with ganglion, trigeminal sensory rhizotomy, gamma knife CH, supporting the hypothesis of a central pain gen- surgery, and microvascular trigeminal nerve decom- pression.1 Radiofrequency trigeminal gangliorhizoly-sis has been shown as effective in up to 75% ofrefractory CCH patients.78,79 In a case series of 27 APPENDIX
patients who underwent this procedure, 2 developed European Federation of Neurological Societies anesthesia dolorosa.79 Other complications included (EFNS) guidelines—evidence classification scheme for a corneal anesthesia, keratitis, and diplopia. Trigeminal root section has been reported to be effective in 88% Class I: An adequately powered prospective, ran-
of 17 patients with refractory CCH, with 76% expe- domized, controlled clinical trial with masked outcome assessment in a representative population or an included corneal abrasion, masticatory muscle weak- adequately powered systematic review of prospective ness, anesthesia dolorosa and the development of CH randomized controlled clinical trials with masked on the other side. One patient, who underwent the outcome assessment in representative populations. The procedure twice, died after the second surgery. The authors concluded that trigeminal nerve section is aviable therapeutic option for selected refractory CCH patients. Microvascular decompression of the trigemi- (b) Primary outcome(s) is/are clearly defined.
nal nerve, with or without section of the nervus (c) Exclusion/inclusion criteria are clearly defined.
(d) Adequate accounting for dropouts and cross- Category 2
overs with numbers sufficiently low to have (a) Drafting the Manuscript
(e) Relevant baseline characteristics are presented (b) Revising It for Intellectual Content
and substantially equivalent among treatment groups or there is appropriate statistical adjust- Category 3
(a) Final Approval of the Completed Article
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