1. Cluster Headache: Diagnosis and Management
W. J. Becker
University of Calgary
Oct 18, 2015

2. Disclosures
Medical advisory board participation: Allergan, Tribute, Amgen, ElectroCore, St. Jude.
Speakers honoraria: Serono, Allergan, Tribute, Teva
Research support: Amgen, Allergan

3. Objectives
After attending this presentation, the participant will be able to:
Diagnose patients presenting with cluster headache
Discuss the management of patients with cluster headache

4. Cluster Headache: Asia (Clinic-based Studies)
Country
Episodic (%)
Chronic (%)
Mean age at onset (Years)
Time to diagnosis (Years)
Male / female ratio
China
N = 120
92.5
7.5 27
8.2
7 : 1
Taiwan
N = 104
100
8.1
3.6 : 1*
Japan
N = 86
96.5
3.5 31
7.3
3.8 : 1
* Most recent time period
Dong Z et al The Journal of Headache and Pain 2013, 14:27
Lin K_H et al Cephalalgia 2004; 24:631–638
Imai N et al Cephalalgia 2010; 31: 628–633

5. Global Epidemiology of Cluster Headache*
Lifetime Prevalence / 100,000
1 year point prevalence / 100,000
Male / female ratio
% Episodic
% chronic
124 53
4.3 : 1 86 14
* Population-based studies
Fischera M et al Cephalalgia, 2008, 28, 614–618

6. Patient One: Mr. C, age 37
Severe left-sided headache starting in the left shoulder, then the pain moves up to the left occipital area, and then becomes very severe behind the left eye.
Attacks last 45 minutes
During the attacks he has lacrimation of the left eye with nasal congestion and rhinorrhea. He may have eyelid swelling and some ptosis. He is restless and agitated.
These headaches usually occur 4 times per day, and go on for 4 months.
They often will awaken him every night at the same time.
Diagnosis?

7. Diagnosis – Cluster Headache
A.  5 attacks
B. Severe unilateral periorbital/temporal pain lasting minutes
D. One every other day to 8/day
E. Not attributed to another disorder
C. Either or both of:
1. At least one of:
conjunctival injection
lacrimation
nasal congestion
rhinorrhea
eyelid edema
facial sweating
miosis
ptosis
2. A sense of:
Restlessness or
agitation
ICHD-3 beta Cephalalgia 2013: 33:

8. Cluster Headache: Location of the Pain
Location of Pain
China (%of patients)
Japan (%of patients)
Temporal 75 52
Retro-orbital 68 80
Forehead 33 19
Occipital 23 22
Neck 4 2
Shoulder --
Dong Z et al The Journal of Headache and Pain 2013, 14:27
Imai N et al Cephalalgia 2010; 31: 628–633

9. Cluster Headache Questions
Why are the attacks so short?
Why are the attacks unilateral?
Why are there usually associated autonomic symptoms?

10. Ipsilateral Hypothalamic Activation in Cluster Headache
Coronal PET Study
May A et al. Lancet 1998;352:

11. Trigeminal Autonomic Reflex
Cluster Headache and Autonomic Symptoms
Trigeminal Autonomic Reflex
Intense afferent activity in the trigeminal nerve fibres (ophthalmic division)
synapses in the superior salivary nucleus to produce parasympathetic activation
via the facial nerve and Pterygopalatine ganglion.
Goadsby PJ Continuum 2012; 18 (4):

12. Is the pain always unilateral?

13. Cluster and Bilateral Headache
The headache is almost always unilateral.
The head pain occasionally switches sides.
In extremely rare cases it can be bilateral.
Goadsby PJ. Cluster Headache.
In: Gilman S, editor-in-chief. MedLink Neurology.

14. Cluster Headache: Unilateral vs Bilateral
Pain Characteristics (N = 180)
% of patients
Strictly unilateral headache – same side all clusters 85
Changed sides from one cluster to another 10
Changed sides during a cluster period 5
Several case reports of:
1. patients going from unilateral headache to bilateral headache during a cluster
2. having bilateral headache during some clusters
Manzoni GC et al Cephalalgia, 1983; 3:
Young WB et al Cephalalgia 1999; 19:

15. Cluster Headache: Unilateral vs Bilateral
Pain Characteristics (N = 180)
% of patients
Japan
%of patients
China
Taiwan
Strictly unilateral headache – same side all clusters 85 86
87.5 80
Changed sides from one cluster to another 10
9.3
Changed sides during a cluster period 5
2.3
Changed sides between and during cluster periods
Dong Z et al The Journal of Headache and Pain 2013, 14:27
Lin K_H et al Cephalalgia 2004; 24:631–638
Imai N et al Cephalalgia 2010; 31: 628–633
Manzoni GC et al Cephalalgia, 1983; 3:
Young WB et al Cephalalgia 1999; 19:

16. What is the differential diagnosis of cluster headache attacks?
Other trigeminal autonomic cephalalgias (TACs) including hemicrania continua
Migraine
Cervicogenic headache
Symptomatic (or secondary) cluster

17. TAC Features Compared Cluster Parox Hemicrania SUNCT Male/Female 3:1
1:2
2:1
Prevalence
1 per 1000
1 per 50,000
Very rare
Attack duration
15 to 180 min.
2 to 30 min.
1 to 600 seconds
Attack frequency
½ to 8 per day.
>5 per day
≥1 per day
Autonomic symp. ++ +
Ekbom K et al The Headaches, 2006
ICHD-3 beta Cephalalgia 2013: 33:

18. Symptomatic Cluster: Causes in 63 Cases
44% Vascular: Aneurysm, AVM, cavernous angioma, moya moya,venous thrombosis, etc
- 11 / 28 had a dissection (carotid or vertebral)
40% Tumour: glioblastoma, meningioma, arachnoid cyst, nasopharyngeal carcinoma, etc
- 10 / 25 pituitary tumour
11% Inflammation: Hypothalamic sarcoidosis, granulomatous hypophysitis, sinusitis, etc
5% Other: Multiple sclerosis, Chiari with syringomyelia, etc
Edvardsson P, SpringerPlus 2014; 3: 64

19. Headache Diagnosis, Normal Exam: Rate of DI Abnormalities
Significant DI Abnormalities
% Rate
Migraine
4 / 920
0.4
Tension type
5 / 665
0.8
Cluster
1 / 20 5
Post traumatic
0 / 69
Indeterminate
7 / 188
3.7
Sempere AP et al Cephalalgia 2005; 25:

20. Patient Two: Mrs. B, Age 42 Diagnosis? Investigation needed?
A 42 year old female presented with a very severe unilateral headache around the left eye which awoke her during the night. It lasted 2 hours, resolved with dihydroergotamine treatment.
She had tearing of the left eye, and sweating of the left side of her face.
With the headache, she had left facial numbness which persisted for 3 weeks.
She had a number of further unilateral headache attacks on the left which lasted less than three hours. With one of these, she had left arm and gait ataxia lasting one week.
Her neurological examination when seen 4 months after her first attack was normal.
Diagnosis? Investigation needed?

21. Recommendations for Imaging
For the initial diagnosis and in the case of an abnormal neurological examination, a CT scan and a cranial MRI should be considered(1).
“We recommend imaging in all patients with TACs” (2).
Not necessary in typical cases, but be alert for atypical signs and symptoms (3).
EFNS guidelines May et al Eur J of Neurol 2006; 13: 1066 – 1077
Favier I et al Arch Neurol 2007; 64: 25 – 31
Seijo-Martinez et al Arch Neurol 2007; 64: 917

22. Does our patient require neuroimaging?
Neuroimaging, preferably contrast-enhanced magnetic resonance imaging/magnetic resonance angiography should be undertaken in cluster patients with:
atypical symptomatology
late onset
abnormal examination (including Horner’s syndrome)
those resistant to the appropriate medical treatment.
Edvardsson B, SpringerPlus 2014, 3:64

23. Cluster Headache, Multiple Sclerosis, with Brachium Pontis Lesion

24. Episodic Versus Chronic Cluster
Episodic Cluster
At least two cluster periods lasting 7 days to 1 year (when untreated) and separated by pain free remissions periods of ≥ 1 month.
Chronic Cluster
Occurring without a remission period, or with remission periods lasting < 1 month for at least 1 year.
ICHD-3 beta Cephalalgia 2013: 33:

25. What should initial pharmacological treatment be?
Cluster Headache
What should initial pharmacological treatment be?

26. Case One: Mr. C He started a new cluster.
He had four attacks per day, with attacks lasting 45 – 60 minutes
Treatment Recommendations?

27. Pharmacological Treatment for Cluster
Therapy Type
Acute
All patients
Transitional
If attacks frequent (> 2 attacks / day)
Prophylactic
Becker WJ Headache 2013; 7:

28. Acute Cluster Therapy – 1st line
Medication
Dose
Subcutaneous sumatriptan
6 mg
Intranasal zolmitriptan
5 mg
Becker WJ Headache 2013; 7:

29. Subcutaneous Sumatriptan 6 mg: Cluster Headache Response rate
Response Definition:
Reduction of pain to mild or none (From grade 2 – 4 to grade 1 or 0).
Sumatriptan 6 mg subcut:
open bars
Placebo: dark bars
Sum Study Group N Eng J Med
1991; 325: 322-6

30. Zolmitriptan Nasal Spray: Cluster Headache Response Rate
Hedlund C et al
Headache 2009;
49:

31. Transitional Cluster Therapy – 1st line
Medication
Dose
Prednisone
Variable: one option – 70 mg daily for 4 days, then taper dose by 5 mg daily
Becker WJ Headache 2013; 7:

32. Prophylactic Cluster Therapy – 1st line
Medication
Dose
Verapamil
Starting dose: 80 mg tid
Increase by 80 mg / week up to 480 mg
If higher doses required, increase by 80 mg every 2 weeks up to 640 mg, occasionally higher if needed and tolerated. (do periodic EKGs)
Becker WJ Headache 2013; 7: 1191 – 1196
Ashkenazi A et al Headache 2011; 51:

33. Case One: Mr. C
He had been provided with medication previously to use himself when his next cluster started.
Sumatriptan 6 mg subcutaneously stopped his attacks within 5 – 10 minutes.
He started prednisone 60 mg daily as soon as his cluster began, and started Verapamil which he built up rapidly to 720 mg daily.
His cluster stopped after 4 days!
EKGs were arranged.
Note: He had built up his verapamil very quickly, but he had used it successfully in previous clusters. Without treatment, his clusters usually lasted 4 months.

34. Cluster Headache
Question: For The refractory Patient, Who fails to respond to initial therapy, what should be tried next?

35. Acute Cluster Therapy – 2nd and 3rd line
Medication
Dose
Oxygen
12 L per minute for 15 minutes (mask)
Subcut / IM DHE
1 mg
Intranasal sumatriptan
20 mg
Others:
Subcut Octreotide
100 ug
Intranasal lidocaine (on side of pain) 4%
Becker WJ Headache 2013; 7: 1191 – 1196
Ashkenazi A et al Headache 2011; 51:

36. High Flow Oxygen for Cluster Headache
Air
Oxygen*
Number of attacks treated
148
150
Pain free at 15 minutes (%) 20 78
*100 % Oxygen (12 L/min for 15 minutes through
a non rebreathing mask).
A double-blind, randomized, placebo-controlled
crossover trial.
Cohen AS et al JAMA. 2009;302(22):

37. Transitional Cluster Therapy – 2nd line
Medication
Dose
Dihydroergotamine (Subcut or IM)
1 mg bid or tid – duration of therapy variable – up to one week (possibly longer at reduced dose)
Occipital nerve block with steroids
Methylprednisolone (slow release) 40 – 80 mg or equivalent. May be repeated and usually given with lidocaine
Becker WJ Headache 2013; 7: 1191 – 1196
Leroux E et al Curr Pain Headache Rep (2013) 17:325

38. Mean number of attacks per day
Occipital Nerve Injection with Steroids Alone as Transitional Therapy in High-Frequency Cluster Headache
Three injections
were given 48-72
hours apart.
Cortivazol 3.75 mg
each injection (no
local anesthetic)
Each injection
equivalent to 60 mg
Prednisone
All received verapamil
Mean number of attacks per day
from Day 1 to 15 are shown
Leroux E et al
Lancet Neurol
2011; 10: 891-
897

39. Lidocaine and Betamethasone Occipital Nerve Blocks in Cluster Headache
All patients received 0.5 % lidocaine
Patients were randomized to additional betamethasone (N = 13) or saline (N = 10)
Double-blind placebo-controlled study
Steroid dose = 90 mg of methylprednisolone
Results: In the first week after injection:
85 % of steroid-treated patients became pain-free
No placebo patients became pain free.
Ambrosini A et al Pain 118 (2005) 92–96

40. Prophylactic Cluster Therapy – 2nd and 3rd line
Medication
Dose
Lithium
Starting dose: 300 mg bid
Increase to 300 tid after one week, titrate higher if necessary, monitor serum levels.
Topiramate
100 – 200 mg
Melatonin
10 mg hs
Others: Methysergide, Valproate, Gabapentin
Becker WJ Headache 2013; 7: 1191 – 1196
Ashkenazi A et al Headache 2011; 51:

41. Prophylactic Cluster Therapy – Other Options
Days to
freedom from
headache
Candesartan
32 mg
vs placebo
Tronvik E et al
Cephalalgia 33;
12:

42. European Federation of Neurological Societies Guideline: Cluster Headache
Effective acute medications:
100% oxygen, 15 l/min (A)
Sumatriptan 6 mg s.c. (A)
Sumatriptan 20 mg nasal (A)
Zolmitriptan 5 mg nasal (A/B)
Zolmitriptan 10 mg nasal (A/B)
Effective prophylactic medications
Verapamil (A)
Steroids (A)
May A et al European Journal
of Neurology 2006, 13: 1066–1077

43. Italian Guideline for Primary Headaches: Cluster Headache
Acute Treatment
Sumatriptan 6 mg subcutaneous
Sumatriptan 20 mg nasal spray
Zolmitriptan 5 – 10 mg nasal spray
Oxygen
Prophylaxis
Verapamil
Prednisone
Pizotifen
Lithium
Sarchielli P et al
J Headache Pain (2012) 13
(Suppl 2):S31–S70

44. Cluster Headache
Question: What are the options for the cluster patient who is refractory to all standard therapies?

45. Potential Options for Super-Refractory Patients
Psychedelic drugs or derivatives
-2-Bromo LSD
- Psilocybin
Hormonal
-Testosterone replacement
Nerve blocks
-Sphenopalatine ganglion blocks
Neuromodulation / stimulation
-Occipital nerve stimulation
-Non-invasive vagal nerve stimulation
-Deep brain stimulation
-Sphenopalatine ganglion stimulation
Tepper SJ et al Headache 2013; 53:

46. Sphenopalatine Blocks for Cluster
Blocks done endoscopically with bupivacaine and steroids
N = 15
Blocks repeated 3 times at intervals of 3 days
Outcome
% of Patients
Complete cessation of symptoms 54
Symptom free for > 8 months %
Symptom free for 1 – 5 months – 33%
Reduction in frequency and intensity 6
No response 40
Pipolo C Neurol Sci (2010) 31 (Suppl 1):S197–S199

47. Sphenopalatine Ganglion Injection of OnabotulinumtoxinA
(25 – 50 Units, one injection) in Chronic Cluster
Open Label, Uncontrolled
Per Protocol analysis
N = 7
Bratbak DF et al Cephalalgia 2015

48. Neuromodulation - Stimulation
Occipital nerve stimulation
% very satisfied: 60%
Non-invasive vagal stimulation
% very satisfied: 36%
Deep brain stimulation
% markedly improved: 55 – 59%
Sphenopalatine ganglion stimulation
% experiencing an acute or frequency response:68%
Magis D et al Headache 2011; Nesbitt AD et al abstract J head pain 2013
Leone M et al Cephalalgia 2008; Fontaine D et al J Headache Pain 2010
Schoenen J et al Cephalalgia 2013

49. On-Demand Sphenopalatine Ganglion Stimulation: Relief at 15, 30, and 60 Minutes After Initiation of Stimulation
F: Full stimulation
SP: Sub-perception stim
S: Sham
Schoenen J et al Cephalalgia 2013; 33:

50. Cluster Headache Frequency Response to Sphenopalatine Ganglion Stimulation
Patients who responded acutely
To SPG stimulation during
Custer headache attacks also
Tended to experience a
Reduction in cluster headache
Frequency (See blue line)
BL = baseline
SS = start of stimulation
EE = end of experimental period

51. Headache Attacks per Week. Baseline Versus Weeks Three and Four after
Non-Invasive Vagal Nerve Stimulation in Chronic Cluster: Reduction in Number of
Headache Attacks per Week. Baseline Versus Weeks Three and Four after
Randomization (open label)
Patients received three
2-minute stimulations 5
Minutes apart twice daily.
They could also treat
Individual Attacks with
Additional stimulation
SoC = Standard of care
(controls received SoC)
Baseline: 16 attacks per week
Gaul C et al
Cephalalgia 2015

52. Patient 3: Chronic Cluster for Years, Changed to Episodic Cluster by DBS*
Interestingly, eventually our patient, after many years of chronic cluster reverted under the influence of stimulation to episodic cluster. Shown here is his cluster headache activity over the past 2 years, and as can be seen, over that time period he had two cluster bouts, one lasting about 4 weeks and one 6 weeks. Stimulator was implanted in 2006.
Our observation is not unique in that Leone has also reported that three of their patients converted from chronic to episodic cluster with hypothalamic stimulation.
We could interpret this by concluding that his stimulator is somehow increasing his threshold for cluster attacks, perhaps to levels where he was years ago when he had episodic cluster, and they are only able to break out at certain times of the year, or when something else is working to make him more headache prone.
Leone in Cephalalgia writes that in three patients who became somewhat refractory to stimulation, the illness changed from chronic to episodic in nature with months of complete remission punctuated by periods of typical attacks.
*DBS: Deep Brain
Stimulation, area near
Post. Hypothalamus

53. Conclusions
Cluster headache diagnosis is primarily a clinical diagnosis, but the need for neuroimaging needs to be considered.
The available treatments need to be applied in a step-wise manner as needed, based on evidence for efficacy and side effects.
When necessary, the proven invasive therapies should be made available to patients.
Several interesting potentially useful compounds and procedures need more research.