Cluster Headache - Cephalgia

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290 Blackwell Publishing Ltd Cephalalgia, 2005, 26, 290294

doi:10.1111/j.1468-2982.2005.01037.x

Blackwell Science, LtdOxford, UKCHACephalalgia0333-1024Blackwell Science, 2005263290294Original ArticleAsleep study in cluster headacheG Della Marca et al.

A sleep study in cluster headache

G Della Marca

1

, C Vollono

1,2

, M Rubino

1

, A Capuano

1

, G Di Trapani

1

& P Mariotti

1

1

Institute of Neurology, Department of Neuroscience, Catholic University and 2

Fondazione Pro Juventute Don C. Gnocchi, Rome, Italy

Della Marca G, Vollono C, Rubino M, Capuano A, Di Trapani G & Mariotti P. Asleep study in cluster headache. Cephalalgia 2006; 26:290294. London. ISSN 0333-1024

Cluster headache (CH) is a primary headache with a close relation to sleep. CHpresents a circa-annual rhythmicity; attacks occur preferably during the night, inrapid eye movement (REM) sleep, and they are associated with autonomic andneuroendocrine modifications. The posterior hypothalamus is the key structurefor the biological phenomenon of CH. Our aim is to describe a 55-year-old manpresenting a typical episodic CH, in whom we performed a prolonged sleep study,consisting of a 9-week actigraphic recording and repeated polysomnography, withevaluation of both sleep macrostructure and microstructure. During the acute bout

of the cluster we observed an irregular sleepwake pattern and abnormalities ofREM sleep. After the cluster phase these alterations remitted. We conclude thatCH was associated, in this patient, with sleep dysregulation involving the biolog-ical clock and the arousal mechanisms, particularly in REM. All these abnor-malities are consistent with posterior hypothalamic dysfunction.

Actigraphy,arousal, cluster headache, polysomnography, posterior hypothalamus, sleep

Giacomo Della Marca, Institute of Neurology, Department of Neuroscience, CatholicUniversity, L.go Gemelli, 8-00168, Rome, Italy. Tel. +

39 06 3015 4276, fax +

39 06 35501909, e-mail [email protected] Received 16 April 2005, accepted 23 May 2005

Introduction

Cluster headache (CH) is a primary headache (1) ofneurovascular origin (2). Clinically, episodic CH ischaracterized by a very severe pain, always unilat-eral and usually retro-orbital, associated with rest-lessness or agitation and autonomic symptoms (2).The attacks of CH occur typically in bouts (clusters)of a few months. The rhythmic course, the auto-nomic activation, the circadian biological rhythmicchanges and the neuroendocrine disturbances (3), inparticular involving melatonin (4), have suggested apivotal role for the hypothalamus which has beendemonstrated by functional neuroimaging withpositron emission tomography (5) and by anatomi-cal imaging with voxel-based morphometry (6).

Clusters have a half-yearly, yearly or even biennialperiodicity (7). Within a CH cluster about 50% ofattacks occur at night, and in the same individualthey often occur at the same hour each day (7). CHis closely related to sleep (8). Wolff (9) observed thatthe majority of cluster headaches occur during sleep,with pain that startles the patient from bed. Dexter

and Weitzmann (10) first reported that episodicattacks of CH tend to occur during rapid eye move-ment (REM) sleep; these data have been confirmed(11) and recently (12, 13) CH attacks have beenobserved during REM sleep, following haemoglobindesaturations.

The aim of the present study was to investigate thesleep pattern of a patient with typical episodic CHduring a cluster and in the pain-free interval. Weused wrist actigraphy to investigate circadian sleepwake cycles, polysomnography (PSG) to analysesleep structure and to observe in which sleep stagepain occurred; also, an analysis of sleep microstruc-ture was made to investigate the relation betweenCH and arousal.

Case report

A 55-year-old man presented with episodic CH sincethe age of 50 years. The typical attacks consisted ofa very severe (10/10) pricking pain in the right retro-orbital and right temporal areas. The pain was asso-ciated with photophobia. Cluster periods occurred


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once per year and lasted 34 weeks. During the clus-ter, attacks occurred twice per day, each attack last-ing 4590 min, and most of them (more than onehalf) awakened the patient from night sleep. Duringthe attacks he had tearing, ipsilateral conjunctivalinjection and eyelid oedema; the right nostril wascongested. At the moment of our first observationthe patient was in the cluster period, which had

begun 12 days before. His physical and neurologicalexaminations were normal. Brain magnetic reso-nance imaging was normal. Prophylactic treatmentwas started with gabapentin up to 900 mg/day;gabapentin was chosen because EKG documenteda sinusal bradicardia (4550 beats/min), which con-traindicated the administration of verapamil. Sub-cutaneous sumatriptan injections (6 mg) for thetreatment of pain attacks were administered on twooccasions. Prophylaxis was immediately effectivein reducing the frequency, duration and severity of

attacks. On a follow-up visit the patient reportedthat these episodes ceased after a period of 3 weeks.As concerns the sleepwake habits, the patient didnot complain of any sleep disorder before, during orafter the cluster episode. The patient gave his writteninformed consent to enter the study.

Methods

Sleep study included: (i) cardiorespiratory monitor-ing; (ii) actigraphy; and (iii) PSG.

Cardiorespiratory monitoring

A one-night polygraphic recording was performedwith MESAM 4 (14) in order to rule out obstructivesleep apnoea syndrome (12, 13).

Actigraphy

Actigraphy was performed to evaluate the circadianrhythms of sleep and wake. Three separate record-ings were performed, each lasting three consecutiveweeks. The first recording started at the moment ofour first observation, 12 days after the onset of the

cluster period; the second was performed duringpharmacological treatment (7 weeks after the onset);the third was performed during follow-up,3.5 months after the last attack and 2.5 months afterdrug withdrawal. Actigraphic monitoring was per-formed in agreement with guidelines reported in theliterature (1517). Data from the single nights in thetwo conditions (cluster period and remission) werecompared by two-tailed unpaired Students t

-testfollowed by Bonferroni correction for multiple

comparisons, with an adjusted significance level of

0.00625.

Polysomnography

Three full-night ambulatory polygraphic recordings(EEG, EOG, EMG) were performed, each lasting 48

consecutive hours, in order to allow the patient tosleep in his home setting and to keep his naturalsleepwake schedule. The first study was performed

before starting the treatment (nights 1 and 2), thesecond during the treatment (nights 3 and 4), thethird during remission, after drug withdrawal(nights 5 and 6). Sleep analysis was performedaccording to the criteria of Rechtschaffen and Kales(18), and, for the arousals, to the rules of the Amer-ican Sleep Disorders Association (ASDA) (19).

Results

Cardiorespiratory monitoring

MESAM 4 ruled out the presence of any significantoxygen desaturation during sleep.

Actigraphy

Figure 1 shows three actograms, two referring to thecluster period (Fig. 1A,B) and one referring to theremission period (Fig. 1C). Several attacks of CHoccurred during the recordings. Actigraphic record-ings revealed that the patients sleepwake schedule

was irregular during the CH period and progres-sively modified, becoming more regular, after remis-sion. In particular, the interdaily variability index(19) was 0.513 and 0.545 in the first two recordings,and rose to 0.681 in the recording after remission.

Several episodes of diurnal sleep (naps) wereobserved in the cluster periods; napping was almostcompletely absent in the remission period. Asconcerns the statistical comparison among condi-tions (C =

cluster period, R =

remission period), weobserved a significant decrease of actual sleep time(AST) (average AST C =

376

74 min; R =

350

61 min; P

=

0.0040) and sleep efficiency index (SEI)

(average SEI C =

73.1

6.8%; R =

67.6

7.8%;

P

=

0.0051). By contrast, we observed a significantincrease in mean activity score (MAS) (average MASC =

20.32

4.22; R =

24.66

6.81; P

=

0.0027) andfragmentation index (FI) (average FI C =

53.30

22.77; R =

73.15

28.71; P

=

0.0002). No significantdifference between the two conditions was foundin time in bed (

P =

0.0558), sleep latency (

P =

0.6017),assumed sleep duration (

P =

0.0134) and wake time(

P =

0.8529).


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Polysomnography

The main results of polygraphic recordings are listedin Table 1, and hypnograms are shown in Fig. 2.Headache attacks occurred during recordings 1 and2; both occurred during REM. Both attacks were

treated successfully with sumatriptan and thepatient returned to sleep. PSGs performed in thecluster period confirmed the great variability insleep duration observed with actigraphy. PSGs 5and 6, after remission, showed slightly shorter sleepduration, and a reduction of the total amount of

Figure 1

Actograms from the three recordings, each lasting three consecutive weeks. (A,B) Cluster period. (C) Remission period.The upper horizontal bar indicates time of day. Arrows indicate the days in which cluster headache attacks occurred. Days whenpolygraphic (PSG) recordings were performed are specified on the left of the actogram. GP, Gabapentin. Start of treatment anddose modification are specified on the right side of the actogram.

12.00 h 18.00 h 00.00 h 06.00 h 12.00 h 12.00 h 18.00 h 00.00 h 06.00 h 12.00 h 12.00 h 18.00 h 00.00 h 06.00 h 12.00 h

PSG 1

PSG 2

PSG 3

PSG 4

PSG 5

PSG 6

GP 600 mg

GP 900 mg

Patient wore off actigraph

A

B C

Table 1

Polysomnography (PSG) parameters

PSG parameters PSG 1 PSG 2 PSG 3 PSG 4 PSG 5 PSG 6

Macrostructure

Sleep onset latency, min 2.0 4.5 20.0 5.5 10.0 2.5

Total sleep time, min 548 545 590 659 466 413

Sleep period time, min 601 588 639 709 537 447

Sleep efficiency, % 91.0 92.2 91.6 92.8 86.6 91.8

Number of REM periods 5 5 7 8 6 4

REM latency, min 54 63 65 72 51 56

Sleep stage percentages

REM, % 25.1 20.3 16.6 20.6 16.1 13.6

Stage 1, % 10.4 7.1 5.7 4.0 15.5 8.9Stage 2, % 33.7 43.6 50.8 42.2 36.0 31.8

Stage 3, % 13.1 14.5 11.6 19.3 11.0 18.7

Stage 4, % 7.4 6.0 6.7 6.7 7.6 18.0

Wake parameters

Total number of awakenings 16 33 32 21 33 26

Awakenings >

2 min 3 5 9 9 10 7

Wake after sleep onset, min 59.5 48.5 95.5 56.0 72.5 40.0

Arousals

Arousal index in total sleep, events/h 11.7 11.0 11.2 13.9 13.3 13.7

Arousal index in NREM, events/h 12.02 9.69 7.08 7.95 11.13 8.95

Mean arousal duration NREM, s 12.3 6.9 12.7 6.3 16.1 10.8 16.1 10.1 11.1 7.0 17.2 5.7

Arousal index in REM, events/h 5.56 3.58 12.45 13.02 15.00 12.79

Mean arousal duration REM, s 14.1 3.9 19.8 3.2 15.6 10.9 14.9 10.9 13.6 6.5 13.8 7.4

Sleep period time, interval between sleep start and sleep end; Sleep efficiency, percentage of time spent asleep whilst in bed.

Sleep stages percentages are calculated on sleep period time.


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REM (in minutes) and of REM percentages. No mod-ification of the arousal parameters across the record-

ings was observed, except for arousal index in REM.This index was much lower in the first two nights,those with attacks (index =

5.56 and 3.58 events/h ofREM sleep), than in the remaining four (12.45, 13.02,15.00, 12.79 events/h of REM sleep).

Discussion

CH induced relevant modifications of the sleepwake pattern of our patient. During the clusterperiod, actigraphy showed an irregular sleepwakecycle, characterized by high interdaily variability,inconstant sleep duration, repeated nocturnal awak-

enings and frequent daytime napping (Fig. 1A,B).When the cluster period ended and gabapentinwas withdrawn (Fig. 1C), the sleepwake patternappeared fully normalized. This indicates that thecluster period was associated with a transient dys-function of the biological clock. Alternatively, theirregular sleepwake cycle could be a consequenceof pain (20). The latter interpretation is not consistentwith the observation that a marked interdaily vari-ability of the sleepwake rhythm still persisted even

when headache attacks were controlled by gabapen-tin. Therefore, we believe that the sleepwake pat-

tern dysregulation observed in our patient is aspecific clinical feature of the CH. This is consistentwith previous data in literature, which documentedthat CH is a chronobiological disorder (7), due tohyperactivation of the posterior hypothalamus (5, 6,21). PSGs confirmed the variability in sleepwakeschedule observed with actigraphy.

As regards the PSGs, the most relevant findingsconcern REM sleep. Two severe attacks occurred inREM at the beginning of the night. Besides, duringthe cluster, REM episodes were fragmented, andinterspersed by periods of NREM sleep. After remis-sion, REM sleep time and REM percentages and

REM fragmentation were reduced (Fig. 2). There-fore, PSG findings suggest some dysregulation of theultradian NREM/REM cyclicity within sleep in thispatient.

At a microstructural level, the arousal index calcu-lated in REM was much lower in the first two nights,in which attacks occurred. An effect of sumatriptancannot be ruled out, but it seems unlikely, sincearousal modifications involved REM sleep. Alter-natively, we may speculate that REM sleep in the

Figure 2

Sleep stage histograms (hypnograms) in the six nights of polysomnographic recording. On the left of the hypnogramssleep stages are indicated (REM, rapid eye movement sleep; 1, stage 1 NREM; 2, stage 2 NREM; 3, stage 3 NREM; 4, stage 4NREM); the lower horizontal bar indicates time. Grey arrows mark headache attack onset.

Attack

REMWake

1

2

3

4

Attack

Time

REMWake

1

23

4

Time

REMWake

1

2

3

4

Time

REMWake

1

2

3

4

Time

REMWake

1

2

3

4

REMWake

1

2

3

4

00:00 h

00:00 h

00:00 h

00:00 h

00:00 h

00:00 h 06:00 h

06:00 h

06:00 h

06:00 h

06:00 h

06:00 h

5

6

4

3

2

1


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acute bout of the cluster is associated with a condi-tion of hypoarousability. Also, the reduced motoractivity during sleep shown by actigraphy in thecluster period is consistent with hypoarousability.Hypoarousal is a pathogenic mechanism in migraine(2224); impaired arousal activity during CH has

been suggested (25, 26). The posterior hypothalamushas a role in the arousal mechanisms, since it projectsdirectly to the cerebral cortex, and its stimulationelicits a cascade of arousal responses, including cor-tical activation, motor activity and sympatheticresponses (27). The posterior hypothalamus alsoplays a crucial role in the inhibitory control of theexecutive mechanisms of paradoxical sleep (28, 29).

In conclusion, we believe that in our patient theCH induced an acute, transient, global modificationof sleep regulation, at several levels. These levelsincluded the circadian sleepwake rhythmicity, themacrostructural pattern of NREM/REM ultradian

cycle, and also the sleep microstructure, that is tosay the dynamics of arousal; this latter abnormalityselectively involved REM sleep. All the observedmodifications are consistent with an abnormal func-tion of the posterior hypothalamus.

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Cluster Headache - Cephalgia