188 Headache Medicine, v.3, n.4, p.188-197, Oct./Nov./Dec. 2012

Cluster headache and the hypothalamus – causal

relationship or epiphenomenon?

A cefaleia em salvas e o hipotálamo – relação causal ou epifenômeno?

VIEW AND REVIEWVIEW AND REVIEW

VIEW AND REVIEW

Dagny Holle, Mark Obermann

Department of Neurology, University of Duisburg-Essen, Essen, Germany

Holle D, Obermann M. Cluster headache and the hypothalamus – causal relationship or epiphenomenon?

Headache Medicine. 2012;3(4):188-97

ABSTRACTABSTRACT

ABSTRACT

Typical clinical features of cluster headache (CH) include

trigeminal distribution of pain, circadian/circannual rhythmicity,

and ipisilateral cranial autonomic features. This presentation

led to the assumption that the hypothalamus plays a pivotal

role in this primary headache disorder. Several studies using

neuroimaging techniques or measuring hormone levels

supported the hypothesis of a hypothalamic involvement in

the underlying pathophysiology in CH. Animal studies added

further evidence regarding this hypothesis. Based on previous

data even invasive treatment methods such as hypothalamic

deep brain stimulation (DBS) were tried for therapy. However,

the principal question whether these alterations are

pathognomonic for CH or whether they might be detected in

trigeminal pain disorders in general in terms of an

epiphenomenon is still unsolved. This review summarizes

studies on hypothalamic involvement in CH pathophysiology,

demonstrates the involvement of the hypothalamus in other

diseases, and tries to illuminate the role of the hypothalamus

based on this synopsis.

eywords:eywords:

eywords: Hypothalamus; Tegmentum; Deep brain

stimulation; Headache pain; Pain generator; Voxel based

morphometry; Functional imaging

RESUMORESUMO

RESUMO

Características clínicas típicas da cefaleia em salvas (CS)

incluem a distribuição trigeminal da dor, o ritmo circadiano/

circanual e as manifestações autonômicas cranianas

ipsilaterais. Esta apresentação levou à hipótese de que o

hipotálamo exerce um papel fundamental nesta cefaleia

primária. Vários estudos baseados em técnicas de neuro-

imagem ou na medição de níveis hormonais apoiaram a

hipótese de um envolvimento hipotalâmico na patofisiologia

subjacente à CS. Estudos envolvendo animais acrescentaram

evidências adicionais relacionadas a essa hipótese. A partir

de dados prévios, foram tentados até mesmo métodos

invasivos de tratamento, como a estimulação cerebral pro-

funda hipotalâmica. No entanto, a questão principal – se

essas alterações são patognomônicas para a CS ou se elas

podem ser detectadas em transtornos dolorosos trigeminais

em geral, na qualidade de um epifenômeno – está ainda

não solucionada. Esta revisão sintetiza estudos sobre o envol-

vimento hipotalâmico na fisiopatologia da CS, demonstra o

envolvimento do hipotálamo em outras doenças e tenta

elucidar o papel do hipotálamo com base nesta sinopse.

alavrasalavras

alavras

chave: chave:

chave: Hipotálamo; Tegmento; Estimulação

cerebral profunda; Cefaleia; Morfometria baseada em voxel;

Neuroimagem funcional

INTRODUCTION

Cluster headache (CH) is a rare primary headache

disorder that is characterized by strictly unilateral headache

attacks accompanied by ipsilateral trigeminal autonomic

symptoms such as lacrimation, rhinorrhea, conjunctival

injection, tearing, facial sweating or ptosis.

(1)

As of its clinical

presentation CH is classified as a trigeminal autonomic

cephalalgia (TAC). Up to eight headache attacks occur

per day often showing a strict time relationship with a

nocturnal predominance of headache attacks.

(1)

Most

patients have an episodic course of disease with a

circannual periodicity of symptoms that occur mainly in

autumn and spring. These clinical features suggested a

pivotal role of the hypothalamus in CH. It was even

Headache Medicine, v.3, n.4, p.188-197, Oct./Nov./Dec. 2012 189

hypothesized that the hypothalamus could be the key "pain

generator" in this primary headache disorder.

The current opinion about the role of the

hypothalamus in CH is based primarily on a strong a

priori hypothesis mainly in regard to the clinical picture.

This review analyses the actual knowledge regarding the

hypothalamus in the pathophysiology of CH and discusses

whether these observations are specific for CH in terms of

a "primum movens" or whether they might be just

epiphenomena in pain/headache diseases in general.

As CH shares many clinical and pathophysiological

similarities with other TACs in general (which are paroxymal

hemicrania, short lasting unilateral neuralgiform headache

attacks with conjuctival injection and tearing (SUNCT)) a

particular comparison with these headache disorders will

not be done in this review.

processing network. However, there is emerging evidence

that it might also be involved in central pain processing

with predominantly antinociceptive effects contributing to

descending pain modulation. The hypothalamus displays

various ascending and descending connections to the

nucleus tractus solitarius, rostroventromedial medulla,

periaqueductal gray, raphe nuclei, and corticolimbic

structures, which have an important function in the central

pain matrix.

(4)

Despite this anatomical evidences there are

also functional data pointing at the hypothalamus to take

part in central pain processing. Stimulation of the

hypothalamic medial preoptic nucleus (MPO) has

antinociceptive effects on spinal cord neurons; after

stimulation of the paraventricular nucleus which is also

localized within the hypothalamus similar antinociceptive

activations on hypothalamic subnuclei was detected.

(5)

Two

hypothalamic neuropetides – orexin-A and orexin-B – also

seem to play an important role in pain central pain

processing of the trigeminal systems as they display

pronociceptive and antinociceptive effects.

(6)

Autonomic nervous systemAutonomic nervous system

Autonomic nervous system

The hypothalamus coordinates the interaction

between autonomic function (facial nerve, para-

sympathetic outflow) and pain processing. The trigeminal

autonomic reflex is thought to be involved in this

connection, which is pictured by the clinical feature of

trigeminal autonomic symptoms in trigeminal autonomic

cephalalgias (TAC) in general, including CH.

(7)

Circadian rhythmsCircadian rhythms

Circadian rhythms

The hypothalamus is often referred to as the

"biological clock" as it is involved in several circadian

patterns such as sleep- wake cycle, temperature, and

hormonal regulation.

(8)

The main anatomic structure for

chronobiological regulation is the hypothalamic

suprachiasmatic nucleus (SCN).

(9)

Via direct neuronal

connections the SCN influences various parts of the brain

and induces, in turn, endocrine and autonomic functions.

CLINICAL PICTURE

The clinical presentation of CH has always been

the foundation to allegedly proof the pathognomonic

involvement of the hypothalamus in this disorder.

However, other diseases share common clinical features

that also suggest hypothalamic involvement. Many

migraneurs report premonitory symptoms that precede

the virtual headache attack up to two days and herald

THE HYPOTHALAMUS

Although the hypothalamus is only a small brain

structure and contributes only to 0.5% of total brain

volume

(2)

it plays a pivotal role in the human organism

being involved in regulation of different biological systems

that are essential for human survival (i.e. hormones,

autonomic nervous system, temperature, emotional

behaviour, arousal, cardiovascular system).

(3)

ain processing and autonomic nervousain processing and autonomic nervous

ain processing and autonomic nervous

systemsystem

system

Interestingly, the hypothalamus is currently not

considered to be part of the classical central pain

CLUSTER HEADACHE AND THE HYPOTHALAMUS – CAUSAL RELATIONSHIP OR EPIPHENOMENON?

190 Headache Medicine, v.3, n.4, p.188-197, Oct./Nov./Dec. 2012

HOLLE D, OBERMANN M

the pain ahead.

(10)

The underlying pathophysiology of

these premonitory symptoms which include irritability,

craving for food, hunger, or tiredness are interpreted as

clinical signs of hypothalamic dysregulation. Interestingly,

most migraine attacks occur in the early morning,

although this circadian rhythmicity is not as obvious as in

CH patients.

(11)

In this context, a hypothalamic involvement

has been suggested. Trigeminal autonomic features are

a key clinical feature in CH, what also supports the

hypothesis of a major role of the hypothalamus in the

pathophysiology of CH. However, similar headache

accompanying cranial autonomic symptoms can be also

detected in many migraneurs during the headache,

questioning the uniqueness of this clinical feature.

(12)

Other

primary headache disorders do also share several

important features of CH. Hemicrania continua (HC), a

rare primary headache disorder, is characterized by strictly

unilateral headache attacks accompanied by trigeminal

autonomic symptoms. Hypnic headache (HH) patients

share the characteristic time dependency and sleep

association with CH. Some HH patients even report

trigeminal autonomic symptoms.

(13,14)

NEUROENDOCRINAL ABNORMALITIES

Neuroendocrinal abnormalities in CHNeuroendocrinal abnormalities in CH

Neuroendocrinal abnormalities in CH

Many neuroendocrinological observations suggested

an involvement of the hypothalamus in CH and suggested

a deranged hypothalamic function. Inside bout a reduced

plasma testosterone concentration was measured in male

CH patients.

(15)

Imbalances of other hormones such as

melatonin, cortisol, luteinizing hormone, follicle-stimulating

hormone, prolactin, growth hormone, and thyroid-

stimulating hormone, whose secretion is mainly controlled

by the hypothalamus, have been detected.

(16)

These

hormonal disturbances support the idea of a hypothalamic-

pituitary-adrenal (HPA) axis malfunction in this primary

headache disorder. Interestingly, changes of the CSF

orexin level, which are considered to play a pivotal role

in the pain processing of CH patients, were not observed

during active CH episodes. Cavoli et al. measured orexin-

A in ten patients with CH by radioimmunoassay. CSF

Orexin levels were in normal range and no association

between clinical presentation and orexin-A level could be

observed.

(17)

Several possbilities were discussed regarding the

observed alterations. First, these changes may be result

of the strong CH pain itself. Second, they may reflect a

stress reaction (pain associated or independent) or, third,

are induced by pain accompanying sleep disturbances.

All of these possibilities would suggest that these alterations

are rather unspecific phenomenon. Interestingly, some of

the observed hypothalamic changes can be also detected

in remission periods (i.e. CH outside bout) what would

imply that these changes can be considered to be specific

for CH itself continuing independently of the pain and

therefore might be a kind of trait marker for the disease

itself.

Neuroendocrinal abnormalities in otherNeuroendocrinal abnormalities in other

Neuroendocrinal abnormalities in other

disordersdisorders

disorders

Even though endocrinal evidence suggests a strong

involvement of the hypothalamus in CH, similar changes

were observed in very different disorders as well. Chronic

migraneurs show an abnormal pattern of hypothalamic

hormonal secretion, such as a decreased nocturnal

prolactin peak, increased cortisol concentrations, and

delayed nocturnal melatonin peak. 338 blood samples

(13 per patient) from 17 patients with chronic migraine

and nine age and gender matched controls were

analysed.

(18)

These observations question the exclusivity

of hypothalamic involvement in CH.

A hyporeactive HPA axis similar to the changes

observed in CH can be also detected patients suffering

from fibromyalgia. Changes included disturbance of

cortisol secretion (flattening of the circadian level, increased

daytime levels in plasma and saliva) and increased

nocturnal melatonin levels.

(19)

HPA axis alterations were

also observed in chronic widespread pain,

(19)

chronic

fatigue syndrome

(20)

and irritable bowel syndrome

(21)

(for

meta-analysis of HPA axis activity in functional somatic

disorders, see reference

(22)

GENETIC STUDIES IN CH

Children rarely suffer from CH. In these rare cases

a genetic background is presumable as 2 to 7% have a

positive family medical history for this disorder.

(23)

First-

degree – relatives develop five to 18 times, second-

degrees one to three times more often CH than the

general population.

(24)

Genetic alterations within the

orexinergic system of the hypothalamus were discussed

to be responsible for this observation. It has been shown

that the G1246A polymorphism of the OX

R gene

(HCRTR2) increases the risk for CH.

(25)

However, these

data were not replicated in larger CH patient

populations.

(26)

In migraineurs this gene polymorphism

was not observed.

(27)

Headache Medicine, v.3, n.4, p.188-197, Oct./Nov./Dec. 2012 191

CEREBRAL IMAGING: VBM, MRI, PET, SPECT

An increasing number of imaging studies was

performed over the last year in CH. Although initial data

were quite promising in detecting specific morphological

changes in CH and distinct activation patterns, recent

studies were often not able to replicate these findings or

question the specificity of these observations for CH.

Structural imagingStructural imaging

Structural imaging

Structural imaging of the hypothalamus in CH

One of the pioneer studies showing hypothalamic

involvement in CH was performed by May et al. in the

late 90ies of the last century. He used the method of voxel-

based morphometry (VBM), that is an automated,

unbiased, whole brain technique. It allows comparing

structural brain images, especially regarding the volume

or density of gray and white matter. May et al. investigated

25 CH patients compared with 29 healthy controls and

detected isolated increased gray matter in the inferior

posterior hypothalamus.

(28)

Because of the low prevalence

of this headache disorder it took several years to repeat

this investigation in a larger patient population and with

newer probably more accurate analysis algorithm. Up to

now, three studies were performed or are still ongoing,

which did not confirm the initial finding. Matharu et al.

investigated 66 patients suffering from CH, and 96 age-

and gender-matched healthy subjects. This study did not

detect any hypothalamic changes at all.

(29)

Similar findings

were reported by two later studies.

(30,31)

Our own working

group investigated 91 CH patients and failed to detect

any hypothalamic changes. However, we were able to

demonstrate several changes within the central pain-

processing network.

(30)

Structural imaging of the hypothalamus in other pain

and headache disorders

An alteration of the hypothalamic gray matter in a

similar area compared to the area described in CH was

detected in hypnic headache (HH).

(32)

HH is a different

rare primary headache entity that mainly affects elderly

patients. Patients report strictly nocturnal headache attacks,

mostly at the same time at night – that is why this headache

disorder is also called alarm clock headache.

(1)

Interestingly,

hypothalamic structural changes are even observed in

diseases that do not share the sleep relationship as CH

and HH do. Additionally, VBM and cortical thickness analysis

showed an increase of hypothalamic gray matter in 11

patients with irritable bowel syndrome (IBS).

(33)

Structural imaging of the hypothalamus in other

diseases

Despite pain and headache disorders structural

hypothalamic alterations can also be observed in other

diseases without or with less prominent pain symptoms.

Boghi et al. investigated 21 anorexic patients and 27

healthy control subjects using VBM. In the patient group

they observed focal atrophy in the hypothalamus besides

other changes. These changes correlated with the body

mass index (BMI). The authors suggested that these

hypothalamic changes point to hormonal dysfunction and

central dysregulation of homeostasis.

(34)

Hypothalamic

gray matter loss was also observed in 52 children and

adolescents with autism. The authors contemplated that

this alteration underlies the theory of dysfunction of the

hormonal system in autism, mainly an alteration of oxytocin

and arginine vasopressin.

(35)

Reduced hypothalamic gray

matter was also found in boys suffering from fragile X

syndrome.

(36)

Several studies showed changes of the hypothalamus

in patients with narcolepsy and cataplexy.

(37,38)

Narcolepsy

is a sleep disorder, characterized by reduced hypocretin

concentration in the cerebrospinal fluid. As hypocretin

neurons are exclusively localized in the hypothalamus

hypothalamic dysfunction was suggested.

Another VBM study showed gray matter atrophy in

the area of the hypothalamus in patients with Huntington's

disease.

(39)

Functional imagingFunctional imaging

Functional imaging

Functional imaging in CH

Functional imaging allows picturing ongoing pain

in the suffering brain in vivo. This technique thus offers a

possibility to investigate acute pain processing and to

figure out which anatomic structures might be involved.

Nitroglycerine triggered headache attacks in nine chronic

CH patients resulted in a strong activation of the

ipsilateral posterior hypothalamus detected by H

positron emission tomography (PET).

(40)

This activation

pattern was also observed in spontaneous CH attacks in

one patient who had undergone deep brain stimulation

(DBS).

(41)

In four patients with episodic CH functional

magnetic resonance imaging (fMRI) confirmed the

activation pattern within the ipsilateral posterior

hypothalamus.

(42)

However, some authors suggested that the detected

activation pattern in the functional imaging shows activation

of an area only close to the hypothalamus, most likely the

midbrain tegmentum.

(43)

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192 Headache Medicine, v.3, n.4, p.188-197, Oct./Nov./Dec. 2012

HOLLE D, OBERMANN M

Functional imaging in other pain and headache

conditions showing hypothalamic involvement

Hypothalamic investigation sometimes appears to be

almost a pathognomonic feature in CH or TACs in general,

but carefully crosschecking the literature does not confirm

this first impression.

In several other pain disorders and even experimental

pain conditions distinct hypothalamic activation during the

acute pain state has been demonstrated suggesting that

hypothalamic involvement might be a more general

feature of pain itself.

In seven migraneurs without aura cerebral activations

O PET) were recorded during spontaneous migraine

attacks without aura.

(44)

The observed activation pattern

included several brainstem areas (bilateral ventral

midbrain, dorsal contralateral midbrain in regard to the

headache side, dorsomedial pons), cerebellum, frontal

cortex, and cingulate cortex, which had been shown in

prior studies. Additionally, activation of the bilateral

hypothalamus was detected during the acute migraine

attack. This activation pattern had never been described

before. In contrast, further functional imaging studies

studying migraneurs did not detect any hypothalamic

activation.

(45-47)

In HC an activation of the contralateral posterior

hypothalamus was observed during acute pain

exacerbation using PET.

(48)

Twelve patients with angina pectoris were treated with

intravenous dobutamine to elicit an acute sensation. Due

to this pain experience the blood flow in the pain matrix

and the hypothalamus increased.

(49)

One patient who was implanted with a stimulation

electrode within the left ventro-posterior medial thalamic

nucleus because of a chronic facial pain was also

investigated using functional imaging methods. The patient

was measured when the stimulation electrode was working

(without pain) and without stimulation (with ongoing pain).

During the experience of pain significant increase of blood

flow was observed in common areas of the central pain

matrix and additionally in the hypothalamus.

(50)

Hypothalamic activation is not only shown during pain

disorders but can also be observed during experimental

pain. Twelve healthy volunteers were stimulated with pain

and warm sensations, which were applied to the left leg.

Pain-related skin conductance reactivity was measured and

association with fMRI activation pattern determined. Pain

sensation activated several areas of the central pain

processing system such as the anterior cingulate cortex,

amygdala, and thalamus, but also in the contralateral

hypothalamus.

(51)

In another PET study ethanol was injected

intracutaneously in the right upper arm of four healthy

volunteers to elicit acute traumatic nociceptive pain. Pain

lead to a strong activation of the contralateral (left)

hypothalamus.

(52)

Another study used the cold pressor

test, which applies prolonged tonic painful cold stimulation

to investigate pain associated activation pattern in healthy

subjects. Additionally, cold non-painful stimulation was

applied. Painful and non-painful sensations lead to an

activity increase in brainstem and hypothalamic areas.

Simultanously the galvanic skin response decreased. In

line with the expectations the painful conditions induced a

significantly stronger activation compared with the cold

sensation.

(53)

Resting state fMRIResting state fMRI

Resting state fMRI

The analysis of low-frequency (<0.1 Hz) fluctuations

seen on fMRI scans at rest allows detection of functionally

connected brain regions, so called resting state networks

(RSNs). Synchronous variations of the BOLD signal can

be measured as percentage signal change compared to

the BOLD mean signal intensity over time.

(54-56)

The

fluctuations observed by resting state analysis are thought

to reflect the intrinsic property of the brain to handle the

past and prepare for the future.

(57)

RS alterations were

observed in chronic pain.

(58)

Rocca et al. studied RS in 13

patients with episodic CH compared with healthy controls.

Patients were studied in a pain free state. Apart from other

changes the authors observed functional connectivity within

the network staring from the hypothalamus.

(59)

Magnetic resonance spectroscopyMagnetic resonance spectroscopy

Magnetic resonance spectroscopy

An additional exciting imaging technique to study

brain biochemistry in vivo is magnetic resonance

spectroscopy. In episodic CH patients hypothalamic N-

acetylaspartate/creatine and choline/creatine levels are

significantly reduced compared with healthy controls.

Interestingly, changes were even detectable when the

patients were outside bout, which means that they had no

actual CH attacks anymore.

(60,61)

This observation led to

the assumption that these alterations cannot simply reflect

an epiphenomenon of pain itself.

(61)

DEEP BRAIN STIMULATION: EVIDENCE OF

HYPOTHALAMIC INVOLVEMENT IN CH?

The clinical picture of CH and the results from imaging

studies provided the rationale for hypothalamic deep

brain stimulation (DBS) in the treatment of CH. It was

Headache Medicine, v.3, n.4, p.188-197, Oct./Nov./Dec. 2012 193

though that this technique might offer a possibility to "turn

off the CH generator" as high-frequency hypothalamic

stimulation would inhibit hypothalamic hyperactivity.

(62)

The

stimulation area was mainly chosen by adoption of the

results from the initial VBM study.

(28)

To assess to what extent

DBS stimulation is able to abort acute CH attacks Leone

et al. investigated 136 CH attacks in 16 chronic CH

patients.

(63)

Only 23 % of patients reported a reduction of

pain intensity by more than 50%, and only 16% of

headache attacks were completely terminated. These data

indicated that DBS is not sufficient in the treatment of active

CH attacks.

(63)

Further studies showed, that only continuous

stimulation over several weeks markedly reduces or

terminates CH attacks (for review

(64,65)

). Fifty-eight patients

with chronic drug resistant CH and posterior hypothalamic

DBS have been documented in literature, yet. Leone et

al. investigated 16 drug-resistant chronic CH patients who

received hypothalamic implants over a mean period of

four years. After the first two years 83.3% of patients had

experienced a pain termination or at least major pain

reduction. After four years, still 62% of patients were pain

free.

(66)

These results were confirmed by several other

studies.

Interestingly, there were no changes in regard to long-

term stimulation in electrolyte balance, sleep-wake cycle,

or hormone levels of cortisol, prolactin, thyroid hormone,

thyroid-stimulating hormone, which were accused before

to be involved in the occurrence of CH attacks.

(62,66-73)

Although the evidence of the imaging studies seemed

to be overwhelming, some authors raised the question of

the precise anatomical localization of the DBS. Sanchez

del Rio and Linera questioned if the shown diencephalic/

midbrain activity pattern corresponds rather to the midbrain

tegmentum than to the genuine hypothalamus.

(43,74)

Although the anatomical boundaries of the hypothalamus

are quite clear (anterior: lamina terminalis; posterior:

posterior margin of the maxillary bodies; superior:

hypothalamic sulcus; medial: third ventricle; lateral:

subthalamus and internal capsule; inferior: optic chiasm,

median eminence, tuber cinereum, mammillary bodies,

and posterior pituitary), the functional boundaries are more

vaguely determined.

(75)

Matharu et al. re-examined the

statistical parametric maps and coordinates of the

activation pattern of PET studies in CH.

(74)

The observed

activation in the diencephalon and the mesencephalon in

CH are centered over the midbrain tegmentum and are

close to the hypothalamus but more anterior.

(40)

In contrast,

functional imaging studies in CH using BOLD-fMRI studies

detected activation of the posterior and middle

hypothalamus rather than the mesencephalon. The authors

suggest that these differences are most likely based on

methodological issues, mainly the problem of insufficient

spatial resolution (fMRI 4 to 5mm; PET 5 to 10mm). They

conclude that these data can only be interpreted in the

context of other knowledge, but might be, therefore, also

influenced by a priori hypothesis. Moreover, stimulation

of the trigeminal pain processing network by greater

occipital nerve (GON) stimulation in CH patients presented

similar results in regard to pain reduction efficacy suggesting

a rather unspecific role of DBS stimulation in CH.

Additionally, positive DBS results were also observed

in other pain disorders, questioning the patho-

physiological concept of specific hypothalamic alteration

in CH and raising some serious concerns regarding their

validity and specificity. Interestingly, hypothalamic DBS

was also effective in treatment of symptomatic trigeminal

neuralgia (TN) in five multiple sclerosis patients.

(76)

These

patients had to be therapy refractory prior to electrode

implantation. Beneficial effects in regard to pain

reduction were observed in three of the patients even

within the first 24 hours after implantation. Symptomatic

TN seems, therefore, according to the opinion of the

study authors, a possible area of application for DBS.

As long as controlled studies are missing in this regard

the results of such studies should be interpreted with

caution and careless utilization should be avoided.

However, one can conclude based on the reported study

results that DBS of the posterior hypothalamus is not

exclusively effective in CH but also shows beneficial

effects in other pain conditions as well.

In contrast, there are also chronic pain conditions

were hypothalamic DBS seems not to be effective. Franzini

et al. reported on four patients with secondary neuropathic

trigeminal pain (pain after resection of a posterior

mandibular carcinoma, unspecified facial pain; pain after

radiotherapy of a nasopharyngeal carcinoma; and no

description) who did not experienced any relevant pain

reduction after electrode implantation.

(76)

However, the

reported patient population was inhomogenous with not

comparable clinical features, which makes an

interpretation of the study results difficult.

HYPOTHALAMUS: PRIMUM MOVENS IN CH

OR ONLY PART OF THE CENTRAL

PAIN-PROCESSING NETWORK?

Looking at the clinical features of CH with trigeminal

distribution of pain, circadian/circannual rhythmicity, and

CLUSTER HEADACHE AND THE HYPOTHALAMUS – CAUSAL RELATIONSHIP OR EPIPHENOMENON?

194 Headache Medicine, v.3, n.4, p.188-197, Oct./Nov./Dec. 2012

HOLLE D, OBERMANN M

ipsilateral cranial autonomic symptoms in combination

with the results from the many imaging studies the patho-

physiological importance of the hypothalamus seems to

be obvious and scientifically proven, but newer data

question the pivotal role of the hypothalamus in CH.

Particularly structural and functional neuroimaging studies

supported the hypothesis of hypothalamic alterations being

involved in the pathophysiology of CH.

(28,41,42)

These data

seemed to be so conclusive that even invasive therapy

methods such as DBS were used to directly influence the

"hypothalamic CH generator". However, other contrary

findings should be also taken into consideration before

prematurely adopt this hypothalamic hypothesis. One

major criticism about most of the interpretations from

previous studies is, that the focus was directed almost

exclusively at results that support the hypothalamic

importance of the hypothalamus in CH, while other data

were often neglected or rendered unimportant. It might

be useful to take a step back and have a look at the

whole picture, as this strong hypothesis driven research

might have led us in the wrong direction.

Hypothalamic activation and structural changes can

also be also detected in other primary headache

disorders such as migraine,

(44)

hemicrania continua

(48)

chronic facial pain

(50)

and hypnic headache

(32)

and is

not an exclusive feature in CH. Interestingly, hypothalamic

changes can even be observed in totally different pain

conditions such as angina pectoris,

(49)

irritable bowel

syndrome

(33)

or even conditions that not involve pain at

all such as anorexia nervosa,

(34)

autism,

(35)

fragile X

syndrome,

(36)

narcolepsy,

(37,38)

and Huntington's

disease.

(39)

However, most of the neuro-imaging studies

that investigated pain disorders other than CH, did not

observe any hypothalamic alterations. However, most

of the CH imaging studies take the involvement of the

hypothalamus a priori as a basis of their analysis, which

allows reduction of the significance level. In contrast, most

of the other studies that investigated pain disorders, did

not predefine the hypothalamus as target anatomic

region, what impedes the dectection of more subtle

activation or structural change below the threshold of

statistical significance.

The exact anatomic localization of the observed

activations or structural alterations in CH has been

discussed quite controversially in the past

(43,74)

in regard

to the limitation of spatial resolution (PET: 2 to 7 mm;

MRI 4 and 5 mm). Based on these methodological

limitations, it was suggested that the observed activations

might be localized in the midbrain tegmentum rather than

in the hypothalamus itself. Taking the limitation of spatial

resolution into consideration, PET and MRI seem to be

not proper methods to distinguish anatomically between

these two regions. This might challenge the validity of

many neuroimaging results presented in regard to

anatomic precision.

Although neuroendocrine

(16)

and genetic studies

(25)

detected changes in CH and also seem to point at

hypothalamic changes, the specificity of these observations

must be questioned. HPA axis disturbances can be also

detected in fibromyalgia,

(19)

chronic fatigue syndrome,

(20)

irritable bowel syndrome,

(21)

and migraine,

(18)

genetic

mutations were not reproducible.

(26)

EXPERT COMMENTARY

Although the clinical picture of CH with trigeminal

distribution of pain, circadian/circannual rhythmicity, and

ipsilateral cranial autonomic features support the

hypothesis of hypothalamic changes in terms of a specific

CH generator as primum movens, more and more

studies results, especially conducted in other pain

conditions, question this hypothesis. Taking all current

information together it seems to be much more probable

that the hypothalamus is only involved in pain processing

in general as part of a pain network.

Previous studies on this topic were often driven by

strong a priori hypothesis and all results were only

interpreted in the context of these hypothesis. We can

mainly learn from this example that overly clear

pathophysiological concepts of any particular disease

evidently lead to overinterpretation and bias. As these

interpretations even lead to invasive treatment

methods, which may even jeopardize patients´

wellbeing, it seems mandatory to question even strong

plausible hypotheses more often, because they might

not explain the whole truth and might point future

science in a wrong direction.

FIVE-YEAR VIEW

There is a need for investigation of the true patho-

physiological background of CH, probably based on a

more multi-causal concept, as research of the last ten

years was at least partly misguided by the main focus

on the hypothalamus in CH pathophysiology. Further

research should concentrate on different structures other

than the hypothalamus that might be involved in the

pathophysiology of CH.

Headache Medicine, v.3, n.4, p.188-197, Oct./Nov./Dec. 2012 195

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Correspondence

Mark Obermann, MDMark Obermann, MD

Mark Obermann, MD

Department of Neurology

University of Duisburg-Essen

Hufelandstr. 55

45122 Essen

Phone: + 49-201-723-84385

Email: mark.obermann@uni-due.de

Received: 11/28/2012

Accepted: 12/15/2012

CLUSTER HEADACHE AND THE HYPOTHALAMUS – CAUSAL RELATIONSHIP OR EPIPHENOMENON?