Pathophysiology

The underlying pathophysiology of CH is incompletely understood. [4, 5] The periodicity of the attacks
suggests the involvement of a biologic clock within the hypothalamus (which controls circadian rhythms),
with central disinhibition of the nociceptive and autonomic pathwaysspecifically, the trigeminal
nociceptive pathways. Positron emission tomography (PET) and voxel-based morphometry have identified
the posterior hypothalamic gray matter as the key area for the basic defect in CH. [1] See the images below.

Cluster headache: Functional imaging shows activation of

specific brain areas during pain. Courtesy of Wikipedia Commons.

Cluster headache (CH): Voxel-based

morphometry (VBM) structural imaging shows specific brain area of CH patients' (hypothalamus) being different to nonCH patients' brains. Courtesy of Wikipedia Commons.

Altered habituation patterns and changes have been observed within the trigeminal-facial neuronal circuitry
secondary to central sensitization, in addition to dysfunction of the serotonergic raphe nuclei-hypothalamic
pathways (though the latter is not as striking as in migraine). Functional hypothalamic dysfunction has been
confirmed by abnormal metabolism based on the N-acetylaspartate neuronal marker in magnetic
resonance spectroscopy.[6]
Substance P neurons carry sensory and motor impulses in the maxillary and ophthalmic divisions of the
trigeminal nerve. These connect with the sphenopalatine ganglion and interior carotid perivascular
sympathetic plexus. Somatostatin inhibits substance P and reduces the duration and intensity of CH.
Vascular dilatation may play a role in the pathogenesis of CH, but blood flow studies are inconsistent.
Extracranial blood flow (hyperthermia and increased temporal artery blood flow) increases, but only after
the onset of pain. Vascular change is considered secondary to primary neuronal discharge.
Although the evidence supporting a causative role for histamine is inconsistent, cluster headaches may be
precipitated with small amounts of histamine. Antihistamines do not abort cluster headaches. Increased
numbers of mast cells have been found in the skin of painful areas of some patients, but this finding is
inconsistent.

Link : http://emedicine.medscape.com/article/1142459-overview#a3

Cluster headache
Pathogenesis and pathophysiology
Article section 6 of 16. Previous Next
By Peter J Goadsby MD PhD

The 3 major aspects of the pathophysiology of cluster headache are the trigeminal distribution of
the pain, the autonomic features, and, more important, the inherent periodicity of the attacks and
bouts (Goadsby 2002a). Ekboms observation of a patient suffering an acute cluster headache
demonstrating angiographic changes in the internal carotid artery suggested a pathological focus
in the region of the cavernous sinus (Ekbom and Greitz 1970). The arguments for this locus for the
disease have been set out clearly (Moskowitz 1988; Hardebo 1994). There are no consistent

markers of inflammation when measured in the periphery (Remahl et al 2000) and signs of
cavernous sinus inflammation when studied with SPECT/MRI (Schuh-Hofer et al 2006). Three lines
of evidence suggest that the cavernous sinus is not the site of the basic biological problem. The
clinical manifestations outlined above, in particular the periodicity, the neuroendocrine changes,
and the functional neuroimaging results (Cohen and Goadsby 2006; DaSilva et al 2007), suggest
that cluster headache involves biological dysfunction in the posterior hypothalamic grey matter
pacemaker neurons.
Pain transmission in cluster headache. The pain of cluster headache is a first division of
trigeminal phenomenon. Many of the autonomic features are due to seventh nerve activation,
whereas the remaining changes are due to a transient cervical sympathetic deficiency. It is both
clinically likely and experimentally clear (Goadsby and Duckworth 1987) that a trigeminalautonomic reflex underlies the pain expression of cluster headache. There are neuropeptide
changes in the cranial circulation in both calcitonin gene-related peptide (CGRP) and vasoactive
intestinal polypeptide (Goadsby and Edvinsson 1994; Fanciullacci et al 1995) and nociceptin
(Ertsey et al 2004) release during headache that reflect the trigeminal and autonomic dimensions
of the syndrome. Human studies have shown that this process does not seem to be active in
cluster headache (May et al 1998c), at least as far as experimental plasma protein extravasation is
concerned (Moskowitz and Cutrer 1993). Interestingly, in rats with 5-HT1D immunoreactivity there
are documented primary afferents fibers that innervate postganglionic neurons in the
sphenopalatine ganglion, suggesting a site for modulation by triptans (Ivanusic et al 2011). Taken
together, the clinical and experimental evidence has suggested the term trigeminal autonomic
cephalalgias as an umbrella term for cluster headache and related conditions (Goadsby and Lipton
1997). Drummond argues for a peripheral sympathetic autonomic disturbance (Drummond 2006),
and minimal systemic autonomic disturbances are reported (van Vliet et al 2006c). For cluster
headache, a crucial aspect of the dysfunction appears to lie within the ipsilateral hypothalamic grey
(May et al 1998a), and it is clear that the carotid flow changes are driven by the ophthalmic
division of the trigeminal nerve and are not due to cluster headache as such. Further evidence of
brain mechanisms in cluster headache patients is the fact that the nociceptive flexion reflex
threshold is asymmetrically reduced (Sandrini et al 2000). More challenging is the observation of a
typical cluster headache patient whose attacks persist after trigeminal root section (Matharu and
Goadsby 2002; Jarrar et al 2003). In comparison to migraine, it is notable that there is no defect
in habituation of the nociceptive blink reflex in cluster headache (Holle et al 2012b), with
lateralized facilitation of central pain pathways (Holle et al 2012a).
Neuroendocrine changes in cluster headache. Kudrow pointed out that testosterone levels are
altered in cluster headache patients during a bout (Kudrow 1976; 1977b). Leone and colleagues
identified reduced responses to stimulation by thyrotropin-releasing hormone (Leone et al 1990),
and interesting observations have been made of disordered circadian rhythm for cortisol, growth
hormone, luteinizing hormone, and prolactin (Chazot et al 1984; Waldenlind and Gustafsson
1987). Despite suggested involvement of the hypothalamic-pituitary axis, somatostatin infusion
does not trigger acute cluster headache even with suppression of growth hormone (Levy et al
2003). One area involved in human clock systems is the suprachiasmatic nucleus in the
hypothalamic grey, which sits at the base of the third ventricle (Moore-Ede 1983; Moore 1997).
Melatonin is produced by the pineal gland and has a strong circadian rhythm, which is regulated by
the suprachiasmatic nucleus. Connections between the retina and the hypothalamus are thought to
provide light cues for the circadian rhythm (Hofman et al 1996). The characteristic nocturnal peak
of melatonin secretion is blunted during the active phase of cluster headache (Waldenlind et al
1987), whereas urinary excretion of 6-sulphatoxymelatonin, the main metabolite of melatonin, is
reduced both within and between bouts compared with controls (Leone et al 1998). This suggests
a defect with some permanent nature possibly amenable to treatment (Leone and Bussone 1998).

Involvement in some part of nitric oxide mechanisms in cluster headache is supported by the
finding of elevated levels of nitrix oxide-oxidation end products in the CSF of patients with cluster
headache (Steinberg et al 2010). Latencies of the endogenous event-related-potential components
are significantly increased during the cluster period as compared with outside the cluster period
and with healthy subjects (Evers et al 1999), further contributing to the notion of a central
nervous system dysfunction. The hypothalamic gray is, therefore, of potential interest in studies of
cluster headache.
Functional imaging and other physiological studies of cluster headache. Acute cluster
headache triggered by nitroglycerin produces brain activations on positron emission tomography
(PET) that fall into 3 categories: areas generally associated with pain, an area that seems specific
to cluster headache, and vascular structures (May et al 1998a). The anterior cingulate was
significantly activated, as would be expected, because in most human PET pain studies, activation
of the anterior cingulate is observed, perhaps as a part of the affective response. Its degree of
activation seems to track the subjective reporting of pain (May et al 2000b) and can be seen in
spontaneous attacks (Sprenger et al 2004) and when using fMRI (Morelli et al 2009). Activation
was also noted in the frontal cortex and insulae and ventroposterior thalamus contralateral to the
side of the pain. In addition, activation in the ipsilateral basal ganglia was observed. This is not the
first observation of basal ganglia changes associated with pain (Chudler and Dong 1995;
Derbyshire et al 1997). This may simply relate to movement, the wish to move that is common in
cluster patients, or even some deliberate inhibition of movement. Moreover, after occipital nerve
stimulation (see Management section), there was normalization of pain matrix areas and lower
pons but not of the posterior hypothalamic region. Remarkably, the perigenual anterior cingulate
cortex was hyperactive in occipital nerve stimulation responders compared to nonresponders
(Magis et al 2011a).
The only activated area that is particular to cluster headache is a region near the base of the third
ventricle, the posterior hypothalamic gray matter. One may speculate that orexinergic neurons
play some role at this level (Holland and Goadsby 2009), and indeed, data demonstrate reduced
orexin levels in the CSF of cluster headache patients (Barloese et al 2014b). Activation of the
hypothalamic gray matter in this region is not seen in migraine (Afridi and Goadsby 2006), nor in
experimental first (ophthalmic) division of trigeminal nerve head pain (May et al 1998b). This
region is not activated when the patient is out of a bout (May et al 2000a) but, remarkably, seems
to have some structural difference when compared to control brains, notably a subtle increase in
gray matter volume in the posterior hypothalamus (May et al 1999a). Moreover, a PET scan of a
patient with both cluster headache and migraine who had a migraine at the time of the PET scan
only showed brainstem, and not hypothalamic, activation (Bahra et al 2001). An increase of 20 Hz
in the local field potential power in the region of the posterior hypothalamus has been noted in a
patient undergoing implantation who had a spontaneous attack of cluster headache (Brittain et al
2009). These observations have led to implantation of deep brain stimulating electrodes into this
portion of the brain with excellent outcomes in otherwise intractable patients (Franzini et al 2003;
Leone 2006). Stimulation of the posterior hypothalamic region using the implanted electrodes
produces a unique pattern of activation and de-activation in the brain, suggesting that the
therapeutic effect is specific and not head pain generic (May et al 2006). Similarly, 1H-MRS studies
have reported reduced N-acetylaspartate levels, implying local neuronal loss or dysfunction in the
posterior hypothalamic region (Lodi et al 2006; Wang et al 2006) whereas resting-state network
fMRI demonstrated increased connectivity between hypothalamic and thalamic nuclei in cluster
headache (Rocca et al 2010). Supporting a brain basis for cluster headache, 11C-diprenorphine
PET studies reveal reduced pineal opiate receptor availability (Sprenger et al 2006) and triggering
of attacks from emotional trauma (Sandor et al 2006). It is to be expected that discussion remains
as to both the mechanism and effective site of stimulation. It has been noted through indirect

means that the optimal site for stimulation is located in the region just posterior to the
hypothalamus (Fontaine et al 2010), although the clear anatomical definition of the posterior
hypothalamus in humans seems unclear if one considers the basis on which the structure has been
defined. It has been shown using high-resolution T1-weighted MRI that cortical thickness in cluster
headache patients is reduced compared to controls, perhaps related to disease duration, ie, as a
consequence not cause (Seifert et al 2012).
During acute cluster headache, activation or signal on the PET studies is observed in the region of
the cavernous sinus (May et al 1998a) and has been shown, using MRA, to be due to internal
carotid artery vasodilation (May et al 1999b). The same region is activated during capsaicininduced experimental head pain (May et al 2000a; 2001), but when capsaicin is injected into the
skin innervated by the mandibular division of the trigeminal nerve or the ipsilateral leg, no carotid
dilation is observed (May et al 2001). Moreover, after trigeminal root section, attacks of tearing
without pain are well recognized (Matharu and Goadsby 2002; Lin and Dodick 2005). These data
imply that the activation of the carotid does not relate specifically to cluster headache, but that it
is a trigeminovascular autonomic reflex to first division pain. The flow changes are, therefore, an
epiphenomenon of the trigeminal activation, and not part of the disease generation process in
cluster headache.

Link : http://www.medmerits.com/index.php/article/cluster_headache/P5