An interesting read and different slant on the pathophysiology of cluster headaches... and the logic expressed appears to be clearly contrary to that of the good Dr. Goadsby...
The slant diverges further in Ref 2 “how” versus “what” of a disease process... if you're really into heavy reading...
Cluster headache: Key pathophysiological issues
Vinod K Gupta, M.D.
Dear Editor,
Ferrari and colleagues find that menstruation, use of oral contraceptives, pregnancy and menopause had a much smaller influence on cluster headache attacks than in migraine.
[1] Although such data appear interesting, they are peripheral to the pathogenesis of the disorder; neither are these issues any more relevant to migraine pathophysiology. Fifteen key pathophysiological issues continue to be completely overlooked in migraine research; in this context, hormones, neuropeptides, magnesium, platelets, deep white matter lesions, neuronal ion channels and genetic linkages are rather peripheral concerns in primary headaches.
[2] Epidemiological data and associations are useful only if they provide clues to aetiology by leading to experiments that deepen our understanding of causal mechanisms.
[3] Unfortunately, this study [1] offers no mechanistic insight regarding cluster headache or any clue towards experiments that further shape our understanding. Science is a process; accretion of data in the absence of a central concept thwarts or impedes the process.
Key issues that can evolve into a comprehensive theory for cluster headache include:[4][5][6][7][8][9][10]
1. The self-limited nature of cluster headache (15-180 minutes) indicates primary involvement of a system that has the intrinsic ability to limit or dampen the headache attack initiating physiological event. Such a system is highly unlikely to be purely vascular or neuronal.
2. Strict lateralization of headache indicates an idiosyncratic cranial structural or anatomical variation that localizes the headache.
3. Absence of vomiting despite a variant of headache that is frequently far more intense and distressing than migrainous headache indicates that vomiting – while frequently remitting migraine – might exacerbate the underlying pathophysiological mechanism in cluster headache.
4. Non-pulsatile nature of headache indicates occurrence of the maximum possible attack-related stretching of the cranial structure primarily involved in cluster headache.
5. Therapeutic effect of oxygen and ergotamine and aggravation / precipitation by alcohol or nitroglycerine (glyceryl trinitrate) strongly indicate primary involvement of peripheral non-neuronal mechanisms.
6. Prophylaxis with verapamil practically confirms a peripheral non- neuronal origin of cluster headache.
7. Long periods of remissions indicate operation of adaptive mechanisms, possibly involving tissue creep.
It is illusionary to believe that advanced neuro-imaging or other laboratory advancements have unlocked the “biology” of cluster headache. All laboratory procedures have their limitations; nothing can supplant careful thinking about the research question(s).
Technology is a tool of science, it is not science itself. Also, undirected epidemiological investigations and nosological or statistical-mathematical sophistication do not further our understanding of cluster headache.
References:
1. van Vliet JA, Favier I, Helmerhorst FM, Haan J, Ferrari MD. Cluster headache in women – relation with menstruation, use of oral contraceptives, pregnancy and menopause. J Neurol Neurosurg Psychiatry published online 11 Jan 2006; doi:10.1136/jnnp.2005.081158
2. Gupta VK. Migraine: Migraine: “how” versus “what” of a disease process. BMJ (published online 8 February 2006). Available at: Multimedia File Viewing and Clickable Links are available for Registered Members only!! You need to

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3. Skrabanek P. The poverty of epidemiology. Persp Biol Med 1992;35:182-185.
4. Gupta VK. Trigeminal autonomic cephalalgias: ‘noso-physiology’ or pathophysiology? J Neurology Neurosurgery & Psychiatry (22 February 2005). Available at: Multimedia File Viewing and Clickable Links are available for Registered Members only!! You need to

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5. Gupta VK. Intractable cluster headache and therapeutic stimulation of the hypothalamus: pathophysiological and management insights from a rare experiment. Brain 2005;128: E26. [Extract] [Full Text]
6. Gupta V. Does the eye modulate the clinical expression of cluster headache? BMC Neurology (17 May 2005) Available at: Multimedia File Viewing and Clickable Links are available for Registered Members only!! You need to

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7. Gupta VK. Is verapamil-triptan combination for cluster headache therapy pharmacologically valid? Headache [In press].
8. Gupta VK. Change in frequency pattern in cluster headache induced by subcutaneous sumatriptan. Headache [In press].
9. Gupta VK. Neuroimaging in hemicrania continua: dissociation between technology and basic sciences? Headache [In press].
10. Gupta VK. MRI imaging in primary headaches. Radiology 2006:238:754-755.
Published 2 March 2006