The clear pathogenesis of cluster headache is still unknown. Various thought processes and pathophysiologic mechanism are considered to be involved in the pathogenesis. Generally 3 brain systems are mostly found to be involved or associated with the pathophysiology of cluster headache. Three brain systems are thought to be involved: hypothalamus, autonomic system and trigeminal nucleus. Orexin/hypocretin receptor 2 (HCRTR2) gene mutations are found to be particularly associated with cluster headaches in a couple of separate independent studies. Cluster headaches may also be associated with or secondary to other conditions such as: Hypothalamic and pituitary tumors, meningiomas (anywhere from the cavernous sinus to the upper cervical spine), carotid artery dissections, vascular malformations and sleep apnea.

The clear pathogenesis of cluster headache is still unknown. Various thought processes and pathophysiologic mechanism are considered to be involved in the pathogenesis. Generally 3 brain systems are mostly found to be involved or associated with the pathophysiology of cluster headache.^{[1][2][3][4][5][6]}

• Hypothalamus
  • The site of the circadian pacemaker in the suprachiasmatic nucleus
  • Posterior hypothalamus activation is most commonly involved with the onset of cluster headache
  • Alterations in hypothalamic and pituitary molecules (orexin, melatonin, and luteinizing hormone)
• Autonomic system
  • The superior salivatory nucleus and the sphenopalatine ganglion, which includes molecules such as vasoactive intestinal peptide (VIP)
  • Depending upon the setting, stimulation of ganglion may stimulate or abort an episode of cluster headache
• Trigeminal nucleus
  • Trigeminovascular system
    • Trigeminal nucleus plus Large cranial blood vessels and meninges
  • The Trigeminocervical complex
    • Trigeminal nucleus plus upper cervical dorsal horns
  • Trigeminal nucleus is usually associated with the pain component of cluster headaches
  • This system includes molecules such as calcitonin gene-related peptide, pituitary adenylate cyclase-activating peptide

• First-degree relatives of sufferers are more likely to have the condition than the population at large.^[7]
• Orexin/hypocretin receptor 2 (HCRTR2) gene mutations are found to be particularly associated with cluster headaches in a couple of separate independent studies.

The following trigger factor may be involved in the pathogenesis of cluster headache:

• Nitroglycerin (glyceryl trinitrate)
• Alcohol
• Nicotine dependence or smoking
• Exposure to hydrocarbons (petroleum solvents, perfume)
• Decreased tolerance to heat, and becoming overheated may act as a trigger.

Cluster headaches may also be associated with or secondary to other conditions such as:

• Hypothalamic and pituitary tumors
• Meningiomas (anywhere from the cavernous sinus to the upper cervical spine)
• Carotid artery dissection
• Vascular malformations
• Sleep apnea

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