Pathophysiology of Cluster Headache
Cluster headache is fundamentally a neurovascular disorder driven by hypothalamic dysfunction that triggers activation of the trigeminovascular system and trigeminal-autonomic reflex, resulting in the characteristic severe unilateral pain and ipsilateral cranial autonomic symptoms. 1, 2
Central Hypothalamic Dysfunction as the Primary Generator
The hypothalamus, particularly the inferior hypothalamic grey matter, serves as the primary generator of cluster headache attacks, as demonstrated by PET imaging showing specific activation in this region during acute attacks that is absent in patients outside of bouts 2
This hypothalamic involvement explains the distinctive circadian and circannual periodicity of cluster headache, with attacks occurring at predictable times of day and clustering in specific seasons, mediated through connections with the suprachiasmatic nucleus 3, 4
The hypothalamus does not act in isolation but rather functions within a complex cortical-hypothalamic-brainstem network that can switch between out-of-bout and in-bout periods through top-down mechanisms 5
Trigeminovascular System Activation
The severe unilateral pain in the trigeminal distribution results from activation of the trigeminovascular complex, which involves the trigeminal nerve's innervation of intracranial and extracranial blood vessels 3, 1
During attacks, neuroimaging demonstrates activation in the contralateral ventroposterior thalamus, anterior cingulate cortex, and bilateral insulae, representing the pain processing network 2
The pathophysiology has evolved from a pure vascular hypothesis to a comprehensive trigeminovascular model, where vascular changes are secondary to neuronal activation rather than the primary cause 5
Trigeminal-Autonomic Reflex
The prominent ipsilateral cranial autonomic symptoms (lacrimation, conjunctival injection, nasal congestion, ptosis, miosis) result from activation of the trigeminal-autonomic reflex, a brainstem connection between the trigeminal nerve and parasympathetic outflow 3, 1
This reflex arc involves the superior salivatory nucleus and sphenopalatine ganglion, explaining why sphenopalatine ganglion stimulation has emerged as a treatment target 1
The autonomic features are consistently ipsilateral to the pain because the reflex is unilateral and does not cross midline 3
Neurolimbic Pain Network Model
Beyond the traditional "pain matrix" concept, cluster headache involves a "neurolimbic pain network" with functional interconnections between cortical structures, hypothalamus, and brainstem 5
This network model explains the sense of agitation and restlessness during attacks, which distinguishes cluster headache from migraine where patients typically seek quiet, dark environments 3
The network can be modulated by various neuropeptides, including calcitonin gene-related peptide (CGRP), which has become a therapeutic target 1
Key Neuropeptide Involvement
CGRP plays a crucial role in cluster headache pathophysiology, with elevated levels during attacks and therapeutic efficacy of CGRP-targeted treatments providing mechanistic insights 1
Somatostatin receptor pathways are also implicated, as evidenced by the therapeutic potential of somatostatin receptor agonists 1
The effectiveness of oxygen therapy (12 L/min via reservoir mask) likely involves vasoconstriction of dilated cerebral vessels and modulation of trigeminal-autonomic pathways rather than correction of systemic hypoxia 6
Clinical Implications of Pathophysiology
The circadian rhythmicity explains why attacks frequently occur at night during REM sleep and at consistent times during the day, with the hypothalamus serving as the biological clock 4, 3
The male predominance (approximately 2.5:1 ratio) suggests hormonal or genetic factors that remain incompletely understood 3
The ability to shift between episodic and chronic forms reflects plasticity in the underlying neural networks, though specific mechanisms governing these transitions remain unclear 3