The 'Pre-Prodromal' or ‘Pre-Premonitory’ Phase Holds the key to the Cause-Effect Basis of Migraine Buried over 25 Centuries: Continuum of the Confusion surrounding Allodynia-Randomized Controlled Trials-Stress-Intraocular Pressure-Migraine Nexus

Migraine is a protean recurrent cephalalgogenic neuro-ophthalmologic disorder caused by an ‘autonomic storm’ (AS) associated external-carotid arterial system linked selective / exclusive aberration of the peripheral division of ophthalmic division of the trigeminal nerve (V1) with lateralizing headache, non-homonymous visual field defects including scintillating scotoma (SS) and other forms of visual / non-visual hallucinations, and unpleasant autonomic nervous system (ANS) symptoms such as nausea / vomiting well-known over 25 centuries, since the intuitive observation of Hippocrates (c. 460-c.370 B.C.). The functional connectome of migraine that affects almost one-fifth of humankind has become an increasingly complex neuro-ophthalmological-endocrinological mystery, constituting a social stigma with exponential increase in statistical but not biologically significant data that form a series of Gordian knots of worsening proportions, both in series and in parallel. Scientific literature of migraine is frustratingly vast, increasingly diverse, and pathophysiologically and clinically disheartening. Recently, pathological (morphological and functional) principles that govern migraine and other primary headaches have been clearly evolved. Migraine is not a pan- or holo-trigeminal disorder, but selectively or exclusively involves aberration of the oculo-peripheral components of the first division of the trigeminal nerve (V1). “Trigeminovascular system” is a misleading term that obscures the overriding clinic-pathological importance of peripheral computations of the oculo-trigeminal system, including V1, oculo-sympathetico-intraocular pressure and sclero-corneal systems. Overemphasis on different symptomatic phases of migraine, absolutely without any neurophysiologic scientific basis or a pivotal systematic structuring of the scattered diversely expanding evidences into a robust, generalizable, predictable, logical, defensible, and constantly enlarging overview has worsened the cause-effect conundrum. Division of a common entity such as migraine into pathophysiologically-incomprehensible apparently distinct phases such as the prodrome / premonitory, aura, headache, and postdrome intervals does not allow for a seamless, comprehensive and gestaltic synthesis. ‘Ictal’ (attack) and ‘interictal’ (between attack) phases complete the presumed circle of migraine, with an erroneous or pseudo-link with epilepsy that extends to both theory and therapy. Lateralizing V1 headache (unilateral, bilateral, side-shifting, or side-fixed) is the most consistent phase of migraine while aura (SS / other hallucinations) is the most varied and inconsistent phenomenon, creating and sustaining the debatable entities, migraine with aura (MwA) and migraine without aura (MwoA). Non-homonymous nasal-visual field sparing digitally-displaceable and ocular movement-synchronous SS is the pathognomonic visual feature of MwA, the typical expression of which requires a normally-functional eye. The origin of migraine lies in the pathophysiologic aberrations of the asymptomatic or subclinical currently unlabeled ‘pre-prodromal’ or ‘pre-premonitory’ phase. Onset of spontaneous / experimental migraine attacks is generally insidious and linked to a threshold that may be primed by a single or multiple triggers. Psychosocial stress is the commonest precipitant of migraine, the pathophysiological mechanism(s) of which remains completely unknown. The psychosocial stress / stressor (overt or subliminal) and other trigger-linked AS that operates in the ‘pre-prodromal / pre-premonitory’ phase covertly generates migraine, with the clinical consequences of the primary ANS aberration, i.e. AS flowing variably into the so-called phases. A conceptual divide between homeostatic / adaptive and pathogenetic physiologic aberrations clarifies both the cause-effect spectrum as well as the typical and hitherto unexplained but characteristically delayed onset of the migraine attack. With increasing understanding of the vasopressin-noradrenaline-serotonin nexus, the vast phenomenology of migraine (central and / or peripheral, episodic or chronic, clinical or pathological) has begun to be clearly categorized either as adaptive or pathogenetic. A hyperfocus on the ‘pre-prodromal’ / ‘pre-premonitory’ phase critically shifts the pathogenesis of spontaneous / experimental, self-limited headache (4-72 hours), and other protean manifestations of migraine attacks (aura-headache) from a pan-trigeminal disorder to V1 as well as to the eye rather than the brain. In 100 years of dedicated research including technological explosion, exponential data expansion, and foundational statistical significances, the prelude of the subliminal AS phase of migraine has not been integrated into any extant brain theory or any generally accepted other phase(s) of migraine. The ‘pre-prodromal’ / ‘pre-premonitory’ phase of AS of migraine is discussed towards a complete evolution of the disorder, including integration of episodic and chronic forms of migraine. A bluish-discoloration of the supero-lateral corneo-scleral envelope is presented as a particularly weakened or susceptible pathophysiologic and functional region of the eye that can generate spontaneous or experimental nociceptive neurologic deformation or activation of V1 to develop sui generis or idiosyncratic but ocular-tamponade self-limited migraine headache attacks (4-72 hours). The higher incidence of migraine in females and decline with age / menopause is also rationalized. The ‘pre-prodromal / pre-premonitory’ phase of migraine is the largest, most unpredictable, attack-initiating patho-functional AS component of migraine. The pathology of migraine and its functional components are thus brought together. A full discussion of the blue-discolouration of the corneo-scleral envelope and its mural components as related to migraine is beyond the scope of this article.