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I read the review by Øie et al. on the possible link between migraine and stroke (1). The authors believe that migraineurs are more likely to have unfavourable vascular risk factors. The increased risk of stroke seems to be more apparent among migraineurs without traditional risk factors (1). The mechanism behind the migraine- stroke association is unknown and clinical implications are uncertain (1).
While migraine and stroke are independently common disorders, the occurrence of migraine-related stroke, in particular ischemic stroke in migraine with aura (MA), is uncommon to rare. Risk of ischaemic stroke associated with migraine without aura (MO) is uncertain (1). MO is by far the larger cohort (~80%), and, the striking absence of link of MO with ischemic stroke (1) merits greater attention. Additionally, as underscored by the authors, longer cumulative exposure to MA, as would be expected with early onset of migraine, is not associated with increased stroke risk in late life (1), an unexplained clinical paradox. The link between migraine and stroke is extremely tenuous and needs a careful re-examination. The authors (1) make no attempt to clarify that, fundamentally, no pathophysiologic difference between MA and MO has been established, and, both cohorts believed to be nosologically distinct respond equally well to abortive and preventive management strategies. What is truly challenging is the scientific basis and logic of the entirely arbitrary creation of noso...
While migraine and stroke are independently common disorders, the occurrence of migraine-related stroke, in particular ischemic stroke in migraine with aura (MA), is uncommon to rare. Risk of ischaemic stroke associated with migraine without aura (MO) is uncertain (1). MO is by far the larger cohort (~80%), and, the striking absence of link of MO with ischemic stroke (1) merits greater attention. Additionally, as underscored by the authors, longer cumulative exposure to MA, as would be expected with early onset of migraine, is not associated with increased stroke risk in late life (1), an unexplained clinical paradox. The link between migraine and stroke is extremely tenuous and needs a careful re-examination. The authors (1) make no attempt to clarify that, fundamentally, no pathophysiologic difference between MA and MO has been established, and, both cohorts believed to be nosologically distinct respond equally well to abortive and preventive management strategies. What is truly challenging is the scientific basis and logic of the entirely arbitrary creation of nosology-based clinical “entities” such as MA and MO, a purely phenomenologic biologically-implausible clinical cul-de-sac that was underscored almost 2 decades previously, and that creates exponentially increasing but confusing data, and, does not allow a unifying overarching hypothesis for migraine to emerge (2). This distancing of science from reason and logic is one of the major factors in the continued limited pathophysiologic understanding of migraine (3,4).
The authors underscore the risk between migraine-related stroke and systemic blood pressure (1). A strong inverse relationship
between BP (systolic, diastolic, and pulse-pressure) and different headache types in an 11-year prospective perspective has been observed, consistent with previous studies (5). Migraine patients tend to maintain a low blood pressure, an adaptive homeostatic measure probably linked to aberrations in the ANS-ocular choroidal blood flow-intraocular pressure (6,7). A low blood pressure retards systemic cerebrovascular atherosclerosis and can be expected to promote longevity. An adaptive physiologic mechanism protects most patients of hypertension from headache; sudden changes in blood pressure with rapid alterations in the ANS-ocular choroid-IOP nexus rather than sustained elevations of blood pressure cause headache in hypertensive patients (7). No systemic influence, including blood pressure, can rationalize the typical lateralizing headache (unilateral, bilateral, side-shifting, or side-locked) of migraine (8,9). Cross-sectional observations do not elucidate the cause-effect paradigm between migraine and blood pressure, but, like-meta-analyses, can present evidences that cannot be reconciled with a larger picture, can be misleading, and cannot correct entrenched pathophysiologic beliefs. The authors clarify that the coronary and carotid arteries of individuals with active migraine are found to be less severely affected by atherosclerosis than in individuals without migraine (1), an insight lost in the huge mass of cross-sectional often conflicting data. Migraine is believed to underlie an evolutionary advantage for longevity (10).
The authors raise the issue of cigarette tobacco smoking as a prominent link to ischemic stroke (1) without in-depth comprehension of the effects of cigarette smoking chemicals, alteration of hematologic, or the cardinal effects of nicotine in the context of migraine, as placed in the migraine scientific domain over a decade ago. The analgesic, vasomotor, and behavior control actions of nicotine are well-defined, and, likely relate to release of arginine vasopressin, serotonin, and norepinephrine by nicotine, among other neuropeptides, at the level of the brain (11). The tripartite nexus of vasopressin-serotonin-norepinephrine is a well-defined variably-exhaustive adaptive/protective mechanism that delays onset of migraine headache in a variety of clinical conditions and circumstances, as well as prevents development of migraine in ~80% of the general population despite almost global exposure in humans to psycho-social non-oxidative stress (6,12,13). Post-stress headache is a typical feature of migraine (10), a characteristic that mandates the operation of a protective mechanism (6). Stress, a euphemism for our ignorance about cellular-level physiological mechanisms that play a key role in migraine, is again a complex issue. Depression is the commonest comorbidity of migraine, and nicotine withdrawal may produce depressive symptoms or precipitate a major depressive episode, while antidepressants may relieve these features (14). Secondly, nicotine may have antidepressant effects that maintain smoking (14). In effect, nicotine, like tricyclic antidepressants, has a migraine-remitting combined central serotonergic and noradrenergic agonistic action at the level of the brain/CNS synapse (11). Cigarette smoking cannot be linked uncritically to migraine-related stroke without such considerations.
In a similar vein, the authors infer an ischemic stroke-inducing effect of estrogen/oral contraceptives (1). In migraine research, it has become amply clear that estrogen withdrawal, rather than its intake as a combination oral contraceptive, is associated with occurrence of migraine attacks (15,16). Any link between estrogen use in female migraine patients and possible development of ischemic stroke (1) cannot be allowed to blunt the clear perspective of migraine protective role of estrogen.
Worsening of migraine during the first trimester of pregnancy (1) indicates loss of a protective/adaptive mechanism. Bioavailablity of placental vasopressinase, a cysteine aminopeptidase that degrades AVP but not desmopressin, progressively increases during pregnancy, as reviewed (12). Thus, forty percent of female migraine patients do not improve with pregnancy (12). Also, hypernatremia associated with hyperemesis gravidrarum decreases the biological vasomotor and analgesic activity of basal and stimulated secretion of AVP (12).
The authors do not consider the role of alcohol, a most commonly consumed recreational drug worldwide. Binge alcohol consumption, the major form of excess alcohol intake in the United States, is linked to vasoconstriction in the cerebral circulation and increased risk of stroke (17,18). Unaware of this important difference between daily alcohol and binge alcohol drinking, I, a migraineur since over 4 decades, developed a TIA for 20-30 minutes with collapse and complete loss of consciousness, and with ensuing confusion and agitation during recovery in 2017 at an airport lounge within approximately 20 minutes of consumption of >150 ml of 40% alcohol (unpublished observation).
Cortical spreading depression, genetic factors, patent foramen ovale, and atrial fibrillation (1) are too poorly understood to make any meaningful contribution to a discussion of migraine-linked stroke (4,13, 19,20). Silent structural infarct-like brain lesions (21) and white matter hyperintensities (22) are perfect examples of the stunting of critical thinking by technology, statistics, and meta-analyses in the absence of a robust core understanding of migraine mechanisms (13).
Future advances (1) can make little headway unless the massive synoptic task of removal of conceptual deadwood of the past is undertaken, including serendipity-based non-working hypotheses such as cortical spreading depression and patent foramen ovale-linked genesis of migraine as well as surmises and speculations linked to a body of fictional myths and assumptions (13). Absence of a biologically-plausible overview/scaffolding for migraine pathophysiologic mechanisms is the crippling missing link for in-depth scientific comprehension of the disorder (6).
Science is a process of systematic demystification. Migraine research is a classic example wherein increasing mystification through untrammeled application of technology at the bench, the accountant mentality of holding numbers/statistics including the p-value as sacred and inviolable, personal philosophic and scientific bias most clearly obvious in the critical omissions of major syntheses already available, and convoluted thinking are expected to yield significant biological dividend. Laboratory medicine is intrinsically reductionist (10), the exclusive focus on 1-2 factors obscuring the whole – seeing the trees for the wood (6). Migraine research stands the cusp of a major course correction.
1. Øie LR, Kurth T, Gulati S, et al. Migraine and risk of stroke. J Neurol Neurosurg Psychiatry 2020;91:593–604. doi:10.1136/jnnp-2018-318254
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