Dear Editor,

Old medical theories, like myths, never die. In every era, long after the initial excitement evaporates, scientific theories that have not gathered logical strength through increasing clinical associations are recycled to address current perceptions. Such theories, like myths, offer a vicarious resolution of the ignorances that lies between our insecurities and our expectations.[1,2] Wilmshurst et al. recently suggest once again that platelets may have a role in the pathogenesis of migraine.[3] They base this impression on the seeming efficacy of the combination of clopidogrel and aspirin in comparison to aspirin alone in managing attacks of migraine with aura in patients who had undergone closure of persistent foramen ovale or atrial septal defect; this salutary effect of combined anti-platelet regimen is believed to work through an effect on serotonin stores.

Migraine theory and therapy is a long chain of tenuously linked assumptions coupled to serendipity of a high order.[4] Several lines of evidence challenge the presumed pathogenetic link between platelets, serotonin, and migraine as well as the conclusions of the authors: (i) Platelet hyperaggregability has been noted in a range of other medical conditions unrelated to migraine and is found with high levels of stress. Stress affects the vast majority of the general population but migraine afflicts only about one-fifth of humankind. (ii) Propranolol, the gold standard migraine prophylactic agent, enhances platelet aggregability [5]. (iii) Contrary to the general impression, evidence for migraine prophylactic value of aspirin is poor.[6] (iv) A negative correlation exists between migraine and antibodies to phospholipids (the membrane- binding moiety increasing platelet aggregability), suggesting a degree of protection against development of migraine.[7] (v) Migraine headache has been reported in patients with thrombocytopenia.[8] (vi) Although platelet aggregation and adhesion are commonly increased in diabetes mellitus, it is hypogylcaemia rather than hyperglycaemia that precipitates migraine.[9] (viii) Menstrual migraine typically improves with pregnancy[10] but estrogens increase epinephrine induced platelet aggregation.[11] (ix) Migraine-like headache is a sequela of cocaine use, [12,13]. but cocaine inhibits platelet aggregation and dissociates preformed platelet aggregates [14]. (x) Amitriptyline, a first-line migraine prophylactic agent, unambiguously stimulates brain noradrenergic as well as serotonergic function.[15] (xi) Development of carcinoid tumour remarkably decreased migraine frequency and intensity leading to a complete remission with postoperative recurrence.[16] (xii) Nicotine increases platelet aggregation [17] but is considered relatively unlikely to lead to migraine.[18] (xiii) Nitric oxide (and endothelium-derived relaxing factor) putatively involved in vascular headaches associated with exercise or infection inhibits platelet aggregation and adhesion.[8,19]

Proponents of the platelet theory of migraine postulate a parallel between the platelet and the neuron by suggesting that platelet activation mirrors trigeminovascular system inflammation. Believing that (peripheral) platelet function tells us anything about brain neuronal function involves complete suspension of scientific disbelief.[15] No systemic influence, including platelet dysfunction, can rationalize the characteristic lateralization (unilateral, bilateral or side-shift) of migraine headache.[21] For internists, cardiologists, and neurologists (especially researchers into primary headaches) familiar with the useful effect of inhibition of platelet aggregation in cardiovascular and cerebrovascular medicine, it is indeed difficult to concede that a similar benefit might not be available to migraine patients. Nevertheless, if migraine has to progress from a vaguely-understood syndrome to a properly defined disease, theories that clutter our thinking need to be addressed squarely and discarded. The platelet theory of migraine is one such concept that might best be passed into history.

Wilmshurst et al.[3] have also reported increased frequency and severity of migraine with aura attacks immediately following closure of atrial shunts, a phenomenon that has important pathophysiological implications. Yankowsky and Kuritzky have earlier reported on aggravation of migraine with aura into a daily pattern with clocklike precision after closure of an atrial septal defect (ASD).[21] Importantly, there is no suggestion of a causal link between ASD and migraine but closure of ASD appears to be associated with appearance or worsening of migraine with aura.[3,21] In uncomplicated ASD, correction of the septal defect would lead to decrease in the elevated right atrial pressure and plasma atrial natriuretic peptide levels would decrease correspondingly.[22] ANP appears to play a role as a counterregulatory hormone in many disorders characterized by volume expansion, including hypertension; also, orthostatic hypotension, a characteristic feature of migraine, is associated with lower levels of ANP, and suggests that noradrenergic hypofunction may be involved in the pathogenesis of migraine.[23,24] A compensatory or adaptive function has been attributed to sympathetic hypofunction associated adrenergic receptor hypersensitivity.[25] The fact that migraine prophylactic agents such as beta-blockers or calcium antagonists or clonidine invariably lower elevated blood pressures or tend to maintain normotension – while only rarely causing symptomatic hypotension – indicates that a low blood pressure is an adaptive feature in migraine. Nausea and vomiting is another facet of a complex vasopressin -mediated adaptive mechanism in migraine.[26,27] Dramatic aggravation of migraine following atrial shunt closures indicates substantial alteration of some physiological variable with prominent circadian variation and a critical influence on the primary pathophysiological process in migraine.[22] In ASD, the reduced filling pressure of the left ventricle causes a smaller than normal stroke volume and reduced cardiac output; consequently a relatively small aorta is commonly seen. Following closure of large atrial shunts, immediate improvement in left ventricular stroke volume and cardiac output occurs. Precipitation of migraine following closure of atrial septal defect [3,21] suggests that a higher stoke volume / cardiac output might worsen or unmask a migrainous diathesis.[22,28]

The theoretical basis for a non-neuronal non-vascular origin of migraine has been recently elucidated.[29] A selective involvement of the ophthalmic division of the trigeminal nerve is likely in migraine and other primary headaches; mechanical deformation of the corneo-scleral envelope by ocular choroidal venous congestion and rise of intraocular pressure (IOP) has been proposed to underlie both the scintillating scotoma as well as the headache of migraine.[29,30] In contrast to the brain, the eye is a low-volume but far more highly vascularized organ; the eye is anatomically less capable of accommodating any sudden increase in stroke volume. The cardiac output increasing effect of closure of larger atrial shunts is somewhat comparable to the immediate peripheral arterial perfusion enhancing effect of glyceryl trinitrate (GTN) manifest by flushing of face and throbbing headache.[31] GTN is the best available experimental human model for migraine; it generally causes migraine headache a few hours after consumption,[32] at which time substantial venous pooling likely develops at the ocular choroidal venous plexus in migraine patients due to an intrinsic regional ocular sympathetic hypofunction. Propranolol, atenolol, metoprolol, nadolol, clonidine, flunarizine, and verapamil lower the IOP, further supporting the nexus between migraine, autonomic dysfunction, and intraocular pressure.[29] Immediate aggravation of migraine attacks after closure of atrial shunts spontaneously regresses after a few months;[21] ocular tissue creep at the level of the corneo-scleral envelope likely dissipates the headache- provoking effect of increased cardiac output in patients with ASD.[29]

Like trait or basal autonomic function, endogenous pain control mechanism, and corneo-scleral distensibility, increase in cardiac output after atrial shunt closure is likely to be a highly variable, idiosyncratic function; these important confounding features might well explain the results of the studies of Wilmshurst et al.[3]

References

1. Gupta VK. Migrainous stroke: are antiphospholipid antibodies pathogenetic, a biological epiphenomenon, or an incidental laboratory aberration? Eur Neurol 1996;36:110-111.

2. Lévi-Strauss C. Then structural study of myth; in Lévi-Strauss C (ed): Structural Anthropology. Harmondsworth, Peregrine, 1977, pp 206-231.

3. Wilmshurst PT, Nightingale S, Walsh KP, W L Morrison WL. Clopidogrel reduces migraine with aura after transcatheter closure of persistent foramen ovale and atrial septal defects. Heart 2005;91:1173-1175.

4. Gupta VK. PFO and migraine: pearls and pitfalls in the theorizing process. Heart (26 October 2005). Available at: http://jnnp.bmjjournals.com/cgi/eletters/74/5/680#55.

21. Yankovsky AE, Kuritzky A. Transformation into daily migraine with aura following transcutaneous atrial septal defect closure. Headache 2003;43:496-498.

22. Gupta VK. Closure of atrial septal defect and migraine. Headache;2004:44:291-292.

23. Gotoh F. Komatsumoto S, Araki N, Gomi S. Noradrenergic nervous activity in migraine. Arch Neurol 1984;41:951-5.

24. Araki N. Autonomic nervous activity in migraine [abstract]. Rinsho Shinkeigaku 1995;35:1336-1338.

25. Boccuni M, Alessandri M, Fusco BM, Cangi F. The pressor hyperresponsiveness to phenylephrine unmasks sympathetic hypofunction in migraine. Cephalalgia 1989;9:239-245.

26. Gupta VK. Conceptual divide between adaptive and pathogenetic phenomena in migraine: nausea and vomiting. Brain 2004;127:E18.

27. Gupta VK. A clinical review of the adaptive potential of vasopressin in migraine. Cephalalgia 1997;17: 561-569.

28. Gupta VK. Percutaneous closure of patent foramen ovale reduces the frequency of migraine attacks. Neurology 2004;63:1760-1761

29. Gupta VK. Migrainous scintillating scotoma and headache is ocular in origin: a new hypothesis. Med Hypotheses 2005 (In press).

30. Gupta VK. Glyceryl trinitrate and migraine: nitric oxide donor precipitating and aborting migrainous aura. J Neurol Neurosurg Psychiatry (22 October 2005). Available at: http://www.jnnp.com/cgi/eletters/76/8/1158#708.

31. Thomsen LL, Iversen HK, Brinck TA, Olesen J. Arterial supersensitivity to nitric oxide (nitroglycerin) in migraine sufferers. Cephalalgia 1993;13:395-9.

32. Thomsen LL, Kruuse C, Iversen HK, Olesen J. A nitric oxide donor (nitroglycerin)triggers genuine migraine attacks. Eur J Neurol 1994;1:73- 80.

Dear Editor,

We have read the article[1] with great interest. Selection of the 23 patients is not clearly mentioned here. There is a lack of some other information too. Once the chest pain started, after what time those patients were selected for angioplasty? What was the percentage of lumen narrowing or stenosis? Was the stenosis complicated or not? What was the material used for primary angioplasty?

Rapid time to treatment with thrombolytic therapy is associated with lower mortality in patients with acute myocardial infarction (MI). Study[2] suggests that physicians and health care systems should work to minimize door-to-balloon times and that door-to-balloon time should be considered when choosing a reperfusion strategy. Time from acute MI symptom onset to first balloon inflation and by time from hospital arrival to first balloon inflation (door-to-balloon time) plays an important role in management of MI.

In a study[3] showed that, patients with AMI treated at hospitals with high or intermediate volumes of primary angioplasty had lower mortality with primary angioplasty than with thrombolysis, whereas patients with AMI treated at hospitals with low angioplasty volumes had similar mortality outcomes with primary angioplasty or thrombolysis. To prevent restenosis or reinfarction in previously stenosed coronary vessels drug eluting stent (paclitaxel-eluting stent) proves superior to bare metal stent.[4] In patients with in-stent restenosis, sirolimus- or paclitaxel-eluting stents is superior to conventional balloon angioplasty for the prevention of recurrent restenosis. Sirolimus-eluting stents may be superior to paclitaxel-eluting stents for treatment of this disorder.[5]

Reference:

1. Should primary angioplasty be available for all patients with an ST elevation myocardial infarction? A de Belder. Heart 2005;91:1509-1511; doi:10.1136/hrt.2004.059485.

2. Christopher P. Cannon; C. Michael Gibson; Costas T. Lambrew; David A. Shoultz; Drew Levy; William J. French; Joel M. Gore; W. Douglas Weaver; William J. Rogers; Alan J. Tiefenbrunn Relationship of Symptom-Onset-to-Balloon Time and Door-to-Balloon Time With Mortality in Patients Undergoing Angioplasty for Acute Myocardial Infarction JAMA, Jun 2000; 283: 2941 - 2947.

3. David J. Magid; B. Ned Calonge; John S. Rumsfeld; John G. Canto; Paul D. Frederick; Nathan R. Every; Hal V. Barron; for the National Registry of Myocardial Infarction 2 and 3 Investigators Relation Between Hospital Primary Angioplasty Volume and Mortality for Patients With Acute MI Treated With Primary Angioplasty vs Thrombolytic Therapy JAMA, Dec 2000; 284: 3131 - 3138.

4. Gregg W. Stone; Stephen G. Ellis; Louis Cannon; J. Tift Mann; Joel D. Greenberg; Douglas Spriggs; Charles D. O'Shaughnessy; Samuel DeMaio; Patrick Hall; Jeffrey J. Popma; Joerg Koglin; Mary E. Russell; for the TAXUS V Investigators Comparison of a Polymer-Based Paclitaxel-Eluting Stent With a Bare Metal Stent in Patients With Complex Coronary Artery Disease: A Randomized Controlled Trial JAMA, September 14, 2005; 294: 1215 - 1223.

5. Adnan Kastrati; Julinda Mehilli; Nicolas von Beckerath; Alban Dibra; Jörg Hausleiter; Jürgen Pache; Helmut Schühlen; Claus Schmitt; Josef Dirschinger; Albert Schömig; for the ISAR-DESIRE Study Investigators Sirolimus-Eluting Stent or Paclitaxel-Eluting Stent vs Balloon Angioplasty for Prevention of Recurrences in Patients With Coronary In-Stent Restenosis: A Randomized Controlled Trial. JAMA, January 12, 2005; 293: 165 - 171.

Dear Editor,

The data presented in Welsh et al.'s paper assessing variations in practice across the 12 countries in the ASSENT 3 PLUS trial may not be representative of UK practice since each of the four constituent countries of the UK have distinct health systems.

In England and Wales, both of which have national standards for the care of STEMI patients -National Service Frameworks- and in which all 130 hospitals caring for heart attack patients participate in the national audit of myocardial infarction, use of emergency ambulance services as opposed to the requirement to contact a primary care physician first, suggested by Welsh et al. as a reason for UK delay, was as reported by Birkead et al. in 2002-03 67% of patients with a final diagnosis of an acute coronary syndrome called for an emergency ambulance and 16.2% contacted the primary care practitioner.

Dear Editor,

We thank Dr Tom Quinn for his interest in this manuscript. His letter addresses the realities of intra-country variation versus inter-country variation in pre-hospital care. Dr Quinn appropriately points out in his letter to the editor that the United Kingdom is made up of distinct nations with distinct health systems. We have recognized this issue in the manuscripts limitations section, “Because our study is based on a non- randomized assessment of variation in process of care across international boundaries in selected centres participating in ASSENT 3 PLUS, it may not be generally representative of the standard of pre-hospital care in the respective country and therefore has inherent limitations”. It is encouraging that the past practice of contacting a primary care physician prior to activate the emergency medical services is being modified, specifically in England and Wales, with direct activation of the emergency medical system and more expedited care.