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Biophysical Semeiotics in preventing stroke: Single Patient Based Medicine beside EBM.
- Sergio Stagnaro (7 January 2005)
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The association between "migraine" and "ischemic stroke" in the Tropics is insignificant indeed
- Abdulfatai Kunle Salawu FMCP,MWACP, Sola Jegede (8 January 2005)
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Migraine: a disease in-waiting
- Vinod K Gupta (11 January 2005)
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Synergistic effects of exogenous hormones, ergot medications and smoking on migraine and strokes.
- Ellen C G Grant (13 January 2005)
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Migraine, ischaemic stoke and antiphospholipid syndrome.
- Shirish R Sangle, David P. D'Cruz, Graham RV Hughes (14 January 2005)
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OCs, HRT, Migraine, ischaemic stoke and antiphospholipid syndrome.
- Ellen C G Grant (17 January 2005)
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Hemiplegic Migraine - ? An independent risk factor for stroke
- M Mamun (1 February 2005)
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Re: Hemiplegic Migraine - ? An independent risk factor for stroke
- Ellen C G Grant (2 February 2005)
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Sergio Stagnaro, Specialist in Blood, Gastrointestinal, Metabolic Diseases. Researcher in Biophysical Semeiotics. Via Erasmo Piaggio 23 /8 16037 Riva Trigoso (Genova) Italy.
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Sirs, As regards the relation between migraine and ischaemic stroke, and as consequence, the preventing stroke, physicians encounter once again some difficulties, characteristic of EBM. In fact, the question is principally whether “my”, single patient, who is suffering NOW from migraine, could suffer in the future also from stroke or NOT! Notoriously, previous work showed no increase in the risk of haemorrhagic stroke in people with migraine, as allows to state also my personal, 47-year-long-clinical experience. However, such knowledge, including the exact migraine forms correlated with stroke, does not help at all those patients, suffering NOW from migraine, who undergo physical examination in day-to-day practice, and who will be next affected, on the contrary, by stroke. As a consequence, even in our western technologized medical world, doctors need clearly to know beside the EBM also the "overlooked" Single Patient Based Medicine (See HONCode web site 233736, www.semeioticabiofisica.it, Biophysial Semeiotic Constitutions, SPBM) , i.e., a new, original, clinical tool, sensitive and reliable in recognizing years or decades before stroke occurrence, inherited, localized impairement in cerebral bood flow microcirculation, which is especially based on congenital alteration of Endoarterial Blocking Devices, dependent, in turn, from a functional mitochondrial cytopathology (2, 3, 4, 5, 6, 7). 1) Thomas D.J. Migraine and ischaemic stroke. BMJ 2005;330:54-55 (8 January), doi:10.1136/bmj.330.7482.54 2) Stagnaro-Neri M., Stagnaro S. Indagine clinica percusso-ascoltatoria delle unità microvascolotessutali della plica ungueale. Acta Med. Medit. 4, 91,1988. 3) Stagnaro S., Valutazione percusso-ascoltatoria della microcircolazione cerebrale globale e regionale. Atti, XII Congr. Naz. Soc. It. di Microangiologia e Microcircolazione. 13-15 Ottobre, Salerno, e Acta Medit. 145, 163, 1986 4) Stagnaro S., Auscultatory percussion of the cerebral tumour: Diagnostic importance of the evoked potentials, Biol. Med., 7, 171-175, 1985 5) Stagnaro Sergio, Stagnaro-Neri Marina. Introduzione alla Semeiotica Biofisica. Il Terreno oncologico”. Travel Factory SRL., Roma, 2004. http://www.travelfactory.it/semeiotica_biofisica.htm 6) Stagnaro S., Stagnaro-Neri M., Le Costituzioni Semeiotico- Biofisiche.Strumento clinico fondamentale per la prevenzione primaria e la definizione della Single Patient Based Medicine. Ediz. Travel Factory, Roma, 2004. http://www.travelfactory.it/semeiotica_biofisica.htm 7) Stagnaro S., Stagnaro-Neri M., Single Patient Based Medicine.La Medicina Basata sul Singolo Paziente: Nuove Indicazioni della Melatonina. Travel Factory SRL., Roma, 2004. http://www.travelfactory.it/semeiotica_biofisica.htm Competing interests: None declared |
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Abdulfatai Kunle Salawu FMCP,MWACP, Consultant neurologist Federal Medical Centre,Nguru.Nigeria, Sola Jegede
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We can not agree more with DJ Thomas on his views on the association between migraine and the development of ischemic stroke.There are gray areas in the study by Etminan et al.It is difficult to rule out the effects of confounding variables.Migraine is a relatively common disease in the Tropics and indeed in the hospital where we practise.Stroke is equally a common disease,but from anecdotal report,we have found no direct association between the two diseases. Competing interests: None declared |
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Vinod K Gupta, Physician Dubai Police Medical Services, PO Box 12005, Dubai, United Arab Emirates
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In an otherwise fairly balanced overview of known evidences about the link between migraine and ischaemic stroke, Thomas (1) asserts that neither migraine nor ischaemic stroke constitutes a single disease entity, thereby giving a concrete expression to the presumption of research- oriented clinicians and neurologists that the definitive nosology of an illness critically depends upon the variations of its clinical presentations. Such a concept is misleading and must be addressed. Almost a year ago, I wrote a brief critique of the current nosologic status of migraine and its negative implications in theory and therapy (2). Identification of narrow homogenous groups actually impedes the creation of an overarching comprehensive pathophysiological system. In the absence of a definitive research vision through which to arrange the steadily increasing number of disparate pieces of the Gordian puzzle that migraine continues to evolve into, along with the enthusiastic embrace of therapeutic fashions as dizzyingly divergent as poisoning a headache (3) or closing a patent foramen ovale (4,5) – both approaches being pleaded for some ‘particular’ sections of the migraine population without regard to critical theoretical reservations or integration with extant knowledge about established pharmacotherapeutic agents, have we not ensured that migraine and other primary headaches remain an insoluble mystery of the hen-egg genre? (6). Or has the “wow” factor of technological / nosological sophistication and the ‘mathematization’ of medical research through arcane statistics that permit randomized controlled trials instilled an unhealthy hubristic disregard for basic conceptual groundwork? Semantic substitution of the term ‘condition’ or ‘syndrome’ for ‘disease’ is not the way forward. Clinical sciences do not always enjoy the precision of pathological diagnoses but unless this limitation is clearly acknowledged, clinical researchers stand to delude themselves as well as their patients. Histopathologically, ischaemic stroke is very much a single disease, with a varied distribution of pale and red infarcts and vasogenic oedema in the affected regions. Evidently, the clinical consequences of atherosclerosis are the varied presentations and outcomes of the evolution of the atheromatous plaque. Still, atherosclerosis remains a single ‘disease’. Moving forward, it is highly unlikely that the neurotransmitters (serotonin, substance P, or calcitonin-gene related peptide and others), the haematological factors (such as platelets or magnesium), the animal models of cortical spreading depression, or the clues gleaned from automated pupillometry or evoked potentials or advanced neuroimaging will emerge as critical components of the elusive pathology of migraine (7,8,9,10). These and other related research efforts merely record the inexhaustible phenomenology (or ‘what’) of migraine in the field or in the laboratory, but, at various points of time, these evidences have been expounded as significant ‘biological advances’. The term ‘biological’ remains hopelessly(?) misunderstood in migraine research (11). At the heart of the matter, nevertheless, lies a yet-to-be-evolved complex integrative synthesis involving the hitherto unexplained (but limited) protective effect of stress, the conceptual divide between forces pushing or pulling patients towards a headache or headache-free state, and the ability of pharmacotherapeutic agents that do not cross the blood- brain barrier to prevent migraine as well as to abort the aura of migraine (11,12). It is then that we might hope to approach the vexing question of characteristic lateralization (unilateral, bilateral, or side-shift) of migraine headache (or cluster headache or chronic paroxysmal hemicrania) (13,14). Today, lateralization of migraine headache is not even an issue, a testament to the immense paradigm shift and hard work that lies ahead. Migraine is indeed a disease, a disease-in-waiting, waiting to be discovered, waiting for our comprehension to evolve sufficiently to grapple with its mystery. The incalculable but hidden intellectual cost of serendipity that the advent of beta-blockers ushered into migraine research includes implication of the adaptive sympathetic nervous system into its pathogenesis (15). References 1. Thomas DJ. Migraine and ischaemic stroke. BMJ 2005;330:54-55. 2. Gupta VK. Classification of primary headaches: pathophysiology versus nosology? BMJ Online (22 January 2004). Available at: http://bmj.bmjjournals.com/cgi/eletters/328/7432/119 3. Gupta VK. Botulinum toxin for treatment of migraine: randomized controlled trials versus basic sciences. J Neurol Neurosurg Psychiatry 2004 [Online -- 12 July 2004]. Available at: http://jnnp.bmjjournals.com/cgi/eletters/75/7/951#212 4. Gupta VK. Closure of atrial septal defect and migraine. Headache 2004;44:291. 5. Gupta VK. Closure of patent foramen ovale to prevent migraine: more trials or more reflection? Neurology. 2004;63 1760-1761. Published online 8 June 2004. [Available at: http://www.neurology.org/cgi/eletters/62/8/1399#1437 6. Gupta VK. Bureaucratisation of migraine. Lancet Neurology 2004;3:396. 7. Gupta VK. Parasympathetic hyperfunction during migraine attacks. Headache 2004;44:730. 8. Gupta VK. Platelet-leukocyte adhesion, migraine, and stroke: a bioclinical perspective. J Neurol Neurosurg Psychiatry 2004 [Online -- 12 July 2004). Available at: http://jnnp.bmjjournals.com/cgi/eletters/75/7/984#197 9. Gupta VK. Magnesium therapy for migraine: do we need more trials or more reflection? Headache. 2004;44: 445-446. 10. Gupta VK. Cortical spreading depression is neuroprotective: the challenge of basic sciences. Headache 2005 (February, in press). 11. Gupta VK. Stress, adaptation, and traumatic-event headaches: pathophysiologic and pharmacotherapeutic insights. BMC Neurology 2004. Available at: http://www.biomedcentral.com/1471-2377/4/17/comments#106454 12. Gupta VK. Management of migraine aura: basic theoretical and clinical reconsiderations. Headache. 2004 (In press). 13. Gupta VK. Non-lateralizing brain PET changes in migraine: phenomenology versus pharmacology? Brain 2004;127:E12. 14. Gupta VK. Neuroimaging in hemicrania continua: dissociation between technology and basic sciences? Headache [In press]. 15. Gupta VK. Sympathetic nervous system dysfunction in migraine: pearls and pitfalls in the theorizing process. Headache 2004; 44: 841-842. Competing interests: None declared |
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Ellen C G Grant, physician and gynaecologist 20 Coombe Ridings, Kingston-upon-Thames, KT2 7JU, UK
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D J Thomas describes migraine as a common condition but it is more helpful to regard migraine as a warning of reversible vascular over- reactivity with an increased the risk of ischaemic stroke, especially for oral contraceptive (OC) users.1 He refers to a single study which did not find an increased risk of haemorrhagic stroke in migraine patients. However, Petitti et al reported a positive interaction between current use of low-dose OCs and smoking and haemorrhagic stroke.2 The world’s largest OC cohort study by the UK’s Royal College of General Practitioners found users had increases in morbidity and mortality for over 60 conditions. The range of vascular diseases increased in smokers or non smokers taking OCs included cerebrovascular accidents, hypertension, heart disease, peripheral vascular disease as well as headaches and migraines, venous thrombosis and strokes.3 Ergotamine medications and OC pills (or HRT or any oestrogen/progesterone use) are main precipitants of frequent headaches, severe migraines and reversible hypertension. This is apparently still unwelcome news for neurologists or doctors running Migraine Clinics.4 There was uproar at an international migraine conference in 1979 when I presented evidence that most headaches and migraine attacks were preventable without medication by avoiding precipitants.5 A neurologist joked, “Migraine is our bread and butter”. Both DJ Thomas and Anne MacGregor want women attending migraine clinics to be able to use oral contraceptives in spite of Etminam et al’s evidence of an 8.7 times increased risk of stroke.6 Kamran Abbasi described James Drife’s BMJ Editorial as a beacon of light when he pointed out that in most of the world the risks of women dying in childbirth was much greater than the then estimated risk of death from taking OCs. 7,8 This is not a “like for like” comparison because family sizes were reduced in the UK for decades before OCs became available. In developed countries maternal deaths from thrombosis are increased by previous contraceptive hormone use causing clotting syndromes such as lupus erythematosus and the anti-phospholipid syndrome. In the 1950s and 1960s many maternal deaths were due to post partum stilboestrol. Ergot medications are still used to prevent bleeding. In 1981 Drife had also written that if OCs doubled the risk of breast cancer that would be very serious because breast cancer is so common.9 Now evidence from the Million Women Study (MWS) confirms current use of progesterones and oestrogens doubles the risk of breast cancer. Less than one year’s exposure to combined hormones accounted for much of this increased risk in both the MWS and the Women’s Health Initiative Study. Do neurologists still not appreciate that headaches and migraines warn of wide spread vascular and immunological changes with increased risk of numerous vascular diseases and cancers? All hormonal contraceptives and OCs are predominantly or exclusively progestogenic. Progesterones cause more breast cancer than oestrogens given alone, and are main precipitants of headaches or migraine and arteriolar thickening, either at the end of a menstrual cycle or throughout treated cycles. More women developed migraine with lower 0.05mg oestrogen combinations than with higher 0.1mg oestrogen combinations. Oestrogen doses in OCs were reduced to 0.05mg or lower in 1969 in an unsuccessful attempt to prevent venous thrombosis because progesterones became more powerful. Micronisation doubled potency and norgestrel, levonorgestrel, desogestrel and gestodene are 2.6, 5.3, 9 and 12.6 times more powerful than norethisterone. Most studies have found extra increased risks of venous thrombosis with third generation pills of 1.4 to 4 times compared with second generation pills. 10 Oestrogen doses in OCs are usually too low to prevent drying up of secretions and reduced blood loss. Monoamine oxidase activities are increased for a few days premenstrually but continuously during progesterone use, increasing the risk of depressive mood changes, early discontinuation, use of anti-depressive medication and suicide. Women attending Migraine Clinics also usually have mood problems. Thomas writes that patients feel better with ergot medications although using vasoconstrictors like ergot or triptans is a theoretical concern. The Canadian Medical Association has warned in a Health and Drug Alert of the risk of stroke, gangrene from ergot drug interactions.11 Current users of ergot alkaloids were more likely to have a stroke than other migraineurs (adjusted RR 1.49, 95% CI 0.93-2.41) in a recent study.12 The synergistic effects of exogenous hormones, ergot medications and smoking greatly increase the frequency and severity of migraines and therefore must inevitably increase the risk of strokes. 1 Thomas DJ. Migraine and ischaemic stroke. BMJ 2005: 330: 54-55. 2 Petitti DB, Sidney S, Bernstein A, et al. Stroke in users of low dose contraceptives. N Engl J Med 1996; 335: 8-15. 3 Galbraith J I. A methodological review of the Royal College of General Practitioners’ oral contraception study. J Nut Environ Med 1998; 8: 187-194. 4 Grant ECG. Hormonal contraceptives cause migraine, ischaemic and haemorrhagic strokes.http://bmj.com/cgi/eletters/330/7482/63#92460, 13 Jan 2005 5 Grant ECG. Clinical review of headache. htp://bmj.com/cgi/eletters/325/7369/881#26539, 27 Oct 2002. 6 Etminan M, Takkouche B, Isorna FC, and Samii A. Risk of ischaemic stroke in people with migraine: systematic review and meta-analysis of observational studies. BMJ 2005; 330: 63. 7 Abbasi K. Website of the week: Oral contraceptives. BMJ 2001 323: 172. 8 Drife J O. The third generation pill controversy ("continued"). BMJ 2001; 323: 119-120. 9 Drife J O. Breast cancer, pregnancy and the pill. BMJ 1981: 283:778 -79. 10 Kemmeren JM, Algra A, Grobbee DE. Third generation oral contraceptives and risk of venous thrombosis: meta-analysis. BMJ 2001; 323: 131-134. 11 Wooltorton E. Risk of stroke, gangrene from ergot drug interactions. CMAJ April 15, 2003; 168 (8). 12 Velentgas P, Cole JA, Mo J, Sikes CR, Walker AM. Severe vascular events in migraine patients. Headache. 2004; 44: 642-51. Competing interests: None declared |
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Shirish R Sangle, Clinical Fellow Lupus Research Unit, The Rayne Institute, Lambeth Wing, St Thomas' Hospital, London SE1 7EH, UK, David P. D'Cruz, Graham RV Hughes
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Sir, The recent BMJ paper by Etminan et al (1) and editorial by A Thomas, again focuses on the link between migraine and stroke. Over and above a statistical ‘evidence based’ review, we would like to highlight one possible strong direct link, touched on by Thomas. The prothrombotic disorder, antiphospholipid syndrome (APS) , described 21 years ago in this journal (2), is characterized by a tendency to migraine headache and to arterial stroke (3). In individuals under 45 with antiphospholipid antibodies (aPL) the risk of stroke has been put as high on 1 in 5; indeed in younger individuals the risk is even stronger (3).The headaches in APS are frequently migrainous, with a history often going back to the teens. In many patients there is a family history: In a recent questionnaire carried out in our unit, no less than 59% of APS patients gave a positive family history of severe headaches (unpublished observation). Given the clinical association, and the high risk of thrombosis, including stroke, in aPL positive individuals, we believe that APS is a potentially important link between migraine and stroke. Two factors make precise associations difficult – firstly the complexity of the definition of headache subtypes, and secondly, the breadth of APS – the recognition that severe complications, including stroke, can occur in the presence of weak positive or even borderline results. In some ways, these caveats make the need for careful studies of APS and stroke even more pressing. References: 1. Etminan M, Takkouche B, Isorna FC, Samii A. risk of ischaemic stroke in people with migraine: systemic review and meta-analysis of observational studies. BMJ. 2005;330: (7482):63. . 2. Hughes GR. Thrombosis, abortion, cerebral disease and the lupus anticoagulant. BMJ 1983; 287: 1088-9. 3. Hughes GR. Migraine, memory lossand “multiple sclerosis”: neurological features of the antiphospholipid (Hughes) syndrome. Postgrad Med J 2003; 79: 81-3. Competing interests: None declared |
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Ellen C G Grant, physician and medical gynaecologist Kingston-upon-Thames, KT2 7JU,UK
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Editor- Shangle, D’Cruz and Hughes highlight the importance of family history in the development of Systemic Lupus Erythematosus (SLE) and Anti- phospholipid Syndrome (APS).1 However the huge increase in the incidence of SLE over the past decades ( from 1.51 per 100,00 in 1950-79 to 124.0 per 100,000 in 1995) suggests that contraceptive hormones are HRT are the main causes of the recent increases.2,3 Professor Hughes records a nine to one female/male sex ratio for APS, which he estimates affects 10% of Pill thrombosis cases.4 In the RCGP OC study takers had 2-5 times more risk of dermatological and neuropsychiatric manifestations of SLE including thrombosis, migraine and epilepsy. Women stopping the pill for side-effects had an abortion rate of 31%. The Nurses’ Health Study found the risk of SLE increased with duration of HRT use and was 2.5 for current users. Hormones use causes generalised immune dysfunction. Hormones users and smokers and ergot users with migraine tended to have higher or lower serum levels of IgG, IgM and IgA which generally return to normal when these precipitants are discontinued. Steroids and further immunosuppressant medications can cause increases in osteoporosis, vascular diseases and cancers.5 Avoiding precipitants and correcting zinc, copper, magnesium, B vitamin and EFA levels are effective and safe treatments.6 Was Dr Thomas in error when he used the word leucoaraiosis which is the name given to periventricular hypo-dense lesions in cerebral CAT scans, in his explanation of CADASIL?7 Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) appears to be the most common form of hereditary stroke disorder. CADASIL thought to be associated with arterial smooth muscle degeneration linked to mutations in the Notch3 gene, whose product is a transmembrane receptor that functions in cell-cell communication. However, Raflowska et al found on electron microscopy, deposits of granular osmiophillic material (GOM) not only in cerebral arteries and veins but also in cerebral capillaries and in vessels of the internal organs.8 The pathological process in CADASIL was generalized and involved also small vessels devoid of smooth muscle cells. Generalised arterial, venous and small vessel abnormalities throughout the body can be caused by short or longer exposures to exogenous progesterones and oestrogens. Women with a genetic risk of CADASIL, and other clotting syndromes would be expected to have a particularly high risk of hormone-induced strokes. 1 Sangle SR, D'Cruz DP, Hughes GVR. Migraine, ischaemic stoke and antiphospholipid syndrome. http://bmj.com/cgi/eletters/330/7482/54#92692, 14 Jan 2005 2 Ruiz-Irastoroza G, khamasta MA, Castellino G, Hughes GVR. Systemic lupus erythematosus. Lancet 2001: 357: 1027-32. 3 Grant ECG. Systemic lupus erythematosus. Lancet 2001: 358: 586. 4 Grant ECG. The Hughes (antiphospholipid) Syndrome. J Nutr Environ Med 1998: 8:153-57. 5 Stratta P, Canavese C, Santi S, et al. Systemic lupus erythematosus. Lancet 2001: 358: 586-7. 6 Grant ECG. The pill, hormone replacement therapy, vascular and mood over-reactivity, and mineral imbalance. J Nutr Environ Med 1998; 8: 105- 116. 7 Thomas DJ. Migraine and ischaemic stroke. BMJ 2005: 330: 54-55. 8 Rafalowska J, Fidzianska A, Dziewulska D, Podlecka A, Szpak GM, Kwiecinski H. CADASIL or CADVaSIL? Neuropathology. 2004; 24: 16-20. Competing interests: None declared |
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M Mamun, Consultant Physician Medway Hospital, Gillingham, Kent, UK ME7 5NY
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I note Etminan et al's meta-analysis of observational studies suggesting that migraine with or without aura may be an independent risk factor for ischaemic stroke, and Thomas's editorial about the shortcomings of such studies and systemic reviews(1,2). In our acute stroke unit admitting over three hundred suspected acute stroke cases over a period of one year (January - December 2004), there were two cases of hemiplegic migraine (both with aura) - one familial and the other sporadic type. The familial one was a seventy year old woman who was admitted with left sided weakness, slurred speech and headache. She has had headache since a teenager, and continues to get attacks several times a week even as an older person but not always associated with hemiplegia. However, over the last ten years or so, she had at least four attacks of hemiplegic migraine requiring hospital admission - and on each occasion there was no clinical or imaging evidence of stroke, and the recovery was near complete after several days as one would expect in this situation. The second (sporadic) case was that of a twenty five year old pregnant woman in her mid-trimester who also had left hemiplegia and facial drooping associated with migraine. This lasted for about a week with good recovery. She has had similar attacks in 1999 and twice in 2004. Again there was little clinical or imaging evidence of new or old stroke. Although these are only two cases, given the relatively long follow-up, one has to be justifiably cautious about the validity of the conclusion drawn from the meta-analysis for observational studies. References: 1.Etminan M et al. Risk of ischaemic stroke in people with migraine: systemic reviews and meta-analysis of observational studies. BMJ 2005;330:63-5. 2.Thomas D J. Migraine and ischaemic attack. BMJ 2005;330:54-5. Competing interests:
None declared
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Ellen C G Grant, physician and medical gynaecologist Kingston-upon-Thames, KT2 7JU,UK
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Dr Mamun describes two women with hemiplegic migraine, out of 300 patients, who were admitted to his hospital’s acute stroke unit in 2004.1 Was the reason the 70 year-old woman with familial migraine had been having recurrent headaches since teenage the use of ergot medication? Did she also use HRT at the menopause? In my experience these are the commonest reason for persistent and frequent severe migraine attacks in older women.2 Was the reason the 25 year-old pregnant woman with sporadic migraine suffered from several attacks of hemiplegic migraine in the past 5 years use of the contraceptive pill before she became pregnant? Did she have the anti-phospholipid syndrome or lupus erythematosus, both of which are more likely if she was one of the 90% of young women who have used progesterones and oestrogens before their first pregnancy?3 ellengrant@onetel.com 1 Mamun M. Hemiplegic Migraine - ? An independent risk factor for stroke (bmj.com,1 February 2005) 2 Grant ECG. Synergistic effects of exogenous hormones, ergot medications and smoking on migraine and strokes. http://bmj.com/cgi/eletters/330/7482/54#92510, 13 Jan 2005 3 Grant ECG. OCs, HRT, Migraine, ischaemic stroke and antiphospholipid syndrome. http://bmj.com/cgi/eletters/330/7482/54#92829,15 Jan 2005 Competing interests: None declared |
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