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CLINICAL REVIEW: Peter J Goadsby Recent advances in the diagnosis and management of migraine BMJ 2006; 332: 25-29 [Full text]

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Curious ommision of acupuncture

Martin J Breach   (6 January 2006)

Migraine: an ophthalmologist’s view.

Tanya N Moutray   (10 January 2006)

Basilar Migraine: Does it exist?

Diraviyam Balasubramanian, Surendra D Varman   (12 January 2006)

Ophthalmic aspects of headaches

Mohammad T Masoud   (12 January 2006)

Migraine is not a drug deficiency disease but a warning symptom

Ellen C G Grant   (13 January 2006)

What about the things we eat and drink?

james n hardy   (17 January 2006)

migraine in childern and adoloscents

ayesha khalid chaudhary   (18 January 2006)

Migraine - an extra risk with the combined contraceptive pill?

Hilary S Cooling   (18 January 2006)

Advances in managing migraine in women

E. Anne MacGregor, Timothy J. Steiner and Paul T. Davies - BASH guidelines writing committee   (6 February 2006)

The Peripheral Circulation in Migraine

Dr Gerard M Glass   (7 February 2006)

Migraine: “how” versus “what” of a disease process

Vinod K Gupta   (8 February 2006)

Advances in preventing migraine in women

Ellen C G Grant   (10 February 2006)

Jolly Good Show for Goadsby

Stasha C. Gominak   (21 February 2006)

Re: Jolly Good Show for Goadsby

Patricia V. Lacerda   (30 November 2007)

Curious ommision of acupuncture 6 January 2006
Martin J Breach, GP principal Haydock, WA11 0JN Send response to journal: Re: Curious ommision of acupuncture	Dear Sir, In this comprehensive review of recent advances in the diagnosis and management of migraine, it is curious that no mention was made of acupuncture. In practice, acupuncture is an extremely effective treatment for patients with migraine, and recent papers in the BMJ have added to growing evidence of its effectiveness. As a safe, effective and cost- efficient treatment for this condition, acupuncture deserves to be considered a first-line therapy. Martin Breach Acupuncture in patients with tension-type headache: randomised controlled trial. Dieter Melchart et al BMJ 2005;331:376-382 Acupuncture for chronic headache in primary care: large, pragmatic, randomised trial. Andrew J Vickers et al,BMJ, doi:10.1136/bmj.38029.421863.EB (published 15 March 2004) Acupuncture improves headache and saves money BMJ 2004;328 (27 March), doi:10.1136/bmj.328.7442.0-d Competing interests: None declared
Migraine: an ophthalmologist’s view. 10 January 2006
Tanya N Moutray, ophthalmology LATS Royal Victoria Hospital, Grosvenor Rd, Belfast,BT12 6BA Send response to journal: Re: Migraine: an ophthalmologist’s view.	As a footnote to the article on migraines by Goadsby (BMJ 2006;332:25 -9), I would like to add an Ophthalmologist’s perspective. Patients are often referred to ophthalmologists with headache associated with eye pain or headache associated with visual disturbances. To add our penny’s worth, ocular causes of headache should not be overlooked, such as acute angle closure glaucoma, iritis in younger patients or temporal arteritis in older patients. Clearly ocular signs, such as a red eye or swollen disc, should be sought. Although ophthalmic causes are frequently diagnosed, other causes such as trigeminal neuralgia, dental, sinus or ear pathology can also be made. Photopsia is a presenting complaint seen several times per day in our eye casualty. The most common diagnosis made after examination is posterior vitreous detachment but the concern is always of a retinal tear or detachment. New floaters or a shadow across the visual field, like a curtain are other features of retinal detachments. Retinal problems can be excluded by using the slit lamp biomicroscope and indirect ophthalmoscope with indentation (to visualise the ora serrata) to examine the retina, and also by excluding the presence of pigmented cells (“tobacco dust, Shaffer’s sign) in the vitreous. Acephalgic migraine is a diagnosis of exclusion, and by definition not associated with headache[1]. The nature of flashes due to acephalgic migraine has been well described: coloured rather than merely white lights, affecting both eyes, like a kaleidoscope, and gradually moving in from the periphery to the centre [2]. The temporal course of such flashes can be a fairly good indication that the basis for the symptoms is not in the eyeball, i.e. symptoms last 20 to 30 minutes and then completely resolve. “Retinal migraine” is a rare primary headache disorder, most commonly reported in women of childbearing age who have a history of migraine with aura (3). This tends to cause monocular visual loss for 10–20 minutes which is be associated with diffuse or unilateral headache(4). Exercise may precipitate retinal migraine attacks(5). The International Headache Society diagnostic criteria for retinal migraine state that the visual loss must be reversible. Otherwise further investigation would be required, particularly if other neurological signs develop, in order to exclude underlying cerebral pathology. Vasospasm of the retinal circulation or ophthalmic artery is traditionally thought to be the cause of the amaurosis-like episode of ocular migraine (4,5,6,7,8). Retinal vasospasm may also be associated with low protein C and S levels; positive antinuclear antibodies; underlying systemic diseases such as SLE (8) and antiphospholipid syndrome (8,9); giant cell arteritis or polyarteritis nodosa (4). A relationship between glaucoma and migraine has been hypothesized by some authors. A study of 460 "glaucoma suspects" (with raised intraocular pressure, but without optic disc and visual field abnormalities) and 460 controls, found a higher prevalence of migraine in the glaucoma suspects (13%), particularly in women (17%), than in controls (7%). Attacks of "ocular pain" were found to occur in 51% of those who were both "glaucoma suspects" and had migraine. (10). There have been other claims of a relationship between migraine headaches and refractive errors and also with binocular vision anomalies, but little supporting evidence. However the evidence to suggest a relationship between migraine headache and pupil anomalies, visual field defects and pattern glare is stronger. The therapeutic use of precision- tinted spectacles to reduce pattern glare (also called “visual stress”) may help some migraine sufferers (11). References: 1. Pradhan S. Chung SM. Retinal, ophthalmic, or ocular migraine. Current Neurology & Neuroscience Reports. 4(5):391-7, 2004 Sep. 2. Kanski JJ. Clinical ophthalmology. A systemic approach. Butterworth Heinemann publishing group. 3. Grosberg BM. Solomon S. Lipton RB. Retinal migraine. Current Pain & Headache Reports. 9(4):268-71, 2005 Aug 4. Burger SK, Saul RF, Selhorst JB, et al. Transient monocular blindness caused by vasospasm. N Engl J Med 1991;325:870–3. 5. Jehn A, Dettwiler B, Fleischhauer J, et al. Exercise-induced vasospastic amaurosis fugax. Arch Ophthalmol 2002;120:220–2. 6. Glaser JS. Topical diagnosis: prechiasmal visual pathways. retinal artery occlusions. Duane’s ophthalmology 2002; CD-ROM ed. Philadelphia: Lippincott Williams and Wilkins, 2002. 7. Wolter JR, Birchfield WJ. Ocular migraine in a young man resulting in unilateral blindness and retinal oedema. J Pediatric Ophthalmol 1971;8:173–6. 8. Winterkorn JMS, Kupersmith MJ, Wirtschafter JD, et al. Brief report: treatment of vasospastic amaurosis fugax with calcium channel blockers. N Engl J Med 1993;329:396–9. 9. Levine SR, Deegan MJ, Futrell M, et al. Cerebrovascular and neurologic disease associated with antiphospholipid antibodies:48 cases. Neurology 1990;40:1181–9. 10. De Marinis M. Giraldi JP. de Feo A. Rinalduzzi S. De Benedetti G. Mollicone A. Accornero N. Migraine and ocular pain in "glaucoma suspect". Cephalalgia. 19(4):243-7, 1999 May. 11. Harle DE. Evans BJ. The optometric correlates of migraine. Ophthalmic & Physiological Optics. 24(5):369-83, 2004 Sep. Competing interests: None declared
Basilar Migraine: Does it exist? 12 January 2006
Diraviyam Balasubramanian, SpR, geriatrics,Bolton Hospital,UK BL4 0JR, Surendra D Varman Send response to journal: Re: Basilar Migraine: Does it exist?	Basilar migraine: Does it exist? Prof Peter Goadsby`s review article on Migraine was very stimulating and informative. As the author points out, the diagnosis and the treatment of migraine can be made difficult by the variability of presentation of symptoms in individuals with headache. In this comprehensive review of recent advances in the diagnosis and management of migraine, it is curious that no mention was made about Basilar migraine a variant of migraine, which frequently affects young women and girls and bears a strong relationship with menstruation.(1) Since it was described in 1961 by Bickerstaff as a rare variant, basilar migraine has been shown to affect all age groups and both sexes with the usual female predominance.(2) The Headache Classification Committee of the International Headache society has come out with the following diagnostic criteria for the basilar migraine. (2) 1. The patient must have two attacks that have three of the following four characteristics: A. One or more reversible aura symptoms indicating cortical or brainstem dysfunction that -- B. Develop gradually over more than four minutes C. There is a limit to each aura of 60 minutes D. A headache that must occur within 60 minutes of the end of the aura, if it occurs at all. 2. The patient must demonstrate two or more aura symptoms of the following types: A. Visual symptoms in both the temporal and nasal fields or both eyes B. Dysarthria C. Vertigo D. Tinnitus E. Decreased hearing F. Double vision G. Ataxia H. Bilateral paresthesias I. Bilateral paresis J. Decreased levels of consciousness. And there is some evidence to suggest that triptans which are commonly used in the management of classical migraine is contraindicated in Basilar migraine. (3) References 1. Bickerstaff ER: Basilar artery migraine. Lancet, 1:15-17, January 7, 1961. 2. Tollison CD, Kunkel RS: Headache: Diagnosis and Management. Williams and Wilkins, Baltimore, 1993. 3. Klapper J, Mathew W, Nett R: Triptans in the treatment of basilar migraine and migraine with prolonged aura. Headache 2001 Nov-Dec 41(10): 981-984 Competing interests: None declared
Ophthalmic aspects of headaches 12 January 2006
Mohammad T Masoud, Senior House Officer, Ophthalmology Stirling Royal Infirmary, Stirling. UK. FK8 2AU Send response to journal: Re: Ophthalmic aspects of headaches	Professor Goadsby’s article on the different aspects of migraine was very informative. As an ophthalmologist I would like to highlight the ophthalmic aspect of headaches that we come across in the eye clinics. Ophthalmologists often have to evaluate patients with eye and facial pain, headaches and headache-related visual disturbances [1]. Some of these conditions are simple and benign, while others can be vision or life threatening. Pain around the eye can be caused by local ophthalmic disorders like conjunctivitis, uveitis, scleritis, angle-closure glaucoma, trauma and foreign bodies. These usually present as a red eye [2]. A formal slit lamp examination helps in the diagnosis of these conditions. Orbital lesions, cranial neuropathies, cavernous sinus lesions [3] and ophthalmoplegic migraine can present with periocular pain, headaches and diplopia. Ophthalmoplegic migraine is a rare syndrome frequently affecting children, in which headache is associated with ophthalmoplegia and third, fourth or sixth cranial nerves palsy [4]. If the oculomotor nerve is involved, pupillary abnormalities and ptosis also occur. Some authorities believe ophthalmoplegic migraine to be an inflammatory cranial neuropathy and not a variant of migraine [5]. Assessment of eye movements therefore forms an important part of examination in all cases of headaches. Pupil examination can provide useful information in patients presenting with headaches or ocular pain. Pupillary abnormalities accompanying headaches can be a manifestation of migraine, cluster headache, Horner’s syndrome, Adie’s pupil, parasellar neoplasms or aneurysms, internal carotid dissection or occlusion, and Tolosa-Hunt syndrome. Headache with a dilated and unreactive pupil may indicate the presence of the life threatening posterior communicating artery aneurysm. Cluster headache (migrainous neuralgia) is a migraine variant characterized by a stereotyped headache, which may be accompanied by lacrimation, conjunctival injection, rhinorrhoea or Horner’s syndrome [6]. Headaches associated with visual disturbances may be due to refractive errors, papilloedema, idiopathic intracranial hypertension, retinal migraine, optic neuritis or giant cell arteritis. Retinal migraine is a primary headache disorder in which transient monocular visual disturbances (scintillations, scotomas or blindness) occur lasting from 5- 20 minutes, simultaneously with migraine headaches or in a patient with a prior history of migraines [7] [8]. They are thought to occur because of hypoperfusion of either the eye or the optic nerve. In contrast to classical migraine, symptoms are always monocular. Classic migraine typically presents as a headache heralded by an aura consisting of bright or dark spots, zig-zags or scintillating(sparkling flashes) scotomata [6]. Flashes and floaters may be symptoms of posterior vitreous detachment or a retinal tear. Dilated fundus examination is therefore required to rule out these conditions. When dealing with headaches in the eye clinic, it is important not to forget conditions like herpes zoster ophthalmicus, trigeminal neuralgia, sinusitis, tonsillitis and dental abscesses as possible causes [2]. Careful ophthalmic examination including visual acuity, eye movements, pupils, anterior eye segments and dilated fundoscopy is the key to successful management of cases of headaches presenting to the eye clinic. References: [1] Friedman DI. The eye and headache. Ophthalmol Clin North Am. 2004 Sep;17(3):357-69, vi. [2] Tomsak RL. Ophthalmologic aspects of headache. Med Clin North Am. 1991 May;75(3):693-706. [3] Rosenblatt MA, Sakol PJ. Ocular and periocular pain. Med Clin North Am. 1991 May;75(3):693-706. [4] Farage L, Castro MA, Macedo TA, Borges PC, Souza LP, Freitas LO. Ophthalmoplegic migraine: MRI findings. Case report. Arq Neuropsiquiatr. 2005 Mar;63(1):173-5. Epub 2005 Apr 13. [5] Levin M, Ward TN. Ophthalmoplegic migraine. Curr Pain Headache Rep. 2004 Aug;8(4):306-9. [6] Kanski JJ. Clinical Ophthalmology. A Systemic Approach. Fifth Edition, Butterworth Heinemann publishing group, 2003; p.650 [7] Kenman D. Gan, Mikael S. Mouradian, Ezekiel Weis and James R. Lewis. Transient monocular visual loss and retinal migraine. CMAJ December 6, 2005; 173 (12). [8] Grosberg BM, Solomon S, Lipton RB. Retinal migraine. Curr Pain Headache Rep. 2005 Aug;9(4):268-71. Competing interests: None declared
Migraine is not a drug deficiency disease but a warning symptom 13 January 2006
Ellen C G Grant, physician and medical gynaecologist Kingston-upon-Thames. KT27JU, UK Send response to journal: Re: Migraine is not a drug deficiency disease but a warning symptom	Professor Goadsby acknowledges financial support from 10 pharmaceutical companies in his review of the management of migraine.1 He lists numerous pharmaceuticals with unpleasant side-effects in a table of preventative treatments. Also both ergot and oestrogen are still being listed as migraine treatments or preventatives. The evidence is overwhelming that use of ergot, oestrogens and progestogens are the main causes of severe and frequent migraines in women and why more women attend acute migraine clinics than men.2,3 Why is this clear cut evidence still being ignored after three decades? Headaches and migraine attacks warn of disturbed biochemistry. Both zinc and magnesium deficiencies commonly disrupt amine pathways and interfere with normal reactions to stress which results in headaches.4 The avoidance of ergot medications, progestogens and oestrogens and smoking gave a 10 -fold reduction in migraine attacks.3 Further avoidance of common dietary migraine precipitants, including alcoholic drinks, resulted in 85% of 60 migraine patients having no further attacks and no patient needed so-called “preventative pharmaceuticals”.5 1 Goadsby PJ. Recent advances in the diagnosis and management of migraine. BMJ 2006;332:25-29 (7 January), doi:10.1136/bmj.332.7532.25 2 Grant ECG, Albuquerque M, Steiner TJ, Rose FC. Oral contraceptives, smoking and ergotamine in migraine. In Current Concepts in Migraine Research. Ed. Greene R. Raven Press, New York 1978 pp 97-100. 3 Grant ECG. Oral contraceptives, smoking, migraine and food allergies. Lancet 1978; 2: 581-2. 4 Grant ECG. The pill, hormone replacement therapy, vascular and mood over-reactivity and mineral imbalance. J Nutr Environ Med 1998; 8: 105-116. 5 Grant ECG. Food allergies and migraine. Lancet 1979; 1: 966-69. Competing interests: None declared
What about the things we eat and drink? 17 January 2006
james n hardy, GP principal Bethnal Green Health Centre, 60 Florida Street, London E2 6LL Send response to journal: Re: What about the things we eat and drink?	Editor I was surprised that Professor Goadsby made no mention of dietary factors in his otherwise comprehensive clinical review of migraine (1). It has always been the first strand of my enquiry with migraine sufferers and it is often raised by patients. Does this omission suggest there is no supporting evidence and that we should abandom this line of questioning? Dr James Hardy 1. Goadsby, P. Recent advances in the diagnosis and management of migraine. BMJ 2006;332:25-29 Competing interests: None declared
migraine in childern and adoloscents 18 January 2006
ayesha khalid chaudhary, clinical attache in psychiatry st francic unit,city hospital nottingham Send response to journal: Re: migraine in childern and adoloscents	sir, the article was informative and stimulating but it would be better if migraine in childern and it;s managment would be mentioned because it is emerging as a very common problem. Competing interests: None declared
Migraine - an extra risk with the combined contraceptive pill? 18 January 2006
Hilary S Cooling, associate specialist Central Health Clinic BS2 0JD Send response to journal: Re: Migraine - an extra risk with the combined contraceptive pill?	Your review states that migraine is “not a disorder of blood vessels but one of brain function". This raises 2 questions: 1. why is migaine associated with increased risk of stroke in women using the combined oral contraceptive pill (COC)? 2. is migraine with aura still seen as evidence of brain ischaemia? If not, what is the rationale for advising women who have migaine with aura to avoid the COC (in order to avoid extra risk of stroke)? (see clinical guidance from the Faculty of Family Planning and Reproductive Health Care “First prescription of combined oral contraception” available at www.ffprhc.org.uk (pdf)) Competing interests: None declared
Advances in managing migraine in women 6 February 2006
E. Anne MacGregor, Director of Clinical Research The City of London Migraine Clinic, 22 Charterhouse Square, London EC1M 6DX, Timothy J. Steiner and Paul T. Davies - BASH guidelines writing committee Send response to journal: Re: Advances in managing migraine in women	Editor, Goadsby’s recent article is a timely update on the diagnosis and management of migraine.1 It is also appropriate to comment on recent developments in the management of menstrual attacks of migraine, which affect 50% of women with migraine.2 These attacks are typically more severe, of longer duration and less responsive to treatment compared to attacks at other times of the cycle.2,3 In spite of the general belief that women’s periods are always regular, the natural variability of the menstrual cycle can make it difficult for women with pure menstrual or menstrually-related migraine to plan their lives around unpredictable attacks.4 Trials using a fertility monitor to predict menstruation, and hence predict menstrual attacks of migraine, have been successful in improving management.4 When symptomatic treatment alone is inadequate, perimenstrual prophylaxis is indicated. Although there is little evidence for Goadsby’s recommendation of ergotamine taken at night, evidence does exist for perimenstrual oestrogen. The most recent advance has been evidence from randomized controlled clinical trials suggesting benefit of perimenstrual triptans.5,6 A number of studies included in a recent meta-analysis confirm the association between migraine and ischaemic stroke, which is strengthened by the oestrogen component of combined hormonal contraception (CHC).7 Cooling queries the rationale for contraindicating CHC in women with migraine with aura if, as Goadsby states, migraine is “not a disorder of blood vessels but one of brain function”. This is not at odds with the contraindication, as strokes at the time of migraine aura are rare.8 It is most likely that migraine with aura is a marker for increased risk of ischaemic stroke, rather than causal. Hence, it is prudent not to contribute to this risk, given that effective contraception without oestrogen is available. More specific information on diagnosis and management can be found in the UK “Guidelines for all doctors in the management and diagnosis of migraine and tension-type headache” developed by the British Association for the Study of Headache.9 These also include a section on the management of migraine in children. 1. Goadsby PJ. Recent advances in the diagnosis and management of migraine. BMJ 2006;332(7532):25-29. 2. Couturier EGM, Bomhof MAM, Neven AK, van DNP. Menstrual migraine in a representative Dutch population sample: prevalence, disability and treatment. Cephalalgia 2003;23(4):302-308. 3. MacGregor EA, Hackshaw A. Prevalence of migraine on each day of the natural menstrual cycle. Neurology 2004;63(2):351-3. 4. MacGregor EA, Frith A, Ellis J, Aspinall L. Predicting menstrual migraine with a home-use fertility monitor. Neurology 2005;64(3):561-3. 5. Newman L, Mannix LK, Landy S, Silberstein S, Lipton RB, Putnam DG, et al. Naratriptan as short-term prophylaxis of menstrually associated migraine: a randomized, double-blind, placebo-controlled study. Headache 2001;41(3): 248-56. 6. Silberstein SD, Elkind AH, Schreiber C, Keywood C. A randomized trial of frovatriptan for the intermittent prevention of menstrual migraine. Neurology 2004;63:261-9. 7. Etminan M, Takkouche B, Isorna FC, Samii A. Risk of ischaemic stroke in people with migraine: systematic review and meta-analysis of observational studies. BMJ 2005;330(7482):63-65. 8. Tzourio C, Tehindrazanarivelo A, Iglesias S, Alperovitch A, Chedru F, d'Anglejan-Chatillon J, et al. Case-control study of migraine and risk of ischaemic stroke in young women. BMJ 1995;310(6983):830-3. 9. Steiner TJ, MacGregor EA, Davies PT. Guidelines for all doctors in the management and diagnosis of migraine and tension-type headache 2nd ed, 2004. www.bash.org.uk. Competing interests: Member of the British Association for the Study of Headache (BASH) writing committee for Guidelines for all doctors in the management and diagnosis of migraine and tension-type headache
The Peripheral Circulation in Migraine 7 February 2006
Dr Gerard M Glass, Retired vascular surgeon 2 Black Causeway Road, Strangford BT30 7LX Send response to journal: Re: The Peripheral Circulation in Migraine	Editor, The peripheral circulation in migraine The review paper on migraine by Goadsby (1) did not contain any reference to studies which reported a relationship between migraine and the peripheral circulation. Evidence of an association between migraine and chronic venous insufficiency was first documented in two studies that identified a severe haemorheological disturbance in the microcirculation in continuity with varicose veins (2), and long term relief of migraine after surgical treatment of coexisting varicose veins (3). Impaired blood rheology in venous disease is associated with increased red cell aggregation and limited blood fluidity (4 -6). Long-term relief of migraine in association with persistent foramen ovale followed closure of right-to-left cardiac shunts (7,8). Migraine in patients with antiphospholipid syndrome was relieved by anticoagulant therapy (9,10) . In these studies the possible roles of microemboli or other substances in the peripheral circulation (7,8) and thrombosis or sludging (9,10) are considered. 1. Goadsby PJ. Recent advances in the diagnosis and management of migraine. BMJ 2006;332:25-9 (10 January) 2. Glass GM. Measurement of the suspension stability of blood in vivo in large blood vessels of the upper limb and in varicose veins. Clin Hemorheol 1986; 6: 413-15. 3. Glass GM, Glass GB. Relief of migraine and other headache following surgical treatment of varicose veins. Vasc Surg 1991;12:654-60. 4. Lowe GDO. Blood rheology and venous thrombosis. Clin Hemorheol 1984;4:571-88. 5. Dormandy JA. Importance of blood rheology in venous thrombosis. Clin Hemorheol 1987;7:119-22. 6. Ernst E, Matrai A, Marshall M. Limited blood fluidity as a contributory factor in chronic venous insufficiency. Clin Hemorheol 1989;4;107-11. 7. Wilmshurst P, Nightingale S, Walsh KP, Morrison WL. Effect on migraine of closure of cardiac right-to-left shunts to prevent recurrence of decompression illness or stroke or for haemodynamic reasons. Lancet 2000; 356:1648-51. 8. Wilmshurst P, Nightingale S. Relationship between migraine and cardiac and pulmonary right-to-left shunts. Clin Sci 2001;100:215-220. 9. Cuadrado MJ, Khamashda MA, Hughes GRV. Migraine and stroke in young women. QJ Med 2000; 93:317-19. 10. Hughes GRV. Migraine, memory loss, and “multiple sclerosis”. Neurological features of antiphospholipid (Hughes’) syndrome. Postgrad Med J 2002;79:81-3. Gerard M Glass, retired vascular surgeon, Strangford BT30 7LX, gmglass@btopenworld.com Competing interests: None declared
Migraine: “how” versus “what” of a disease process 8 February 2006
Vinod K Gupta, Physician Dubai Police Medical Services, Dubai, United Arab Emirates Send response to journal: Re: Migraine: “how” versus “what” of a disease process	As a medical mystery that has persisted well over two millennia and defied modern technology in particular advanced neuroimaging, the maze or catacomb (replete with cul-de-sacs) that migraine represents would have done Sherlock Holmes proud – to grapple with its intricacies and uncertainties is one of the pleasures afforded to any mind that takes Doyle’s delight to heart. Professor Goadsby’s recent overview of migraine [1] addresses none of the burning issues that confound theory and therapy in primary headache research and practice. Since research and clinical practice cannot be dissociated, the generally well-masked despair of the therapist managing migraine and other primary headache syndromes is a genuine concern with substantial ethical overtones. If we as therapists are ourselves uncertain about the pathogenesis of migraine, what we communicate to the patient will be, at best, nothing but a half-truth or a perceived truth. A leading researcher in primary headaches recently claimed in a rebuttal (Diener HC. Reply to "Topiramate for migraine prophylaxis: addressing the blood brain barrier related pharmacokinetic-pathophysiological disconnect". Int J Clin Pract, 2006—in press) that it is no longer correct to maintain that use of propranolol is empirical, as the role of this agent has been substantiated in randomised controlled trials (RCTs). RCTs in primary headaches compare one empirically used agent with another empirically used agent – but unless the scientific basis of action of therapeutic agent(s) and the pathophysiology of migraine is clearly understood, all such agents will continue to be labelled as empirical. Also, recruiting patients into RCTs for migraine preventive therapies at a time when the range of potential therapies – and the underlying scientific suppositions -- varies enormously from pharmacological agents to biological toxin (botulinum) to closure of patent foramen ovale or atrial septal defect is a clinical practice that is balanced precariously on the razor’s edge of science and ethics and is one that misuses an important clinical research tool. The critical mass of understanding that justifies RCTs has not yet been achieved in primary headache research. Finally, most consensus statements about migraine therapy are based on statistical- mathematical validity rather than biological validity. Current migraine research enterprise steadfastly refuses to countenance the following critical issues [2][3][4][5][6][7][8][9]: 1. Is migraine a pan-trigeminal disorder or an ophthalmic nerve disorder? 2. Is brain penetrability of migraine prophylactic agents pharmacokinetically inconsequential? If atenolol can prevent migraine as well as propranolol, can brain dysfunction including the putative ion channelopathy or ionopathy [1] be central to migraine pathogenesis? 3. Are there any adaptive mechanisms that delay onset of migraine aura or headache for many hours or a few days (post-stress, post-alcohol consumption, post-catastrophic psychical distress) or maintain migraine patients in prolonged remissions or prevent occurrence of migraine in approximately four-fifths of the general population that is as exposed to common daily stresses of living as are migraine patients? 4. Does migraine begin with the aura or headache or with the prodrome or (more strictly and appropriately) with the pre-prodromal phase? 5. Do migraine aura-aborting agents cross the blood-brain barrier? 6. Are tricyclic antidepressants (including the prototype, amitriptyline) overall anti-serotonergic or serotonomimetic agents? Does amitriptyline increase or decrease brain intrinsic noradrenergic function? If amitriptyline is potentially epileptogenic, how can we reconcile its fairly established migraine preventive effect with that of new anti- convulsants? 7. If brain neuronal dysfunction indeed underlies migraine, why does caffeine- or cocaine-withdrawal rather than consumption precipitate migraine? 8. Is the scintillating scotoma of migraine a monocular or a binocular phenomenon? As a monocular positive functional phenomenon, the scintillating scotoma cannot arise from the occipital visual cortex, thereby introducing a conceptual distinction in the site of origin of the scintillating scotoma and other visual auras (e.g., homonymous hemianopia). 9. Does advanced neuroimaging after onset of aura or headache reflect the “what” or the “why” of migraine? 10. Why is vomiting not a feature of cluster headache or tension-type headache? 11. Why and how does vomiting commonly remit migraine headache? 12. Is there evidence for a neuroprotective role for cortical spreading spreading depression (CSD)? 13. Can retinal spreading depression explain clinical features of the migrainous scintillating scotoma? 14. How might blood pressure be linked to migraine and to theories that maintain brain dysfunction at their core? 15. Does biology of an illness reflect (simplistic ictal arousal-related “markers”) measurements in sophisticated laboratories or the elucidation of the physiological forces that push an individual towards disease or health? The current classification of primary headache disorders is an elaborate exercise in phenomenology that has no pathophysiological or biologic basis but has rendered the creation of a unifying hypothesis for primary headaches virtually impossible. The second seemingly unsurmountable conceptual roadblock is the implication of intrinsic noradrenergic activation in the pathogenesis of migraine, as underscored in the biobehavioral model of migraine. Since noradrenergic activation is a prominent component of the stress response, the biobehavioral model of migraine does not lend an explanation either for the characteristic delay in onset of headache in a wide variety of clinical circumstances or for disappearance of prolonged headache with a step up in central autonomic activation, as is documented with General Grant’s headache [10] with the news of surrender of the Confederates in the American Civil War. Just as the atheromatous plaque underlies angina, Prinzmetal’s angina, and the several myocardial infarction-related coronary syndromes, I predict that a common idiosyncratic ocular haemo-hydrodynamic disturbance underlies migraine, cluster headache and other trigeminal autonomic cephalalgias (TACs), and tension-type / chronic daily headache, the clinical variations being an expression of ocular handling of sudden or sustained ocular choroidal congestion. To maintain that a distinct physiological basis will eventually be discovered for each of the many primary headache variants delineated in the Headache Classification of the International Headache Society is a classic example of irrational scepticism that requires complete suspension of clinical disbelief [5]. The ocular compression manśuvre will find clinical application in benign- cough induced headache [6][7] and, eventually, also in TACs. Any comprehensive theory for migraine must address all the issues discussed herein. Till then, the science of migraine will remain at its infancy and all “biological” advances will be illusionary. The hyper-focus on neuropeptides, magnesium, sex hormones, platelets, or deep white matter lesions is simply diversionary in nature [11]. No biologic meaning can yet be given to genetic linkages detected at this level of comprehension. References 1. Goadsby PJ. Recent advances in the diagnosis and management of migraine. BMJ 2006;332:25-29. 2. Gupta VK. Migrainous scintillating scotoma and headache is ocular in origin: a new hypothesis. Med Hypotheses 2006; 66:454-460. Available online 13 December 2005. 3. Gupta VK. Migraine, cortical excitability, and evoked potentials: a clinico-pharmacological perspective. Brain 2005;128:E36. 4. Gupta VK. MRI imaging in primary headaches. Radiology 2006:238:754-755. 5. Gupta VK. Classification of primary headaches: pathophysiology versus nosology? BMJ 2004; published online Jan 22. Available at: http://bmj.bmjjournals.com/cgi/eletters/328/7432/119 6. Gupta VK. Is benign cough headache caused by intraocular haemodynamic aberration? Med Hypotheses 2004;62:45-48. 7. Gupta VK. Ocular compression manśuvre aborts benign cough-induced headache. Headache 2005;45:612-614. 8. Gupta VK. Lamotrigine, migraine aura and headache: tightening the Gordian knot of primary headache? J Neurol Neurosurg Psychiatry (28 November 2005). Available at: http://jnnp.bmjjournals.com/cgi/eletters/76/12/1730#764 9. Gupta VK. Intraocular pressure, systemic blood pressure, and headache: occult pathophysiological link? Br J Ophthalmol (21 December 2005). Available at: http://bjo.bmjjournals.com/cgi/eletters/89/3/2848. 10. Jarcho S. General Grant’s headache. Bull N Y Acad Med 1967;43:1224- 1226. 11. Gupta V. Silent or non-clinical infarct-like lesions in the posterior circulation territory in migraine: brain hypoperfusion or hyperperfusion? Brain 2006;129:E39. Competing interests: None declared
Advances in preventing migraine in women 10 February 2006
Ellen C G Grant, physican and medical gynaecologist Kingston-upon-Thames, KT2 7JU,UK Send response to journal: Re: Advances in preventing migraine in women	Anne Macgregor and colleagues consider that it is prudent not to contribute to the increased risk of ischaemic stroke in women with migraine with use of progestogen/oestrogen combination contraception, given that effective contraception without oestrogen is available.1 Do they mean that women with migraine should use progestagen-only contraception which can cause breast cancer and has a high first year discontinuation rate, because of irregular bleeding, weight gain and depression, and also causes osteoporosis in young women? Migraine occurs as a result of upset amine metabolism and is therefore a disorder of both blood vessels and brain function.2 Kato and colleagues write that progesterone in hormonal preparations increases the incidence of breast cancer and that tissue factor (TF), the initiator of the extrinsic coagulation pathway, is associated with metastasis in a wide variety of cancers. They demonstrated that TF mRNA and protein are up-regulated by progesterone in the breast cancer cell line ZR-75. The increase in TF was rapid and reached a maximum at 24 hours. An increase in TF corresponded to an increase in procoagulant activity. Furthermore, progesterone increased the invasion of ZR-75 cells through a matrigel, an effect that was blocked by an antibody against TF. Because TF expression is associated with an enhanced risk of metastasis, Kato postulates that the progesterone-dependent up-regulation of TF provides a survival advantage to burgeoning breast cancer cells and may contribute to the increased risk of cancer associated with combined hormones.3 Also Mirkin and colleagues found that progesterone and progestins increased vascular endothelial growth factor (VEGF) mRNA in T47-D breast cancer cells and concludes that effect of progesterones on the angiogenic gene in the T-47 D cells may relate to breast cancer growth.4 High single doses of progestins or long-acting progestin implants may be available for use for emergency or continuous contraception but the reasons for the disastrous consequences of such use are becoming more clearly understood than ever. 1 MacGregor EA, Steiner TJ, Davies PT. Advances in managing migraine in women. http://bmj.com/cgi/eletters/332/7532/25#127693, 6 Feb 2006 2 Grant ECG. The influence of hormones on headache and mood in women. Hemicrania 1975;6:2-10. 3 Kato S, Pinto M, Carajal A. Progesterone Increases Tissue Factor Gene Expression, Procoagulant Activity, and Invasion in the Breast Cancer Cell Line ZR-75-1. J Clin Endocrinol Metab 2005; 90: 1181–1188. 4 Mirkin S, Wong BC, Archer DF. Effect of 17 beta-estradiol, progesterone, synthetic progestins, tibolone, and tibolone metabolites on vascular endothelial growth factor mRNA in breast cancer cells. Fertil Steril. 2005; 84: 485-91. Competing interests: None declared
Jolly Good Show for Goadsby 21 February 2006
Stasha C. Gominak, East Texas Neurologic Institute 700 Olympic Plaza, Suite 904, Tyler, Texas, USA 75701 Send response to journal: Re: Jolly Good Show for Goadsby	Feb 20, 2006 Dear Editors: I am writing to compliment Dr. Goadsby on his truly outstanding article on diagnosis and management of migraine. (1). His recent article comes much closer to describing the reality of what I see in my large headache practice than do most authors writing review articles today. I had become so frustrated by the direction of the headache literature over the last 10 years that I had virtually stopped reading it until I stumbled across Dr. Goadsby’s articles about a year ago. I agree with several points that he makes that I have been waiting for several years to see in the headache literature. 1) Daily headache is usually daily migraine, 2) Migraine is an ionopathy, or a channelopathy; an increased tendency to make a headache because of an ion channel or ion pump mutation. 3) Migraine is almost always accompanied by a change in mental status that cannot have to do with the blood vessels or just the trigeminal nerve. 4) Dr. Goadsby starts with the clinical presentation and asks, “where in the brain could all of these symptoms arise in unison?” then explains, in brie, his group’s theories about the posterior brain stem as the migraine generator. There were also, importantly, two recent “theories” that were missing. ”Medication overuse headache” and “Rebound headache” as cause of daily headache. A contrasting article is Dr. Dodick’s recent article in NEJM on “Chronic Daily Headache” wherein the concepts of medication overuse headache and rebound headache get all of the attention, and recent advances in the genetics of migraine are completely ignored. “Rebound headache” or “medication overuse headache” is an idea that was created by an unnamed headache expert. It was then repeated so many times that it became “truth” despite having absolutely no basis in any sort of scientific study, and now almost everyone, (with the prominent exception of Drs.Goadsby and Welch) is afraid to question its validity. (1, 3) The overwhelming majority of daily headache in my practice is migraine. Most of the patients I see have daily headache and they have headaches that have all of the features of migraine. A mild migraine becomes a severe migraine, but they are both the same underlying chemistry. There is no reason to call daily headache “transformed migraine”, it is true that it starts episodically then becomes daily, but it is just daily migraine. It seems more appropriate to change our definition of what a “migraine” can be than to add modifiers. Apparently the International Headache Society (IHS) has recently begun to turn this direction as well. (1) The migrainer has a lowered threshold for making a headache due to a genetic mutation. Migrainers also have an increased risk of lapsing into a daily headache syndrome. They can do so after mild head trauma, or when exposed to increased levels of gonadotropin releasing hormone during menopause, or when sleep deprived from a sleep disorder. When the triptans came out over 10 years ago we told our patients that they should use them only for their “migraines”. But our patients found that if they used the triptans earlier in the headache, i.e. on a milder headache, they had more consistent success in aborting them. When the milder headaches; the “tension”, or “muscle contraction”, or “sinus” headaches, are easily aborted by the triptans it means that the chemistry of those headaches are the same as “migraine” and the detailed nosology recommended by the IHS in the past is unnecessarily complex; some of the headaches are small migraine, some are big migraine. In the late 1990’s a colleague who was treating patients with Familial Hemiplegic Migraine (FHM), right after the Ca++ channel (CACN) mutation reports came out, taught me two very important things; one, verapamil worked well for those patients but it took a month before they noticed improvement and two, they had to go up to very high doses of verapamil; 360-720mg. Up until that time I, like many Neurologists, had had very patchy success using Ca++ channel blockers (CCB’s) as preventatives. However, once I started using higher doses I had about a 60% success rate with verapamil. Many of my patients with severe daily headache (whether they are taking daily pain medications or not) are cured by verapamil. Once they get to the correct dose their headaches decrease to 1-2 per month and are easily aborted with the same triptans that did not work for them before. The effect of verapamil does not wear off, there are no severe side effects and it works equally well in children, teenagers and adults. There is no reason to blame these daily headache sufferers for their own disease. Their headaches are not caused by taking medication daily. Teenagers with daily headache (who generally do not like taking medication) grow up to be adults with daily headache. Both groups respond in the same way to the right medication There is an odd disconnect currently, especially in the U.S. headache literature, between the basic science and clinical science of migraine. The basic science of migraine has advanced dramatically in the last 10 years but it is as though we are so resistant to changing our thinking that most authors tend to ignore the basic science because it does not fit with the current trigemino-inflammatory theory. There are many reported Ca++ channel mutations linked to migraine.( 4-7 ) There are Ca++ pump mutations linked to migraine. There are mouse models that show that when Ca++ channel mutations are caused in mouse astrocytes they cause a lowered threshold for spreading depression .( 8 ) Also, the basic scientists writing about their ion channel discoveries are forced by the current trigemino-inflammatory dogma (which absolutely does not have room for Ca++ channels) to add the caveat that familial hemiplegic migraine is rare, as though their findings are not applicable to migraine patients in general. This, despite the fact that the reports about FHM clearly show that most of the family members with the mutation have migraines that are not accompanied by paralysis, the family members with paralysis have headaches frequently and paralysis rarely, and a significant number of general headache patients have also been found to have Ca++ channel mutations. (9- 12) Migraine, if you ask any migrainer, is not just a disorder of head pain, but a disorder of head pain and altered level of thought and consciousness. This additional symptom is present in almost all migraine suffers as the headache becomes severe, and is present in many daily headache patients even when their head pain is mild. The migrainer often goes to bed, not just because of pain, but because of the inability to think. The trigeminal nerve does not govern global intellectual functioning therefore it cannot explain this most important effect of migraine. This is an aspect of migraine which has been relatively ignored in the headache literature, and must be explained by any theory of the pathophysiology of migraine. This symptom could be explained by widespread inhibitory input of astrocytes on neurons, which may be what happens in spreading depression, as suggested by Dr. Welch’s group. (13) It could also be explained by malfunction of the Serotonergic Raphe Nuclei (SRN), as suggested by Dr. Goadsby’s group in London. (14-17) Once the CACN mutations of FHM were published and the physicians treating them found that verapamil prevented their headaches, there was an appropriate scientific basis for large, case-controlled trials of CCB’s in headache patients. Unfortunately, to the best of my knowledge, large trials with verapamil still haven’t been published, even though flunerazine (a calcium channel blocker not available in the U.S.) is used in many clinics in Europe as first line therapy for migraine prevention, and high dose verapamil has been successful in preventing cluster headache. (18) Verapamil may be used for migraine prevention more widely than is represented in the current migraine review articles, but unfortunately most reviews mention it last, if at all. (1, 14, 19) There appear to be some distinctive features about verapamil that make it different from the other calcium channel blockers (CCB’s). (20-22) Verapamil works on L type calcium channels but all the CACN mutations reported in migraine have been P/Q type channels. (4-7 ) All of the known P/Q type blockers are poisons, which is presumably why the ion channel biochemists have not been suggesting CCB’s to treat FHM or Familial Episodic Ataxia (FEA). However, there is literature to suggest that some of the L type blockers can be P/Q type blockers at very high doses.(20-22) My experience with verapamil, as well as some of the smaller trials that have been successful, probably suggest that verapamil is chemically distinctive. Verapamil is a benzothiazepine, all of the other calcium channel blockers currently available are either dihydropyridines or phenylalkylamines. It may be that verapamil, among these three categories, is the only L type CCB that can cross over to act on the P/Q type channels at higher doses. Also there are specific issues about the state of the Ca ++ channel and the binding of the CCB’s which may explain the long delay in its action. (20-23) It is my thought that the prior clinical trials were not designed with these specifics in mind therefore the results were inconsistent. I have also had excellent success with verapamil in treating FEA, another episodic disorder of neurologic dysfunction caused by P/Q type, voltage-gated, Ca++ channel mutations. (24) I have also observed that, once controlled, they can have break through episodes of vertigo when exposed to monosodium glutamate. Migraine is clearly an episodic disorder caused by altered brain excitability. The blood flow observations in migraine were real but they are an epiphenomenon. At last, most of the European literature and several U.S. authors have disposed of the “vascular” theory of migraine and it is now mentioned only as an historical point. (25-27) Now the “trigeminal inflammatory” part of the theory deserves a similar fate. For the past decade, migraine researchers have directed their attention to the distal trigeminal nerves where they end on the vessels and the meninges, instead of the trigeminal caudal nucleus (TCN). (28) Just because the parenchyma of the brain does not have pain fibers does not mean that our experience of spontaneous headache occurs in the organs of the brain that do have pain fibers. It’s as illogical to look at the blood vessels and meninges for the cause of migraine as it would be to look at the nerve endings in the skin for the source of pain in a post stroke pain syndrome. The pain is being sent to consciousness from the TCN, just as the pain of thalamic stroke is sent to consciousness from the injured thalamus, not from the painful arm or leg. Multiple studies directed at inhibiting these inflammatory chemicals have failed to make a dent in migraine. (15) The release of inflammatory neurochemicals in the meninges are indeed real observations but the only role they play in migraine is that they make the scalp and meninges hurt after the headache has been present long enough, producing the allodynia of migraine that is receiving so much attention recently. The triptans are known to work on Serotonin 1B and 1D receptors which are feedback inhibitors of the release of Serotonin. Currently we are being taught that these medications are acting on the Serotonin receptors in cerebral blood vessels. Importantly, however, all of the symptoms of migraine; the inability to think, the mild nausea, the mild neck tension, and mild photophobia, all go away in unison when the triptans are used early in the headache. This means that either the triptans work at several different places simultaneously or there is a central generator where migraine starts, and if caught soon enough, can be turned off. (14-17,29) The SRN, in the periaquiductal grey of the dorsal brain stem is where most of the Serotonin released in the brain originates. The SRN are also one of the central volume controls for vigilance, the nausea center, the chemotrigger zone, is in the floor of the 4th ventricle, right next door, the TCN, causing headache pain, is just anterior, and just in front of the TCN is the salavatory nucleus that gives facial congestion to all of the migrainers who think they have “sinus headache”. It seems obvious that for all of these disparate symptoms to resolve in synchrony the triptans must act in an area that can produce all of them. Unfortunately, the daily headache patients are unsuccessful with the triptans because they are always too far into the headache to use them in the “brainstem phase”. However, as soon as the correct preventative converts the daily headache into an episodic headache the triptans become successful again. Sadly, most of the headache experts in the U. S. are not yet teaching this model despite the fact that the PET Scan studies showing the posterior brain stem “lit up” in migrainers are over 10 years old. (30) Once the altered excitability of the brain stem is understood many other clinical observations follow quite logically. The excitability of the brainstem and its tendency to make a migraine will be affected by other neurotransmitters like glutamate in monosodium glutamate or the Gonadotropin Releasing hormones (GRH). The effects of GRH as a neurotransmitter explain why migraine begins in boys and girls at puberty, why the headaches are less frequent in men after age 18, as they have constant levels of testosterone suppressing spikes of GRH in the brain. It explains why there is a monthly pattern in menstruating women following the GRH spikes, why migraine gets better in pregnancy while GRH is suppressed by progesterone, why very severe menstrual migraine can be stopped by leuprolide, ( 31 ) why the headaches get worse during menopause when the GRH is very elevated, and why migraine goes away after menopause. Altered excitability of the brainstem caused by an ion channel mutation also fits well with the last 7-8 years of experience using epilepsy medications for prevention of migraine. Depakote, Zonegran and Topamax have all been used very successfully as migraine preventatives and, not surprisingly, they are all channel stabilizers. (13) Any theory about the pathophysiology of migraine should also explain many long standing clinical observations in migraine such as the link between sleep deprivation and migraine. Many migraine sufferers with severe migraine since their teens have also had trouble sleeping since teen years. The periaquiductal grey is heavily involved in putting us to sleep; those patients with the inability to turn their brain off to go to sleep may have hyperactivity in the same area causing their increased incidence of migraine. Also, I have recently observed that in my patients with daily headache who fail two or three preventatives the incidence of an untreated sleep disorder such as sleep apnea is very high, even in young female patients who are not obese. My experience with verapamil has dramatically changed my level of success with treating daily headache patients, which is now a very rewarding part of my practice. I would like to encourage physicians who do clinical trials in daily headache to design large, case-controlled clinical trials of verapamil in higher doses. I would also like to challenge our clinicians who treat daily headache to take on the responsibility of finding the right preventative agent for the daily headache patient instead of blaming them for their disease. Migraine is one of the most common, disabling disorders of young, healthy people and it can be effectively cured in most patients using the medications we have today. The fact that it is so common will probably mean that there are many genes that can lower the threshold for making a headache, (34) but the underlying concept of hyperexcitability is a unifying one that combines our clinical observations with the newer scientific studies and gives us new directions for successful treatment. Stasha Gominak, M.D. East Texas Medical Center Neurologic Institute 700 Olympic Plaza, Suite 904 Tyler, Texas 75701 SGominak@Yahoo.com References: 1. Goadsby PJ Recent advances in the diagnosis and management of migraine. BMJ 2006;332-29. 2. Dodick DW. Chronic Daily Headache. NEJM 2006;354:158-165 3. Welch KMA, Goadsby PJ. Chronic daily headache:nosology and pathophysiology Curr Opin Neurol 2002;15:287-295. 4. Joutel A, Bousser MG, Biousse V, et al A gene for familial hemiplegic migraine maps to chromosome 19. Nat Genet 1993;5:40-45. 5. Gardner K, Barmada MM, Ptacek LJ, Hoffman E. A new locus for hemiplegic migraine maps to chromosome 1q31. Neurology 1997;49:1231-1238. 6. Ducros A, Joutel A, Vahedi K, Cecillon M, et al. Mapping of a second locus for familial hemiplegic migraine to 1q21-q23 and evidence of further heterogeneity. Ann Neurol 1997;42:885-890. 7. Kraus RL, Sinnegger MJ, Koschak A, Glossmann H, Stenirri S, Carrera P, Striessnig J. Three new familial hemiplegic migraine mutants affect P/Q type Ca++ channel kinetics. Jour Biol Chem, 2000;275:9239-43. 8. van den Maagdenberg AM, Pietrobon D, Pizzorusso T, Kaja S, Broos LA, et al. A CACNA1a knockin migraine mouse model with increased susceptibility to cortical spreading depression. Neuron. 2004 Mar 4;41(5):701-10. 9. Ducros A, Denier C, Joutel A, Cecillon M, et al. The clinical spectrum of familial hemiplegic migraine associated with mutations in a neuronal calcium channel. NEJM 2001;345:17-24. 10. Nyholt DR, Lea RA, Goadsby PJ, Brimage PJ, Griffiths LR. Familial typical migraine. Neurology 1998;50:1428-32. 11. Terwindt GM, Ophoff RA, Haan J, Vergouwe MN, et al. Variable clinical expression of mutations in the P/Q-type calcium channel gene in familial hemiplegic migraine. Neurology 1998;50:1105-1110. 12. Joutel A, Ducros A, Vahedi D, et al. Genetic heterogeneity of familial hemiplegic migraine. Am J. Hum Genet 1994;22:21-26. 13. Welch KM. Brain hyperexcitability: the basis for antiepileptic drugs in migraine prevention. Headache 2005;45:S25-S32. 14. Goadsby PJ, Lipton RB, Ferrari MD. Migraine – Current understanding and treatment. NEJM 2002;346:257-270. 15.Goadsby PJ. Migraine pathophysiology. Headache 2005;45:S14-S24. 16. Knight E, Goadsby PJ. The periaquiductal grey matter modulates trigemino-vascular input: A role in migraine? Neuroscience 2001;106:793- 800. 17. Knight YE, Bartsch T, Kaube H, Goadsby PJ.P/Q-type calcium- channel blockade in the periaquiductal gray facilitates trigeminal nociception: A functional genetic link for migraine? J Neurosci 2002;22:RC213. 18. Leone M, D’Amico D, Attanasio A. Verapamil is an effective prophylactic for cluster headache: results of a double blind multicentre study versus placebo. Olesen J, Goadsby PJ, eds. Cluster Headache & Related Conditions. Oxford: Oxford University Press, 1999:296-9 19.Silberstein SD Preventive treatment of headaches. 2005,Curr Opin Neurol ;18:289-92 20. Doering CJ, Zamponi GW. Molecular pharmacology of non –L-type calcium channels. Curr Pharm Design 2005;11:1887-1898. 21. Hering S, Aczel S, Kraus RL, Berjukow S, Striessnig J, Timin EN. Molecular mechanism of use-dependent calcium channel block by phenylalkylamines: Role of inactivation. Proc Natl Acad Sci; 1997;94:13323 -13328. (Ca states and binding) 22. Striessnig J. Pharmacology, structure and function of cardiac L- type Ca++ channels Cell Physiol Biochem 1999;9:242-169. 23. Kraus RL, Sinnegger MJ, Glossmann H, Hering S, Striessnig J. Familial hemiplegic migraine mutations change alpha 1A Ca++ channel kinetics. Jour Bio Chem;273:5586-5590. 24. Ophoff RA, Terwindt GM, Vergouwe MN, et al. Familial hemiplegic migraine and episodic ataxia type 2 are caused by mutations in the Ca++ channel gene CACNL1A4. Cell 1996;87:543-552 25. Pietrobon D, Striessnig J. Neurobiology of migraine. Nat Rev Neurosci. 2003 May;4(5):386-98. 26. Silberstein SD. Migraine. Lancet 2004;363:381-91 27.Welch KMA. Research developments in the physiopathology of primary headaches. Neurol Sci 2004;25:S97-S103 28. Moskowitz, MA, Bolay H, Dalkara T. Deciphering migraine mechanisms: Clues from Familial Hemiplegic Migraine genotypes. Ann Neurol 2004;55:276-280. 29. Bartsch T, Knight YE, Goadsby PJ. Activation of 5HT 1B/1D receptor in the periaquiductal gray inhibits nociception. Ann Neurol 2004;56:371-381. 30. Weiller C, May A, Limmroth V, Juptner et al. Brain stem activation in spontaneous human migraine attacks. Nature Med 1995;1(7):658 -660. 31. Murray SC, Muse KN. Effective treatment of severe menstrual migraine headaches with gonadotropin-releasing hormone agonist and “add- back” therapy. Fertility and Sterility 1997;67:390-393. 32. van den Maagdenberg AMJM, Vanmolkot KRJ, Welch KMA, de Vries B, et al. Mutations in the neuronal voltage-gated sodium channel SCN1A in familial hemiplegic migraine type 3. Cephalalgia 2005;25: 1189-1205. Competing interests: I have accepted lecture stipends from Glaxo Smith Kline and Pfizer for Headache lectures.
Re: Jolly Good Show for Goadsby 30 November 2007
Patricia V. Lacerda, Professor Brazil 30310400 Send response to journal: Re: Re: Jolly Good Show for Goadsby	I'm not an expert like you doctors, but I'm a victim of migraines since I was a baby, so I think my experience is valuable. First, I would like to apologize for any writing errors, for I'm not an english native speaker. I remember my ealy days of life only because of migraines. Every night at bed I used to see wonderful waterfalls made of multicoloured stars (that is how they looked like back then)even if my eyes were wide opened. I thought this was normal until I was a teen-ager and found out that I had migraines. My symptoms since then are: tinnitus, a bloated sensation in stomach, intestines and ear, nausea, tingling, numbness, briliant or black spots, neck and eye pain, photophobia, phonophobia, constant yawning, among other less common symptoms and, of course, the terrible left temporal pain. I have found out many different triggers like monosodium glutamate, sodium bisulfite, ethanol, menstruation, sleep disturbances, sudden changes in routine, etc, but none of these triggers alone is sufficient to cause migraine. I kept a daily record of my life for many years trying to figure out the main trigger and after 30 years I finally found it. Weather change, specifically low atmospheric pressures, associated with hot weather and storms. I can predict a storm 3 days before it happens, even contradicting meterological forecasts. I started taking flunarizine (it is available here in Brazil) only during the summer season and it worked, not preventing completely all the symptoms but the terrible headache. After more 10 years of personal research I found out the dark side of the moon... I have Ehlers-Danlos Syndrome, the vascular type, and many of the migraine symptoms are common among sufferers. A connective tissue defect could be one more candidate for migraine? Ehlers-Danlos Syndrome is far more common than once thought, many types being inherited as an autosomal dominant trait. Just a contribution of a non-expert, confused and intrigued sufferer. Competing interests: None declared