CASE VIGNETTE

“Then I can’t see and I start to panic. How am I going to work? How am I going to get home?”

Theresa, a 26-year-old unmarried administrator, How often do you get these headaches? Mother has migraine and depression. presents with severe headaches accompanied by Has their severity or frequency changed? vision problems. She has had several consultations Began at age 13 years; occurred 3-4 times per year. You are worried about your job, and you in the past and is currently taking propranolol (20 In the past, vomiting always relieved the headache. also feel depressed at times. Is your mg/day) as prophylaxis. However, attacks have Headaches gradually worsened over the years. First social or family life affected? Are you become more frequent. Vital signs and physical consulted doctor at age 18 years and was prescribed able to enjoy yourself? examination are normal. oral ergotamine (Cafergot). The medication made Leads full, active social life except when she has a her nauseated, and she had cramps in limbs. headache bout. In probationary period with new Tell me about the vision problems, Cafergot was discontinued and she was started on job, which she enjoys. Lives in apartment with Theresa. What happens to your vision propranolol 20 mg daily. Gradually became roommate. Both parents live locally. One sibling, a and how long does the problem last? headache-free. She subsequently developed dysmen- sister. Family ties close. The vision problems warn her that a severe orrhea and was treated with oral contraceptives headache is developing. She first notices that any (OCs). Dysmenorrhea lessened but headaches Aside from these severe headaches, do bright light “catches her eye.” Then a diagonal returned; OCs discontinued. Isolated attacks of you have other headaches that also need band, mainly on the right side, slopes down across migraine recurred. They were unrelated to periods attention? her vision “colored like a rainbow with sparkles.” and always accompanied by visual problems. She has mild headaches that can be either ignored The bands multiply until almost all vision, mainly Restarted propranolol. Attacks have become more or easily controlled with 1-2 acetaminophen tablets. on the right side, is gone – she can’t read or see to severe and frequent. She was off work 2-3 days and They do not interfere with work and are attributed to drive. These take 10-15 minutes to develop. The is worried that she may lose her new job. stress or fatigue. headache starts in 30 minutes and the vision prob- lem fades in 2-3 minutes, but vision remains How do you manage during these Does anything seem to trigger your blurred for sometime. lengthy attacks? What do you do to try severe headaches? to get relief? Stress, missed meals, bright sunshine and air travel How about the headache itself? Where She had been told that nothing helps once the have precipitated attacks. do you feel the pain and how long does attack begins and prevention is the best approach. the attack last? Do you have any other She takes over-the-counter naproxen but to little symptoms with the headache? Do you effect. Vomiting no longer gives relief. Hot com- PRETEST ever have numbness, tingling or other presses, warm showers help. During the attack, she 1) What is the diagnosis? unusual sensations during or before the becomes irritable and angry and avoids contact with 2) Does this patient require imaging? If yes, which attack? others, taking the phone off the hook. studies and why? The headache is frontal behind the eyes, mainly on 3) What features help to determine the diagnosis? the right, and spreads to include the back of the You mention feeling irritable and angry a)Duration of visual symptoms. head. These severe headaches last about 2 days. during your attacks. Have you had any b)Unilateral location of visual and pain Then the pain fades and she feels “bad” for another other problems with your mood? symptoms. 24 hours before she can return to work. The Her headaches make her very depressed and the c) Duration of attack. headache is accompanied by nausea and vomiting. aura makes her feel panicky, especially if at work. d)Timing of visual symptoms and headache. She cannot tolerate light or loud noise; perfumes She also has bouts of depression unrelated to her e) Paresthesias. and cooking aromas aggravate the headache. headaches – worse during winter. She saw a psychi- f) Lack of response to propranolol. Occasionally she has diarrhea with the attack. atrist and was treated with sertraline (Zoloft). She g)Light/sound sensitivity. During the attack she notices her left hand and fore- noticed no improvement in mood but could not h)Intolerance to odors (osmophobia). arm develop “pins-and-needles” sensations. continue therapy because of insurance problems. i) Positive family history. j) Vomiting associated with headache. Does anyone else in your family have k)Diarrhea associated with headache. headaches or depression or other mood 4) What are the goals of therapy for this patient? problems? chologist for supportive therapy if indicated. Choice COMMENTARY of propranolol as preventive therapy is questionable, Theresa has migraine with aura (formerly known as given her depression and low frequency of attacks. “classic migraine”). She will be referred for a Editor However, given that Theresa also reports feeling anx- psychiatric consultation for evaluation and Carol Hart, PhD ious at the onset of her aura, the propranolol should diagnosis of comorbid depression/anxiety. be discontinued by tapering the doses since it also has anxiolytic effects. Amitriptyline may be consid- Editorial Board Tell me about the vision problems, ered after review with the consulting psychiatrist. J. Keith Campbell, MD Theresa. What happens to your vision R. Michael Gallagher, DO and how long does the problem last? Does anyone else in your family have Robert Smith, MD Theresa describes a typical migraine aura consisting headaches or depression or other mood of visual disturbances largely confined to one visual problems? AASH Board of Directors field. While she experiences some continued blurring A positive family history is common for both President of vision, the aura itself lasts less than one hour, migraine and mood disorders; comorbidity occurs James R. Couch, MD, PhD meeting the International Headache Society (IHS) more frequently than by chance, as shown in a President-Elect diagnostic criteria for migraine with typical aura. number of epidemiological studies. Richard B. Lipton, MD Treasurer How about the headache itself? Where do You are worried about your job, and you Paul Winner, DO you feel the pain and how long does the also feel depressed at times. Is your Secretary attack last? Do you have any other social or family life affected? Are you Robert B. Daroff, MD symptoms with the headache? Do you able to enjoy yourself? Immediate Past President ever have numbness, tingling or other Her active life and positive attitude suggest that her J. Keith Campbell, MD unusual sensations during or before the quality of life is not significantly impaired by either Members-at-Large attack? the depression or the migraines. She might respond Harvey J. Blumenthal, MD The location and duration of the headache are well to nonpharmacologic management, such as Steven B. Graff-Radford, DDS compatible with a diagnosis of migraine. Her biofeedback and relaxation therapy. Alvin E. Lake, III, PhD nausea/vomiting and light and sound sensitivity are Elizabeth W. Loder, MD also diagnostic. Strong odors are known to trigger Aside from these severe headaches, do John F. Rothrock, MD and/or exacerbate attacks in some migraineurs. In you have other headaches that also need Thomas N. Ward, MD migraine with aura, sensory disturbances, such as attention? the unilateral paresthesia she describes, often follow It is not uncommon for depressed migraineurs to Executive Director the visual disturbances. Fatigue or weakness can have frequent tension-type headaches that last days Linda McGillicuddy occur in the postdrome or final phase of the attack; to weeks. Unless this question is asked, the clinician however, Theresa’s comment about feeling so “bad” may fail to diagnose and treat these less severe but AASH Headache Profiles is published by after the migraine that she misses work suggests the persistent headaches. the American Association for the Study of need for further questioning about depression. Does anything seem to trigger your Headache, with business offices located at 19 How often do you get these headaches? severe headaches? Mantua Road, Mt. Royal, NJ 08061. Our world Has their severity or frequency changed? These are all common migraine triggers; they are wide web address is http://www.aash.org. Even when the diagnosis seems clear and the also largely preventable or avoidable. One can men- Letters to the editor should be sent to the above headache condition is long-standing, it’s vital to tion some simple prevention strategies, such as address, or emailed to [email protected] determine if there has been a change in the wearing sunglasses outdoors on bright days to avoid Copyright 1999 by the American Association for headache pattern that might suggest the emergence the visual stimulation. For air travel, one can sug- the Study of Headache. of secondary headache due to underlying pathology. gest packing snacks, water and pain relievers in a Her concern about losing her new job provides an carry-on. Some basic instructions on deep breathing answer to a related issue: “Why is this patient with a for stress reduction might also be worthwhile. AASH Special Membership Offer long-standing complaint here today? What has Theresa’s response to these suggestions will help in First-year dues are only $99 changed?” deciding whether she is a good candidate for behav- ioral approaches versus pharmacologic prophylaxis. ($150 per year upon renewal) Onset at puberty is very common in women. Oral Your AASH membership includes: contraceptives are frequently implicated in worsen- The propranolol is discontinued by tapering the Headache • A one-year subscription to ing migraine. doses. Options for acute treatment are discussed with • A CD-ROM disk containing all 37 years of Theresa. Given the rapid onset of her migraines, a Headache and all 17 years of Cephalalgia— How do you manage during these fast-acting triptan or nasal DHE would be a reason- a comprehensive searchable database of lengthy attacks? What do you do to try able choice. She is reluctant to try sumatriptan by major headache research to get relief? injection. A second-generation triptan is prescribed, • Reduced registration fees for the AASH Annual Theresa has been misinformed about migraine and and Theresa is instructed to take it during the aura, Scientific Meeting and the fall and winter is in need of more effective abortive therapy. rather than waiting for the headache to build. Headache Symposia • Patient education materials published by You mention feeling irritable and angry ACHE, the American Council for Headache during your attacks? Have you had any Sponsored by an unrestricted Education other problems with your mood? educational grant from: Contact AASH at 856-423-0043 or Her depressive symptoms warrant an initial psychi- Glaxo Wellcome Inc. [email protected] atric evaluation. She could then be referred to a psy-

2 SCOTOMA motion, a phenomenon known as metamorphopsia. THE CLINICAL In some patients, these evanescent phosphenes are In contrast to most visual auras, which are often usually a prelude to a longer-lasting second stage accompanied by an illusion of motion, some VARIETIES OF THE which consists of a far more elaborate hallucination patients experience what has been referred to as cine- MIGRAINE VISUAL within the visual field – the migraine scotoma. In matographic vision, where motion appears to be lost. others the scotoma may precede the scintillations or At such times, the patient sees only a rapidly flicker- AURA occur in their stead. The majority of migraine sco- ing series of “stills,” as in a film run too slowly. tomata present as a hazy spot or sudden brilliant Lilliputian (micropsia) and brobdingnagian David W. Dodick, MD, FRCP(C), FACP. Mayo luminosity near the center of vision which gradually (macropsia) vision denote an apparent diminution Clinic. Scottsdale, AZ expands and moves slowly towards the edge of the or enlargement in the size of objects, or an apparent visual field, assuming the form of a giant crescent or recession or approach of the visual world. If such Aura symptoms occur in approximately 15% of all horseshoe. At the fringes of the scotoma there may changes occur gradually rather than abruptly, patients with migraine and form the basis for the be a spectrum of colors, from which the term patients will experience zoom vision – a closing- classification of the migraine syndrome into those migraine spectra is derived. The term scintillating down or opening-out in the size of objects as if attacks with and without aura, formerly known as scotoma denotes the characteristic flickering of observing them through the changing focal lengths classic and common migraine respectively. On luminous migraine spectra, and the rate of scintilla- of a zoom lens. occasion, the aura symptoms may represent the sole tion has been estimated to range between 8–12 scin- The fascination and curiosity that the migraine manifestation of a migraine attack, a phenomenon tillations per second. The margin of the scotoma, visual aura has aroused since antiquity has contin- referred to as a migraine equivalent. Although the which may resemble the fortifications of a walled ued into the modern era. Highly sophisticated func- aura associated with migraine may involve one or city (fortification spectra), usually advances at a tional neuroimaging and neurophysiologic studies more sensory, motor or cognitive domains, the visual constant rate and usually takes between 10 and 20 are beginning to unfold the pathophysiologic mys- aura accounts for approximately 90% of all cases. minutes to pass from the fixation point to the edge of the visual field where it finally disappears. In tery of the visual aura and, in the process, provide Much of our information concerning the varieties of some auras, the shape of the scotoma is very well new insights into the underlying biology of the the visual aura comes from detailed descriptions preserved as it drifts, whereas in others the shape migraine syndrome. from physicians and scientists who themselves changes as it proceeds across the visual field. suffered from migraine with aura. Supplementary Suggested Reading information has been obtained from retrospective Usually the scotoma affects both the upper and Oleson J. Migraine with aura and its subforms. In: reviews of patients charts, as well as from question- lower quadrant of the right or left hemifield of Oleson J, Tfelt-Hansen P, and Welch K.M.A. (eds): naires, interviews, and drawings by artistic patients. vision, but occasionally only the upper or lower quadrant is affected. Bilateral scotomas may evolve The Headaches. New York: Raven Press, 1993:263- Although there is considerable variability in the synchronously in both half-fields. The negative 274. nature, complexity, and duration of the visual aura scotoma can last from 5 to 30 minutes, but there is Sacks O. Migraine. Los Angeles: University of between and even within patients, most descriptions considerable inter- and intra-patient variability. California Press, 1993:51-99. of the aura confine themselves to the phosphene and the scotoma. The visual aura described in this case represents a Aurora SK, Ahmad BK, Welch KMA, et al. typical temporal sequence and time course whereby Transcranial magnetic stimulation confirms PHOSPHENE the patient experiences a sudden bright luminous hyperexcitability of occipital cortex in migraine. Phosphene refers generally to a luminosity perceived band (phosphene) which moves in her right hemi- Neurology 1998;50(4):1111-4. when the retina undergoes non-luminous stimula- anopic field and becomes filled with a scintillating Welch KMA, Cao Y, Aurora SK, et al. MRI of the tion, as by pressure on the eyeball when the lid is spectrum of colors (scintillating scotoma) which occipital cortex, red nucleus, and substantia nigra closed. Often the first and simplest hallucination, multiply until a hemianopic field of visual loss during visual aura of migraine. Neurology this “positive” phenomenon takes the form of a results (negative scotoma). The aura evolves over a 1998;51(5):1465-9. burst of stars, sparks, flashes or simple geometric period of 10-15 minutes but she is left with blurred forms across the visual field. Phosphenes of this type or dazzled vision for some time thereafter and well are usually white but may have brilliant spectral into the headache phase. colors. They may number many hundreds and move Diagnosis: Migraine with Aura OTHER DISRUPTIONS OF rapidly back and forth across the visual field. At least 3 of the following 4 characteristics are present: Occasionally a single phosphene may predominate VISUAL PERCEPTION and then disappear suddenly, leaving a trail of Although the phosphene and scotoma comprise the 1) One or more fully reversible aura symptoms indicating dazzlement or blindness in its wake. Although such majority of migraine auras, there are other more focal dysfunction of cerebral cortex or brainstem. phosphenes may be confined to one half or one complex phenomena that are equally characteristic. 2) At least one aura symptom develops gradually over quadrant of the visual field, they are often bilateral Polygonal shapes such as squares, rhomboids, > 4 min, or 2 or more symptoms occur in succession. and not infrequently cross the midline. Other trapezoids, hexagons, or more complex shapes, 3) No single aura symptom last more than 1 hour. elementary hallucinations that are commonly expe- sometimes comprising tiny replicas of themselves, 4) Headache follows aura with a symptom-free interval rienced are rippling, shimmering, and undulation dominate the picture. These shapes may coalesce to < 60 min (alternatively, it may develop before or con- in the visual field, which patients may compare to form meshes or what patients may describe as webs, currently with the aura). The headache usually lasts the appearance of wind-blown water or heat waves honeycombs, mosaics, networks and lattices. These 4-72 hours, accompanied by nausea/vomiting and/or rising from pavement. During or after the passage of latticeworks may appear superimposed upon the light/sound sensitivity, as with migraine without aura. these phosphenes, patients may notice, upon background visual world to create a grid-like effect. closing the eyes, a brilliantly colored motif that This fragmentation of the visual scene is sometimes And: History, physical and neurologic exams do not appears as a mosaic or honeycomb pattern which referred to as mosaic vision. Sometimes spirals or suggest underlying pathology; or, suspected abnormalities might rapidly transform into a kaleidoscope. circles are seen, and these complex geometric have been ruled out by appropriate investigations. designs may continuously change shape, size and 3 • Episodic migraine with aura that becomes a attack within a day, so multiple auras are abnormal. UNUSUAL AURAS: chronic daily headache in the absence of The author saw a female patient with a history of explanatory transforming factors (eg, analgesic migraine with aura who experienced 5 distinct aura WHEN TO WORRY overuse, head trauma) spells within a 2-day period. Some of the auras • Headaches unresponsive to conventional occurred with headache and some without. Todd D. Rozen, MD. Assistant Professor of Neurology. therapies Laboratory testing revealed an antiphospholipid Thomas Jefferson University Hospital/Jefferson • Associated new-onset seizures antibody syndrome. On daily aspirin she has had no Headache Center. Philadelphia, PA • Abnormal examination findings including repeat multiple aura events. papilledema and changes in awareness The migraine aura is a complex array of symptoms Although rare, carotid artery dissection can representing focal cortical or brainstem dysfunction. The epileptic aura can be very similar to the present with transient symptoms suggestive of a The aura develops gradually over 5 to 20 minutes, migraine aura and, without the presence of migraine aura. Differentiation from true migraine lasts for less than 60 minutes and is followed by a tonic/clonic activity, differentiation can be difficult. with aura can be difficult, especially when vessel migraine headache within one hour’s time. The characteristics of the aura will help in making dissection is associated with a unilateral headache Migraine auras are typically visual, although they the correct diagnosis. along with focal neurologic symptoms. (Headache is can be characterized by sensory, motor, language the most common symptom of internal carotid Red flags suggestive of epileptic aura [3]: and brainstem disturbances. Auras are part of the artery [ICA] dissection, occurring in 84% of migraine process; thus, by definition, they are • Auras of short duration (<2 min) patients.) benign events. There are reported cases, however, of • Aura includes changes in awareness, positive apparently typical migrainous auras caused by motor phenomena or automatisms Red flags suggesting ICA dissection [5,6]: underlying pathologic conditions. • Abnormal EEG findings • Prolonged aura symptoms Arteriovenous malformations (AVMs) are one • Multicolored spherical or circular patterns are • Maximum severity of aura symptoms at onset of the most feared underlying causes of aura. The more typical of epileptic visual auras • Spread of aura symptoms from one modality to true relationship between intracranial vascular mal- • Brief stinging, cramping or burning sensations another (visual to motor or sensory) formations and migraine is not known, but AVMs are are more typical of epileptic sensory aura • Headache starts during rather than after aura • Associated hemiparesis and hemineglect linked to migraine and a migrainous aura may be Scintillating scotomas, which are very common (eg, lapses in grooming on one side) on the only clinical manifestation of an indolent AVM symptoms of the migraine aura, may also be a man- examination before it bleeds. Arteriovenous malformations in the ifestation of a lesion in any part of the visual occipital, parietal, and temporal lobes are most sensory pathway, the most common sites being Migraine-like auras have been associated with AVMs likely to present with aura-type symptoms. the retina, the vitreous, and the occipital striate and tumors, seizures, carotid artery dissection, Red flags suggestive of an cortex.[4] Acute vitreous or retinal detachment can ocular disease and connective tissue disorders. A underlying AVM [1]: present with flashes or sparks of light that mimic complete aura and headache history in regard to photopsias or scintillating scotomas of migraine. aura duration, progression of aura symptoms, age of • Late age of onset of symptoms Visual symptoms from retinal or vitreous disease onset of aura and headache, whether aura • Absence of a family history for migraine affect the vision of one eye only, are longer in dura- symptoms side-shift or are locked to one side, and a • Auras of short duration (5-10 minutes) tion than the migraine visual aura and lack the pres- complete neurologic examination can help the • Aura symptoms always on the same side ence of headache. Vascular malformations or tumors physician identify which auras need to be evaluated • Absence of typical angular, scintillating features involving the occipital cortex can present with visual for secondary organic causes. of migraine visual aura symptoms reminiscent of the migraine aura. • Complicated auras (eg, hemiparesis) with References Cerebral venous thrombosis, when it causes residual symptoms 1. Bruyn GW. Intracranial arteriovenous malforma- damage to one or both occipital lobes, may manifest • Unusual neurologic symptoms including tions and migraine. Cephalalgia 1984;191-207. as positive visual symptoms suggestive of a migraine seizures and coma 2. Lord GDA. Clinical characteristics of the aura. Headache and neurologic symptoms (seizures, • Headache starts before rather than after aura migraine aura. In: Amery WK, Wauquier A focal motor or sensory disturbances) are typical of • Headaches of short duration (several hours) (eds.): The Prelude to the Migraine Attack. cerebral venous thrombosis. Cerebral venous • Significant examination findings including London, Bailliere Tindal, 1986:87-98. thrombosis should be considered as an etiology of cranial bruits and distortions in one quadrant of 3. So NK, Andermann F. Differential diagnosis. In: new-onset migraine with aura in the setting of visual field Engel Jr J, Pedley TA (eds.): Epilepsy: A severe infection, dehydration, pregnancy, cancer, Comprehensive Textbook. Philadelphia, Intracranial neoplasms can also present with antiphospholipid antibody syndrome, sickle-cell dis- Lippincott-Raven, 1998:791-800. secondary migrainous aura. Meningiomas, ease, or polycythemia vera. specifically involving the occipital lobes, are the 4. Miller NR. Migraine. In: Walsh and Hoyt’s most common primary tumors to present with aura Systemic lupus erythematosus (SLE) can Clinical Neuro-opthalmology. Baltimore, symptoms.[2] Tumors involving the occipital cortex cause scintillating scotomas suggestive of a Williams and Wilkins, 1991:2515-2574. typically produce scintillating scotomas very migraine aura.[4] SLE is a concomitant disorder in 5. Ramadan NM, Tietjen GE, Levine SR, Welch KM. reminiscent of those seen in migraine. Brain metas- some migraineurs, but in others SLE probably leads Scintillating scotoma associated with internal tases to the superficial cortex can present with aura, to changes in the retinal vessels causing transient carotid artery dissection. Neurology probably secondary to parenchymal irritation. visual phenomena. 1991;41:1084-1087. 6. Silverman IE, Wityk RJ. Transient migraine-like Multiple discrete aura attacks that occur within a Red flags suggesting an underlying symptoms with internal carotid artery dissection. single day, even with associated migraine headache, neoplasm: Clin Neurol Neurosurg 1998;100:116-120. may suggest an underlying coagulopathy. • Late age of onset of symptoms Typically migraineurs only experience a single aura • Aura symptoms always on same side

4 neuronal pathways that are activated in the wave 10. Welch KMA, Levine SR, D’Andrea G, et al. MECHANISMS OF THE of depolarization and subsequently suppressed. Preliminary observations on brain energy metab- Dysmodulation of these brainstem centers could olism in migraine studied by in vivo phospho- MIGRAINE AURA alter the nociceptive aspects of their function and rous 31 NMR spectroscopy. Neurology alter the appreciation of pain via central trigeminal 1989;39:538-541. K.M.A. Welch, MD. University of Kansas School of structures. 11. Ramadan NM, Halvorson H, Vande-Linde A, et al. Medicine. Kansas City, KS Low brain magnesium in migraine. Headache Enhanced excitability of occipital cortex neurons 1989;29:590-593. It has long been thought that the migraine aura has been proposed as the basis for the spontaneous 12. D’Andrea G, Cananzi AR, Jospeh R, et al. Platelet might result from an phenomenon observed in or triggered onset of the migraine aura.[7] In a spreading depres- glycine, glutamate and aspartame in primary rodent brain and retina known as study using transcranial magnetic stimulation sion (SD) of Leao headache. Cephalalgia 1989; 9:105-106. , although it could also be termed (TMS), 11 of 11 migraineurs with aura visualized spreading activation.[1,2] In this neuroelectric phosphenes (luminous sensations) on occipital event, neuronal depolarization is followed by cortex stimulation, compared to 3 of 11 controls.[8] MIGRAINE suppression of neuronal activity and associated The patient with the lowest threshold level experi- oligemia in a wave that spreads slowly across the enced her typical migraine aura in response to TMS. surface of the brain from the occipital cortex. This PROPHYLAXIS experimental phenomenon correlates well with the The reasons for increased neuronal excitability in features of a typical visual aura, in which peripheral migraine patients remain to be determined and may Ninan T. Mathew, MD. Houston Headache Clinic. scintillations (a stimulative, positive symptom) pre- be multifactorial. Calcium channel abnormalities Houston, TX cede an expanding visual scotoma (a suppressive, have been inferred following the discovery of muta- One-quarter of migraine patients in the general pop- negative symptom). Cerebral blood flow (CBF) has tions in a P/Q type neuronal calcium channel gene ulation have > 4 migraine attacks a month, and been observed to fall to oligemic values in posterior (CACNL1A4) found in several families with a rare one-third have very disabling episodes. Migraine regions of the cortex during attacks of migraine with migraine subtype called familial hemiplegic treatment is complicated by the fact that attacks can aura.[2] Investigation of this model in humans, migraine.[9] Disorder of mitochondrial energy vary in frequency, severity, duration and associated however, remains far from complete and has not yet metabolism, deficiency of systemic and brain Mg2+, symptoms. Cycles of frequent headache can occur served to establish SD as the mechanism of aura. and abnormalities of glutamate metabolism may from time to time. Patients differ in comorbidity, also be implicated.[10-12] In addition to contribut- The early depolarizing or activation phase of coping abilities, response to abortive medications ing to the excitability of neurons, these same factors and treatment preferences. experimental SD is associated with a transient but may be involved in propagating SD. pronounced CBF increase, presumably in response to Indications for prophylactic pharmacotherapy increased demand of neurons attempting to repolar- References include, but are not limited to: ize. This transient hyperemia has not been observed 1. Leao AAP. Spreading depression of activity in 1. Two or more attacks a month that produce until recently in migraine patients, possibly because cerebral cortex. J Neurophysiol 1944;7:379-390. disability that lasts 3 or more days most studies have relied on indirect measures of CBF 2. Lauritzen M. Links between cortical spreading 2. Contraindication to, or ineffectiveness of, and patients were not studied until well into the depression and migraine: Clinical and experi- abortive medications aura. Clinical studies of the early seconds to minutes mental aspects. In: Olesen J (ed): Migraine and 3. Use of abortives more than twice a week of an attack are of interest, since the vasodilation Other Headaches: The Vascular Mechanism. New seen in the earliest stage of SD may be linked to the York, Raven Press, 1991;1:143-151. Goals of prophylaxis include: (1) reducing the fre- mechanisms of the headache. 3. Welch KMA, Cao Y, Aurora S, et al. MRI of the quency and severity of the attacks, (2) making acute occipital cortex, red nucleus, and substantia attacks more responsive to abortive therapy, and (3) Our own studies employing the fMRI-BOLD nigra during visual aura of migraine. Neurology improving quality of life. technique (which measures relative changes in 1998;51:1465-1469. oxygenation of brain circulation) have shown Steps before prophylactic therapy is initiat- 4. Aicardi G. Guifrrida R, Rapisarda C, Albe-Fesardi ed include recognition of comorbidity such as hyperoxygenation of the occipital cortex occurring D. Effects of cortical spreading depression on early in the course of visually activated headache depression, panic attacks, anxiety and bipolar disor- spontaneous activity of red nucleus cells in the der. Overuse of symptomatic medications, including and in one case of spontaneous migraine aura.[3] guinea pig. Arch Ital Biol 1988;126(3):199-203. We also observed activation and subsequent hyperox- analgesics, ergotamine, and triptans, with resulting 5. Kumar A, Raghubir R, Dhawan BN. Possible drug-rebound headache must be recognized. Such ia of the red nucleus (RN) and substantia nigra involvement of nitric oxide in red nucleus stimu- (SN). Experimental SD directly alters RN function patients have to be detoxified from analgesic/ lation-induced analgesia in the rat. Eur J narcotic medications. Pharmacotherapy should via subcortical projection neurons in the guinea pig, Pharmacol 1995:279:1-5. and stimulation of the RN in the rat induces analge- always be combined with non-pharmacological 6. Peroutka, SJ. Dopamine in migraine. Neurology approaches including dietary adjustments, reducing sia. [4,5] Abnormal function of the RN therefore 1997;49:650-656. may be relevant to the head pain experienced by the triggers, physical exercise, and relaxation training. 7. Welch KMA, D’Andrea G, Tepley N, et al. The con- Ensuring adequate contraception for women with patient. Nigrostriatal dysfunction may be associated cept of migraine as a state of central neuronal with the pain, nausea, vomiting and other dysauto- potential to become pregnant is extremely important hyperexcitability. Neurol Clin 1990;8:817-828. prior to beginning prophylactic treatment. nomic features of the migraine attack. [6] 8. Aurora SA, Ahmad BK, Welch KMA et al. The mechanisms of bilateral RN and SN Transcranial magnetic stimulation confirms Practical Considerations involvement in the migraine attack remain to be hyperexcitability of occipital cortex in migraine. 1. Start low, go slow. It is extremely important determined. Hyperoxia of these structures does not Neurology 1998;50:P111-114. to start small doses of prophylactic medications determine if their function is activated or suppressed. 9. Ophoff RA, Terwindt GM, Vergouwe MN, et al. initially and gradually build up the dosage as These studies do suggest that brainstem structures Familial hemiplegic migraine and episodic the patients tolerate the medications better by involved in pain and associated symptoms of the ataxia type 2 are caused by mutations the Ca2+ this strategy. Migraineurs frequently require a migraine attack may be involved through direct channel gene CACNL1A4. Cell 1996;87:543-552. lower dose of a preventive medicine than is needed for other conditions. 5 Continued on next page. 2. Give adequate trial with optimum dose antidepressant such as amitriptyline could be tried; Reasons for Failure for at least 3 months before the medication is selective serotonin reuptake inhibitors such as fluox- Some reasons for prophylactic treatment failure pronounced ineffective. etine (Prozac) are sometimes used for migraineurs include wrong diagnosis, not recognizing comorbid- 3. Withdraw the medications gradually. with comorbid depression; however, their efficacy has ity, inadequate dosage of medications, inadequate This is particularly important with beta- not been well studied to date. treatment period, and unrealistic expectations. blockers, calcium channel blockers, and SSRIs. Agents that may interfere with effective prophylaxis Long-term Management If the headaches are well controlled, a drug hol- include concomitant use of excess analgesics partic- Generally, prophylactic treatment is given for at least iday can be undertaken following a slow taper ularly combination analgesics, excess ergotamine, 6 months. It is very important to let the patient program. Many patients experience continued excess triptans, oral contraceptives, and vasodilator understand that prophylactic medications take a relief after discontinuing the medication or may drugs such as nitroglycerine and nifedipine. number of weeks to begin to show the desired effect. not need the same dose. A dose reduction may In many, the medications may have to be resumed provide a better risk-to-benefit ratio. Suggested Reading after a while and many patients with chronic Tfelt-Hansen P, Welch KMA. Migraine: Prioritizing The Role of Comorbidity migraine need continuous prophylactic therapy. prophylactic treatment. In: Olesen J, Tfelt-Hansen P, Comorbidity may result in certain therapeutic Clinical experience has indicated that tachyphylaxis Welch KMA (eds.): The Headaches. New York, Raven opportunities, and/or it may impose therapeutic becomes a problem in long-term management with Press, 1993:403-404. limitations in using certain medications. Both prin- prophylactic agents. Therefore, it is important to Silberstein SD, Lipton RB, Goadsby PJ. Headache in ciples are illustrated by the case vignette, where the monitor the patient over a period of time and clinical practice. Oxford, ISIS Medical Media, 1998. patient has been prescribed a beta blocker that may medications may have to be changed. exacerbate her depressive symptoms. A tricyclic Ramadan NM, Schultz LL, Gilkey SJ. Migraine prophylactic drugs: proof of efficacy, utilization, and Migraine Prophylactic Agents cost. Cephalalgia 1997;17:73-80. POSTTEST—TRUE OR FALSE Class Agent Dosage 1. Headache must follow or accompany the aura in Beta-adrenergic *Propranolol (Inderal) 40-240 mg/day in divided doses order for the diagnosis of migraine with aura to Blocking Agents *Propranolol long-acting (Inderal LA) 60-160 mg once daily be made. Nadolol (Corgard) 40-160 mg once daily 2. Preventive treatment, when indicated, should be *Timolol (Blocadren) Up to 20 mg twice daily given a trial of at least 3 months at optimal dos- Metoprolol (Lopressor) 50-100 mg/day ing before the decision is made to discontinue as Tricyclic Amitriptyline (Elavil & others) 10-200 mg/day ineffective. Antidepressants Nortriptyline (Pamelor, Aventyl) 10-75 mg/day 3. Use of acute agents (e.g., triptans, ergotamine) Protriptyline (Vivactil) 10-40 mg/day should be avoided in patients on prophylactic Calcium Channel Verapamil (Calan, Isoptin) 80-360 mg/day medication. Blockers Diltiazem (Cardizem) up to 200 mg/day 4. Brief, sudden auras are more likely to be benign 5-HT2 Antagonists *Methysergide (Sansert) 4-8 mg/day in origin than prolonged auras. Cyproheptadine (Periactin) 4-16 mg/day 5. In the presence of other unusual findings, aura NSAID Naproxen sodium (Anaprox) 500-1000 mg/day symptoms that always occur on the same side Antiepileptic Agents *Divalproex sodium (Depakote) 500-1500 mg/day may suggest the possibility of underlying disease. Gabapentin (Neurontin) 600-2400 mg/day *Approved by the FDA for migraine prophylaxis. Answers—Pretest Choice of Agent 1. Migraine with aura. She requires further evalua- Based on a combination of the published literature developed a comparated rating using a scale from + tion for comorbid depression/anxiety. and personal experience, Tfelt-Hansen and Welch to ++++. 2. Imaging would not be considered necessary by most experienced clinicians. Her aura and Drug Clinical Scientific proof Side effect Examples of side effects migraine symptoms are quite typical; the condi- efficacy for efficacy potential (contraindications) tion is long-standing; and she reports no recent change in symptoms or the pattern of the attack. Beta blockers ++++ ++++ ++ Tiredness, cold extremities, vivid 3. The diagnosis can be made on the basis of a, b, c, dreams, depression (asthma, brittle diabetes, A-V conduction defects) d, and j; e is a frequent aura symptom but not required for the diagnosis; h and i are typical of Divalproex ++++ ++++ ++ Nausea, asthenia (liver disease) migraine, providing additional support for the Gabapentin ++++ +++ ++ Fatigue, sleepiness, dizziness, ataxia diagnosis. Methysergide ++++ ++ +++ Hair loss; chronic use 1/2500 4. Controlling the pain and associated symptoms of patients—fibrotic disorders (cardio- her rapid-onset attacks so that she can continue vascular diseases, renal disease) to function or at least rest more comfortably. Naproxen ++ +++ ++ Dyspepsia, peptic ulcers Providing cost-effective treatment for her depres- (active peptic ulcers) sion/anxiety (avoiding her insurance problems). Amitriptyline ++ ++ ++ Sedation, dry mouth, weight gain (glaucoma) Offering stress management strategies that may aid in controlling both her anxiety and her SSRIs ++ + + migraines. Verapamil + + + Constipation (bradycardia, A-V conduction defects) Answers—Posttest SSRI = selective serotonin reuptake inhibitor. Modified from Tfelt-Hansen & Welch, 1993. 1. F 2. T 3. F 4. F 5. T