2openNappi, G; Termine, C.Nappi, G; Termine, Cristian

Nappi, Giuseppe

Termine, Cristiano

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Nappi, G

TERMINE, CRISTIANO

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Giuseppe Nappi, MDa,b,d, Cristiano Termine, MDc,da IRCCS “C. Mondino Institute of Neurology” Foundation, Pavia, Italyb Chair of Neurology, University “La Sapienza”, Rome, Italyc Child Neuropsychiatry Unit, Department of Clinical and Biological Sciences, University of Insubria and “Macchi Foundation Hospital”, Varese, Italyd University Centre for Adaptive Disorders and Headache (UCADH), Sections of Varese and Pavia, Italy Corresponding author: Giuseppe Nappi, MDIRCCS C. Mondino Institute of Neurology FoundationVia Mondino 2, 27100 Pavia, ItalyWhat is migraine? What is migraine aura? One of the difficulties in answering these questions, which are only super-ficially simple and banal, lies in the great variety of ways in which these disorders can manifest themselves. Eventhough diagnostic practice is based on the detection of a series of symptoms and features, set out in the ICHD-II (1),clinical observations show that migraine is highly heterogeneous. It can evolve in very different ways in different indi-viduals and, over time, even in the same individual (2). The frequency and intensity of the attacks, the accompanyingneurovegetative symptoms, the response to symptomatic drugs, and the impact on the patient’s life can all vary con-siderably. In short, we are faced with a complex disease: a range of possibilities that may be manifested in a myriadof neurological symptoms named aura. The most frequent aura type is visual (3), while a minority of patients may ex-perience sensory (4), motor (5) or language disturbances (6), prosopagnosia, dyschromatopsia, ideational apraxia,alien hand syndrome, proper name anomia, or aphasia (7), indicating that other areas of the cortex distinct from theoccipital lobes must be affected. Visual migraine auras are windows onto the visual brain. Because they occur in awake, aware individuals whose self-re-ports are not subject to the uncertainties of other conditions that would qualify as hallucinations (i.e. visions without a stim-ulus), such as dreaming, psychoses or drug-induced states (8), they provide a valuable route for studying the neuralmechanisms of visual awareness. The range of visual aura symptoms is wide (9) even though the majority of patientspresent, as a cardinal feature of the phenomenon, simple positive and/or negative (scotoma) components. The most com-mon reports are of visual phosphenes and simple geometric patterns. The positive components are always described asvery bright, usually white or silver but coloured in some instances, and as scintillating, flashing, or flickering. A secondstriking property of many, but not all, visual auras is that they spread in a stereotyped pattern across the visual field. The most familiar descriptions of visual auras refer to the form known as fortification spectra. One historical exampleof such descriptions is that of Sir JFW Herschel, which dates back to 1866 and reads: “I was startled by a singularshadowy appearance at the outside corner of the field of vision of the left eye. It gradually advanced into the field ofview and then appeared to be a pattern in straight-lined angular forms, very much in general aspects like the drawingof a fortification, with salient and re-entering angles, bastions, and ravellings with some suspicion of faint lines ofcolour between the dark lines” (10).    Lashley’s 1941 self-report (11) clearly illustrates why visual aura can be used as a window onto the visual brain.Lashley described the progression of fortification spectra across his visual field during his own migraine aura andmapped these onto his visual cortex, concluding that the aura moved across his visual cortex at a rate of approxi-mately 3 mm/min. A few years after this, Leão found that noxious stimulation of the exposed cortex of a rabbit pro-duced a spreading decrease in electrical activity (cortical spreading depression, CSD) that moved at a rate of 2-3mm/min (12). Some time later, Milner made the connection between Leão’s CSD and Lashley’s fortification spec-tra, proposing that CSD is the mechanism of aura (13). Whether or not Leão’s CSD is the mechanism underlyingmigraine aura, it is nevertheless now widely accepted that a “spreading depression-like” process underlies the vi-sual aura in migraine (14). Several recent studies using magnetoencephalography and high-field strength, high-res-olution magnetic resonance imaging have established a link between migraine aura and CSD (15,16). For exam-ple, the propagation of CSD within the human primary visual cortex during migraine visual aura has been found tobe congruent with the retinotopic progression of the visual percept that is generated by the phenomenon (16). Thewavefront of neural excitation operating on intrinsic cortical networks is presumed to underlie the positive halluci-nations and the subsequent neuronal depression, the scotoma (8). Auras generally precede headache onset andFunctional Neurology 2008; 23(3): 109-112 109Migraine auras and the eyes of the mindeditorialexperimental data, showing that CSD activates the trigeminovascular system (17,18), suggest that it is this activa-tion that provokes the headache (19). The question that remains unanswered is how CSD is triggered in the hu-man cortex during migraine aura. It has been suggested that genetic and environmental factors may modulate in-dividual susceptibility by lowering the CSD threshold, and that cortical excitation may raise extracellular K+ and glu-tamate levels sufficiently to initiate CSD (20). The majority of positive migraine auras fall into the elementary hallucination category. Ictal blindness (scotoma) mayaccompany the positive features or may present alone in a variety of forms including complete hemianopia and tun-nel vision. Much less frequent are auras classifiable as illusions or distorsions. These include objects or persons ap-pearing to be split, along fracture lines of varying form and orientation, into two or more parts that may be displacedand separated from each other (“illusory splitting”) (21); the visual illusion of an extra edge around an object (“coronaphenomenon”) (22); the breaking up of the visual image into crystal-like facets (“mosaic vision”) (23); the loss ofsmooth movements of observed scenes (“cinematic vision”) (23); altered perception of shape (metamorphopsia) andsize (micropsia and macropsia) (24), and impaired sense of the passing of time (“Alice in Wonderland syndrome”)(24); out-of-body experiences, like the visual sensation of perceiving the environment from a location in space outsideone’s physical body (“autoscopy”), or the somaesthetic sensation of a duplicate of the body (“parasomatic body”) (25).In addition, a patient may see little people, brightly coloured and clearly defined, tiny animals or fantastic creatures.In these latter cases, reality judgement may be well preserved, with the accompanying affective state characterisedby feelings of delight and joy and only rarely by fear or terror (“Lilliputian hallucinations”) (26). But how does migraine aura impact on the lives of patients? Some people manage to live with their migraine and itsaura manifestations quite well, leading a practically normal life, while others are heavily penalised on a personal, fam-ily, social and professional level. Furthermore, if, moving on from the observation of migraine aura’s multiple clinicalmanifestations, we also consider the psychological aspects of this disease and the adaptive strategies patients em-ploy, we find that the level of heterogeneity increases still further.Aura is a visual disturbance, an “experience” that does not impair cognitive abilities. From a clinical point of view, thischaracteristic is so important that it is one of the criteria for the differential diagnosis of migraine aura. Indeed, duringaura, a patient, in a state of perfectly lucid consciousness, can observe, describe and draw the phenomena that heor she experiences and consider them rationally and this is a fundamental factor differentiating the aura experiencefrom dreaming and from psychosensorial phenomena (epileptic or induced by hallucinogenic drugs). These peculiar-ities are at the root of the emergence and development of “migraine art” (27), a phenomenon that arose in Britain inthe 1980s out of the decision of the British Migraine Association (since re-named the Migraine Action Association) andBoehringer Ingelheim UK Limited jointly to sponsor an art competition open only to migraine sufferers. A good 900paintings were submitted, but since some of the artists wanted their work back, only 562 are today included in the re-sulting collection of migraine art, an archive of extraordinary importance from a research perspective. For the patient,“migraine art” is a way of illustrating his pain, of expressing how he feels and what he sees during a migraine attack;it is also a way of highlighting the social consequences ofmigraine. In this field, the different pictorial techniquesavailable can provide efficient and sometimes even thebest possible means of expressing and conveying the pa-tient’s experiences, both the symptoms themselves and themigraine patient’s reactions to his disturbances (e.g.21,22,25,26). The word “art” is here used in its widestsense, without reference to specific aesthetic values. The pattern of migraine aura manifestations is highly person-al, whereas the far more frequent visual phenomena are, inmost cases, surprisingly similar, being characterised by con-stant, recurring shapes. However, some “creative mi-graineurs” such as Giorgio de Chirico, Friedrich Nietzsche,Gerolamo Cardano, Lewis Carroll, and Hildegarde of Bingencan be credited with turning what for some is merely disabil-ity into an opportunity for the spreading of knowledge andawareness. For individuals such as these, migraine providesthe initial stimulus for a complex elaboration (technical, sty-listic, cultural or philosophical), this process of elaborationbeing the element that distinguishes art from everything thatis not art (28). Hence, de Chirico’s statues suspended inemptiness, his disconnected atmospheres, his forms whichevolve into seemingly impossible constructions, and thestrong sense of suspended time exuded by his paintings areall brilliant and highly personal variants of a language whosevocabulary manages to overcome the purely subjective di-mension (29) (Fig. 1). 110 Functional Neurology 2008; 23(3): 109-112Figure 1 - Giorgio de Chirico: “Return to the Castle” (Ritorno alcastello), 1970.Hildegard of Bingen (1098-1179), a German abbess andmystic with extraordinary intellectual insight and literaryprowess, experienced throughout her life (starting in earlychildhood) “visions” of which she left remarkable accountsin two illuminated books: Liber Scivias and Liber divinorumoperum semplicis hominis. Close examination of these ac-counts and illustrations suggest that her visions were of mi-grainous origin. Hildegard wrote: “The visions I have cometo me not in sleep, in dreaming, or in folly. I perceive themnot with my carnal eyes or ears, or in hidden places; fullyalert, I perceive them in wakefulness, with the eyes of mysoul and with my inner ears; I see them clearly through theeyes and according to the will of God.” Hildegard’s visions,charged with this feeling of ecstasy and full of profound re-ligious and philosophical significance, contributed to herchoice to live a deeply devout life. They provide a rare ex-ample of how a physiological event, which most peoplewould dismiss without second thought as a nuisance orsimply as a source of discomfort and distress, can become,in a heightened consciousness, the substrate of supremeecstatic inspiration (23) (Fig. 2).How is it that some people can transform migraine aura and migraine into a “short route to consciousness”, a sourceof creative inspiration? Perhaps more in-depth investigation (particularly using the new functional neuroimaging tech-niques) of the neurophysiological bases underlying these phenomena will enable us to tackle, with greater knowledgeof the facts, questions that have, until now, been confined to the “grey area” between science and philosophy. Is therea physiological basis for those recurrent visual patterns that in the past have been called archetypes, paradigms, andeven Platonic ideas, mental pictures and letters from the language of the Gods? Is the brain truly capable of “visualthought” (along the lines of Giordano Bruno’s hermetic diagrams), as well as propositional and symbolic thought? Isthere a physiological basis for what is known, in philosophical tradition as the “mind’s eye"? The fact is that today weare able to approach migraine aura as a “window” onto the mind and on to its modular functioning, and we have Gior-gio de Chirico, Hildegarde of Bingen and other “creative” migraineurs to thank for helping us to open it.References11. Headache Classification Subcommittee of the International Headache Society. The International Classification of Headache Dis-orders – 2nd Edition. Cephalalgia 2004;24 (Suppl 1):9-16012. Nappi G, Costa A, Tassorelli C, Santorelli FM. Migraine as a complex disease: heterogeneity, comorbidity and genotype-pheno-type interactions. Funct Neurol 2000;15:87-9313. Cologno D, Torelli P, Manzoni GC. Migraine with aura: a review of 81 patients at 10-20 years’ follow-up. Cephalalgia1998;18:690-69614. Jensen K, Tfelt-Hansen P, Lauritzen M, Olesen J. Classic migraine. A prospective recording of symptoms. Acta Neurol Scand1986;73:359-362 15. Thomsen LL, Olesen J. Sporadic hemiplegic migraine. Cephalalgia 2004;24:1016-102316. Almeida DB, Arruda WO, Ramina R, Pedrozo AA, Raskin S. Migraine with aphasia. Report of a family [Article in Portuguese].Arq Neuropsiquiatr 1999;57:111-11317. Vincent MB, Hadjikhani N. Migraine aura and related phenomena: beyond scotomata and scintillations. Cephalalgia2007;27:1368-137718. Wilkinson F. Auras and other hallucinations: windows on the visual brain. Prog Brain Res 2004;144:305-32019. Queiroz LP, Rapoport AM, Weeks RE, Sheftell FD, Siegel SE, Baskin SM. Characteristics of migraine visual aura. Headache1997;37:137-14110. Herschel JFW. Familiar lectures on scientific aspects. London; Alexander Straham1866:40611. Lashley KS. Patterns of cerebral integration indicated by scotomas of migraine. Arch Neurol Psychiat 1941;46:33112. Leão AAP. Spreading depression of activity in cerebral cortex. J Neurophysiol 1944;7:359-39013. Milner P. Note on a possible correspondence between the scotomas of migraine and spreading depression of Leao. Electroen-cephalogr Clin Neurophysiol 1958;10:70514. Sanchez Del Rio M, Reuter U. Migraine aura: new information on underlying mechenisms. Curr Opin Neurol 2004; 17:289-29315. Cao Y, Welch KM, Aurora S, Vikingstad EM. Functional MRI-BOLD of visually triggered headache in patients with migraine. ArchNeurol 1999;56:548-554 16. Hadjikhani N, Sanchez Del Rio M, Wu O et al. Mechanisms of migraine aura revealed by functional MRI in human visual cortex.Proc Natl Acad Sci USA 2001;98:4687-469217. Moskowitz MA, Nozaki K, Kraig RP. Neocortical spreading depression provokes the expression of c-fos protein-like immunore-activity within trigeminal nucleus caudalis via trigeminovascular mechanisms. J Neurosci 1993;13:1167-117718. Bolay H, Reuter U, Dunn AK Huang Z, Boas DA, Moskowitz MA. Intrinsic brain activity triggers trigeminal meningeal afferents ina migraine model. Nat Med 2002;8: 136-142Functional Neurology 2008; 23(3): 109-112 111Figure 2 - Hildegard of Bingen: “The Fall of the Angels” (fromLiber Scivias), 1141.19. Moskowitz MA. The neurobiology of vascular head pain. Ann Neurol 1984;16:157-16820. Ayata C, Jin H, Kudo C, Dalkara T, Moskowitz MA. Suppression of cortical spreading depression in migraine prophylaxis. AnnNeurol 2006;59:652-66121. Podoll K, Robinson D. Illusory splitting as visual aura symptom in migraine. Cephalalgia 2000;20:228-23222. Podoll K, Robinson D. Corona phenomenon as visual aura symptom in migraine. Cephalalgia 2001;21:712-71723. Sacks O. Migraine. London; Faber and Faber 199124. Todd J. The syndrome of Alice in Wonderland. Can Med Assoc J 1955;73:701-425. Podoll K, Robinson D. Out-of-body experiences and related phenomena in migraine art. Cephalalgia 1999;19:886-89626. Podoll K, Robinson D. Recurrent Lilliputian hallucinations as visual aura symptom in migraine. Cephalalgia 2001;21: 990-992 27. Wilkinson M, Robinson D. Migraine art. Cephalalgia 1985; 5:151-15728. Nicola U, Podoll K. L’aura di Giorgio de Chirico. Milan; Ed. Mimesis 200329. Nappi G, Nisticò P, Nicola U, Podoll K. Artemicrania? Opere e parole tra mal di testa e metafisica. Rome; Il Cigno Galileo Galilei2003112 Functional Neurology 2008; 23(3): 109-112

Migraine auras and the eyes of the mind

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Migraine auras and the eyes of the mind

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