Fig. 5.3  11-year-old girl’s drawing of an episode of higher cortical dysfunction she experienced on her way to school one morning. Her perception of scene before (left) and after (right) “She stood at a crosswalk facing her school. In front of her was a friend who was wearing a stocking cap with a pompom and writing on the cp the spelled ‘M-M good.’ Suddenly, she felt ill and everything looked funny. The writing disappeared from the stocking (right); the school and schoolyard became a jumble of colorless, disorganized figures and windows. Colors were desaturated; Everything looked gray. She felt disoriented and became pale.” This description depicts development of migranious central achromatopsia and word anomia. Courtesy of James J. Corbett, M.D.

difficulty reading (alexia with or without agraphia), and transient global amnesia35,101,107,116,152,176,288 (Fig. 5.3). The Alice in Wonderland syndrome, characterized by distortions of time, sense, and body image, has also been described as a manifestation of pediatric migraine.136,387

Although the term migraine connotes a benign and fundamentally reversible condition, a subgroup of patients develops infarction following a severe episode. Rossi et al338 described seven children who had at least one episode of CT-documented infarct, possibly during an attack of migraine. Although a causal relationship could not be assured, the epidemiological data suggest that childhood migraine can be a contributing risk factor for childhood stroke.253 Whether reports of optic nerve and retinal infarction in patients with retinal vasoconstriction (which have been traditionally designated as migraine) are related to underlying migraine diathesis (such as that seen with anticardiolipin syndrome) is unknown.

Ophthalmoplegic migraine usually manifests as a unilateral third nerve palsy in the wake of a migraine headache.404 It has a predilection for young children, and the first episode may occur in infancy.335,408 Even in children, ophthalmoplegic migraine is rare and has always been considered a diagnosis of exclusion. Numerous reports of magnetic resonance (MR) imaging in ophthalmoplegic migraine have described focal gadolinium enhancement of the oculomotor nerve in the perimesencephalic cistern,371 providing neuroimaging confirmation of this condition92,249 (Fig. 5.4).

In the second edition of the International Classification of Headache Disorders (ICHD II), the entity of ophthalmoplegic

Fig. 5.4  Axial and coronal MR images showing nodular enhancement of right cisternal nerve in child with opthalmoplegic migraine. Courtesy of Thomas Carlow, M.D.

migraine is no longer classified with migraine but as a neuralgia, because in many cases of this rare condition, signs of inflammation of the affected nerve have been found on gado- linium-enhanced MR imaging.179,291 It is now believed that repeated inflammation (rather than vasoconstriction) could lead to a demyelination/remyelination process with Schwann cell proliferation and “onion bulb” formation.53,256 The clinical features of ophthalmoplegic migraine are detailed in Chap. 6.

Carlow53 has proposed that inflammation of the oculomotor nerve, which is the only cranial nerve adjacent to the circle of Willis at its exit, can still be initiated by a migraine stimulus affecting the trigeminovascular system.53 Neuro­ peptides are secreted at the level of the circle of Willis and adjacent vessels that cross a relatively open blood-nerve barrier junction at the oculomotor nerve exit. A sterile inflammation is induced that further opens the blood-brain barrier. Demyelination results in Schwann cell proliferation and edema in the ocular motor nerve as it emerges from the brainstem. Subsequent third nerve compression from nerve hypertrophy and scar formation, after repeated episodes of demyelination and remyelination, could result in permanent oculomotor nerve paralysis or aberrant regeneration.53

Pathophysiology

Numerous theories have been advanced to provide a unified theory for migraine phenomenology and the associated headache. Most agree that migraine represents a complex system malfunction and that the system can malfunction in many different ways. The centerpiece involves a susceptibility to recurrent headaches that are initiated by inappropriate environmental triggers. Affected patients have probably inherited one or more polymorphisms that, somewhere along the cascade of migraine events, cause instability. One susceptibility is to

cortical aura, but whether the aura is causal to the headache or simply another manifestation of the same genetic/environmental susceptibility that causes the headache is hotly disputed. Understanding migraine pathogenesis is further complicated by the dynamic nature of the system. A repeatedly activated biologic system changes over time so that a dynamic system malfunction that has most of its roots in genetic susceptibility can evolve new characteristics.

The original vasogenic theory,432 which viewed migraine as a form of vascular dysregulation, assumed that the aura was due to a transiently induced ischemia, and the headache due to a rebound vasodilatation that caused a mechanical depolarization of primary nociceptive neurons within the walls of engorged intracerebral and extracerebral vessels.71 This theory has been largely supplanted by the neurogenic theory, which views migraine as a disorder of the brain in which vascular changes follow neuronal dysfunction.71,218,295 However, neither theory can fully account for all of the clinical and treatment responses of migraine, alone.71

Olesen et al294 have used serial cerebral blood-flow measurement by the intracarotid xenon-133 technique to show that patients with classic migraine have localized decreases in blood flow beginning in the occipital lobes that spread continuously along the cerebral cortex and do not follow a vascular pattern. Bilateral cerebral hypoperfusion beginning in the occipital lobes and spreading anteriorly into the temporal and parietal lobes was also recently documented by positron emission tomography (PET) scanning during a classic migraine attack.433 The region of decrease in cerebral blood flow expands at a rate of 2.2 mm/min, which is similar to the rate of spread of experimentally produced spreading depression through the occipital lobe, as well as the involvement of the visual scotoma reported by many patients with classic migraine.209,218 The concept of spreading depression was introduced on the basis of experimental data in which changes in intracellular/extracellular potassium ion concentrations were induced to spread across the cortex after a central depolarization.222 It was surmised that the reductions in cerebral blood flow, and the spread of the reduction in cerebral blood flow, at a rate similar to spreading depression, could occur because the blood flow to the area decreases in response to the metabolic abnormality.218

Critics of the vasogenic theory contend that the migraine aura is often accompanied by multiple neurological symptoms that are difficult to localize within one neurovascular territory. They also point out that neuroimaging studies conducted during spontaneous, classical visual auras indicate that the decreases in cortical blood flow observed during aura are not sufficient to cause ischemia and that the subsequent vasodilatation does not take place until well after the onset of headache.73 In humans, spontaneous spreading depression is difficult to record because the slowly varying phenomena of spreading depression cannot be observed in surface electro-

encephalography (EEG), but a similar phenomenon has been observed with PET scanning, and it has been demonstrated by magnetic encephalography.414 Whether cortical spreading depression, as it occurs in animals, occurs in the human cortex is unknown, but a related spreading wave of hyperexcitation followed by suppression has been demonstrated using PET scanning to occur in the occipital cortex during visual aura.153

The role of cortical spreading depression in producing migraine is now thought to reflect vasoneural coupling, with the resulting hyperemia followed by oligemia representing a neurometabolic rather than a blood flow phenomenon. Patients complain of throbbing pain in the head, but there is no reliable relationship between vessel diameter and the pain207 or its treatment.237 According to Goadsby, migraine aura cannot be the solitary trigger for pain because the aura occurs in less than 30% of migraine patients. Conversely, the aura can be experienced without any pain at all. These findings indicate that cortical spreading depression does not cause migraine pain but that the aura and the trigeminovascular activation are manifestations of the same neuronal hyperexcitability.133

In addition to examining cortical spreading depression and its relationship to visual migraine symptomatology, the study of migraine pain has elucidated mechanisms of trigeminal nerve activation.130,219,282 According to the trigeminovascular theory of Moskowitz,282 migraine headache involves dysfunction of brainstem pathways that normally modulate sensory input. The key pathways for pain are the trigeminovascular input for the meningeal vessels, which passes through the trigeminal ganglion and synapses on secondorder neurons in the trigeminovascular complex. The dura mater is innervated by branches of the trigeminal nerve.128 Stimulation of the trigeminal ganglion results in plasma protein extravasation,257 cerebral vasodilatation,130 and local nerve stimulation in dural vasodilatation.424

Neurogenic inflammation is associated with release of neuropeptides and cytokines (e.g., substance P, CGRP, neurokinin A), dilatation of vessels, leakage of plasma and plasma proteins into surrounding tissue, and a mast cell response with release of histamine.133 Stimulation of the superior sagittal sinus activates neurons in the trigeminal nucleus caudalis and in the dorsal horn at the C1 and C 2192 levels in the cat and monkey (the trigeminocervical complex).128,131 This trigeminocervical system permits convergent sensory input from the head and neck to the trigeminal nucleus caudalis and C1, C2, and C3 to refer head pain to the back of the neck.

Knight and Goadsby201 postulated that the role of the periaqueductal gray is to inhibit afferent trigeminal nociceptive traffic and that brainstem dysfunction might lead to disinhibition of trigeminal afferents and be important in the process of migraines.