During a migraine attack, patients show increases in regional blood flow in the anterior cingulate cortex (which modulates emotional response to pain) and in the auditory and visual association cortex. Contralateral increases in brainstem blood flow involving the dorsal midbrain to regions including the periaqueductal gray (PAG), the dorsolateral pontine tegmentum,411 and the periaqueductal gray area may be a major trigger for migraine pain. Functional brain imaging with PET has shown activation of the dorsal midbrain, including the PAG and the dorsal pons close to the locus coeruleus, in studies during migraine without aura.411 Dorsolateral pontine activation is observed with PET in spontaneous, episodic, and chronic migraine263 and with nitroglycerintriggered attacks.4,22

Goadsby133 has proposed that migraine aura (a cortical process) and pain (a brain stem process) probably involving the PAG are not causally related but represent dual manifestations of central hyperexcitability. According to Goadsby, either cortical spreading depression or local factors (e.g., substance P, Nitrous oxide (NO), vasoactive intestinal neuropeptide) can trigger activation of the trigeminal autonomic reflex. These abnormal pathways may become entrained by whatever pathophysiology causes overexpression of neuronal activity in different modules of the brain. Migraine has also been attributed to excessive sympathetic nervous system stimulation and its effects on the trigeminovascular system,312 but it remains to be established whether increased sympathetic activity is the cause, rather than the effect, of migraine. At a molecular level, there is evidence for increased extracellular potassium and glutamate and reduced intracellular magnesium levels in the brains of migraine patients.413,414 Stimulation of the serotonergic pathways from the brainstem to the cortex and cerebral arteries may initiate the migraine. Large quantities of serotonin from neurons and platelets are released during the aura, with subsequent depletion of serotonin in the headache stage to follow.

The other major physiologic abnormalities described in migraine pathogenesis relate to platelet function. Elevation of the serum content of the platelet factors has been documented during migraine attacks, including beta-thrombo- globulin and platelet factor IV.74,157 Patients experiencing a migraine attack have been documented to show a decrease in serotonin and a rise in urinary 5-hydroxyindoleacetic acid (5-HIAA).74 It had been postulated that spontaneous platelet aggregation and release of platelet contents in the occipital cortex could trigger spreading depression, with a subsequent drop in regional cerebral blood flow following the migration of spreading depression.176 However, it now appears that platelet activation represents an epiphenomenon, possibly of an underlying endothelial dysfunction in migraineurs.

As stated previously, the known pathophysiology, clinical manifestations, and treatment of migraine bear little resem-

blance to those of isolated vasospasm, with secondary constriction and dilation of intracranial and extracranial arteries. Migraine seems to be a common inherited diathesis, probably dominantly involving central nervous system (CNS) neuronal excitability,413 with vascular epiphenomena involving primarily large and medium-sized vessels. The visual aura in migraine may be related to cerebral ion flux and the headache to edema. It is usually treated with vasoconstriction and anti-inflammatory drugs.428 In contrast, vasospasm denotes a temporary reduction in arterial caliber that is grossly discernible on angiography or retinal examination. It is usually demonstrated in the anterior circulation and best studied at the microvascular level. Vasospasm is rarely accompanied by headache and can be successfully treated with vasodilating agents.427 Therefore, intracranial vasoconstriction is now considered to be an epiphenomenon of vasoneural coupling rather than a cause of migraine.

Genetics

Hereditary factors are important in the individual susceptibility to migraine attacks.71,151 These factors may operate either by inappropriately activating a normal trigeminocervical pain system or by appropriate stimulation of trigeminovascular pain systems with relatively low activation thresholds or in which there are defects in inhibitory modulation.71 The genes for several hereditary migraine syndromes have been discovered.151

There is a clear familial tendency to migraine, which has been well defined in the autosomal dominant form of familial hemiplegic migraine (FHM). In patients with FHM, missense mutations in the alpha1 subunit of the voltage-gated P/Q-type calcium channel have been identified. FHM mutations so far identified include those in CACNA1A (P/Q volt- age-gated Ca2+ channel, ATP1A2 [N+-K+-ATPase] and SCN1A [Na+ channel]) genes. In the early 1990s, FHM became the first migraine syndrome to be linked to a gene defect. The syndrome was later found to be associated with point mutations in the gene CACNL1A4 located on chromosome 19p13 in 50% of affected families.297

Another genetic mutation in a group of families with FHM has been assigned to chromosome 1q31, implying genetic heterogeneity.90 Attempts to link chromosome 19 with the common form of migraine have heretofore been unsuccessful.381 More recently, linkage analysis has been used to identify novel migraine susceptibility genes for the migraine with and without aura in several families on chromosomes 4q24, 6p12.2-21.1, and X(Xq24-2). It is possible that other ion-channel mutations contribute to migraine without aura, because it is primarily cases of migraine with aura that have been linked to the FHM locus.381

It is doubtful that all patients with migraine with aura share the same genetic or pathophysiologic underpinnings.70 Whether migraine aura and its sensory accompaniments are necessarily based on a single proximate pathophysiologic event is also doubtful.70,72 Given that cortical spreading depression can occur without migraine, and vice versa, it seems likely that many factors can trigger the migraine circuit, and spreading depression is just one of them. Migraineurs have a genetically determined reduced threshold for migraine triggers.396 It now seems likely that numerous modules in the brain can be independently affected, and identifying threshold genes and deciphering their function will help unravel the triggering mechanisms for migraine attacks.396

Sequelae

Although migraine is considered to be a largely benign disorder, cortical spreading depression may produce a hypoxic state in the absence of a reduction in cerebral blood flow under conditions of high energy demand.380 Lewis et al234 analyzed the Humphrey 30-2 threshold test results in 60 migraine patients and found visual field abnormalities in 35%. The prevalence of visual field loss was greater with increasing age and duration of disease. More recently, McKendrick et al found long-lasting dysfunction in contrast discrimination, color perception, prolonged visual evoked potentials (VEPs), and decreased visual field sensitivity in people with migraine.8,266,361,438

Some children with migraine develop persistent visual phenomena lasting months to years. Visual symptoms involve the entire visual field and consist of diffuse small particles such as TV static, snow, lines of ants, dots, and rain.243 These patients have normal neurological examinations, neuroimaging, and EEGs, and the persistent symptoms seem refractory to treatment. These persistent positive visual phenomena do not appear to be related to a prolonged migraine aura181 but may be akin to allodynia (pain evoked by nonnoxious stimuli) and to the hyperesthesia that reflects generalized CNS hyperexcitability in these patients.

Although we assure patients that the condition is benign, migraineurs in general have an elevated risk of asymptomatic white matter lesions and stroke compared with nonmigraineurs,82,206,239,403 suggesting that, in some patients, migraine behaves as a chronic, progressive disorder.

Treatment

Before predicating treatment, migraines must be distinguished from the recurrent headaches in children and adolescents in the absence of a family history of migraine and the presence

of a normal neurologic examination.230 Once the diagnosis is established, reassurance that the migraine symptoms are benign is the mainstay of initial therapy. Most practitioners treating children with migraine have noted that there is a significant reduction in the frequency and intensity of migraine in children once the anxiety is relieved.318 Over the long term, most children do well, and many outgrow their migraines. Parents are understandably concerned that their child may have a brain tumor or some other neurological disorder. The parents are often migraine sufferers who have adapted to the condition and are familiar with the fundamentally benign nature of the diagnosis. On occasion, it is possible to introduce the parents to a therapeutic program for their own migraine headaches at the same time the child’s headaches are diagnosed and managed.

Symptomatic relief of pain and nausea is the second order of treatment. Because there is a disappointing lack of evidence from controlled, masked, clinical trials, there are conflicting and insufficient data to make any other recommendations for the preventive therapy of migraine in children and adolescents.231 For children older than 6 years of age, ibuprofen is effective and can be considered for the acute treatment of migraine.155,233

Acetaminophen is superior to placebo in the treatment of migraine.154,164,200,308,366,382,415 However, many children who seek medical attention for their headaches either have tried over-the-counter analgesics with minimal relief from pain, or there has been a change in the frequency, or intensity of their headaches has changed. The avoidance of medications with addictive potential should be encouraged in any treatment plan.

Pharmacological treatment for pediatric headache can be divided into abortive and prophylactic therapy. A few clinical studies have evaluated the use of either abortive or prophylactic medications in the pediatric population. Although most migraine medications do not have pediatric indications for treating headache, many have been used extensively in children and are considered safe and effective. Abortive therapy should be considered for children who experience infrequent headaches (less than two per month), especially if the headaches are preceded by a visual, sensory, or motor aura. Abortive medications are most effective in the preheadache phase. In children under 10 years of age, Imitrex (sumatriptan) nasal spray is effective if administered before central allodynia sets in.46 These medications are less attractive to use in children who are less likely to ask for medication until they have significant head pain or are experiencing other symptoms of migraine, such as vomiting.

Abortive medications include Fioricet (acetaminophen, caffeine, and butalbital), taken 1 or 2 given every 6 h for headache; and Imitrex, 6 mg given subcutaneously at onset of headache.250 Ergotamines are rarely used in children due to their propensity to cause vomiting. Compazine and DHE-