Migraine

Migraine

    * History

 The history of man's suffering from headache dates back to 9000 years ago when basic drastic therapy of that time was trepanation(1). Headache with neuralgia was recorded in the medical documents of the ancient Egyptians as early as 1200 BC. (2)

In 400 BC Hippocrates described the visual aura that can precede the migraine headache, and the relief that can be induced by vomiting. Aretaeus of Cappadocia (3) is credited as the discoverer of migraine because of his classic description of the symptoms of a unilateral headache associated with vomiting with headache free intervals in between attacks in the 2nd century. (4)

        Galenus of Pergamon used the term "hemicrania", from which the word "migraine" was derived. He thought there was a connection between the stomach and the brain because of the nausea and vomiting that often accompany an attack. For relief of migraine. Spanish-born physician Abulcasis, also known as Abu El Quasim, suggested application of a hot iron to the head or insertion of garlic into an incision made in the temple. (6)

 In the medieval Ages migraine was recognized as a discrete medical disorder with treatment ranging from hot irons to blood letting and even witchcraft. Followers of Galenus explained migraine as caused by aggressive yellow bile.(6)

 Ebn Sina (Avicenna) described migraine in his textbook “El Qanoon fel teb” as  “… small movements, drinking and eating, and sounds provoke the pain… the patient cannot tolerate the sound of speaking and light. He would like to rest in darkness alone”. (5)

Abu Bakr Mohamed Ibn Zakariya Râzi noted the association of headache with different events in the lives of women, “...And such a headache may be observed after delivery and abortion or during menopause and dysmenorrhea”. (5)

In 1712 Bibliotheca Anatomica, Medic, Chirurgica, published in London, characterized five major types of headaches, including the "Megrim," recognizable as classic migraine. (6)

          Graham and Wolff (1938) published their paper advocating ergotamine tart for relieving migraine. Later in the 20th century, Harold Wolff (1950) developed the experimental approach to the study of headache and elaborated the vascular theory of migraine, which has come under attack as the pendulum again swings to the neurogenic theory.(6)

  In 1962, an Ad Hoc Committee established descriptive definitions of migraine, tension-type headache (TTH), and other headache disorders.  In 1988, the International Headache Society (IHS) published a formal classification system for the diagnosis of headache disorders. This system is currently being reevaluated, modified, and improved (7)   The French word migraine is said to be derived from megrim, which in turn was derived from the Latin word hemicrania and its corrupted forms are hemigranea and migranea.(8)

  Classification of Migraine
International Headache Society Classification of Migraine (9)

          Migraine without aura
          Migraine with aura
          Migraine with typical aura
          Migraine with prolonged aura
          Familial hemiplegic migraine
          Basilar migraine
          Migraine aura without headache
         Migraine with acute-onset aura
          Ophthalmologic migraine
          Retinal migraine

Epidemiology of migraine

  Migraine is a painful, disabling, and common disorder that imposes a substantial burden on individual headache sufferers and society at large (10). Most individuals with migraine suffer severe pain and disability, however many do not seek medical care (11). Only about 50% of migraine sufferers seek medical attention for their headaches. Of these consulters, approximately half receive a physician diagnosis of migraine (12)
Migraine creates a significant and chronic burden for the patient in terms of pain and its effects on functional capacity and quality of life during and between attacks. (13,14) Patients with chronic headache have a lower quality of life than do healthy people (15) and often function less well than do patients with arthritis, diabetes, depression, or back problems, The World Health Organization ranks migraine among the world’s most disabling medical Illnesses. Severe migraine was deemed to be more painful and disabling than many serious disorders for which medical legitimacy is never questioned (e.g., paraplegia and hemiplegia). (10)
 The indirect costs of migraine are far greater than the direct costs. The U.S. annual direct medical costs for migraine were about $1 billion. Of the direct medical expenses, physician visits comprised 60% of the costs. (16)
Incidence
 Few studies of migraine incidence have been performed. One study reported that the rate of migraine is a of 17.0 per 1,000 person years (24.0 women, 6.0men) however these data are limited by the  relatively narrow age range . a population-based study conducted by Rasmussen showed that the annual incidence of migraine is  3.7 per 1,000 person years (women 5.8; men 1.6). Neither age-specific incidence nor incidence by migraine subtypes was reported. (17)
   Prevalence

In a meta-analysis of international studies during the years 1962 to 1992, estimated prevalence for migraine ranged from 13% to 17% of women and 7.6% to 14% of men, depending on the sample (18).

In the United States (US), migraine occurs in approximately 12% of the population. (18) In the first American Migraine Study (AMS-1) (1989), 17.6% of women and 6% of men had had one migraine attack in the previous year (18). The second American Migraine Study, done 10 years later, had similar prevalence estimates (18.2% in women and 6.5% in men). (19)

Migraine prevalence varies by age, gender, race, and income. Before puberty, migraine prevalence is approximately 4%. As adolescence approaches, prevalence increases more rapidly in girls than in boys (20). It increases until approximately age 40, and then declines. In the United States, migraine prevalence is inversely related to income (i.e., migraine prevalence falls as household income increases). (21, 19)
In France overall lifetime prevalence for migraine is 7.9% (11.2% for women and 4.0% for men). Whereas that of migrainous disorder (IHS category 1.7) was 9.1%. (22) While in Oman a positive family history of headache was found in 57.6% of students. The prevalence rate of migraine and tension-type headache was found to be the same (12.2%), with a difference in distribution across sexes: 6.6% of the men and 15.5% of women had migraine, while 13.9% of men and 11.1% of the women suffered from tension-type headache (23)
In a study of Egyptian school children in Assiut, the prevalence of migrainous headache was 16.6% with higher rates for females 18.8% than males 14.4 % with female to male ratio 1.33 migraine without aura represented 81.1% of the studied group. There was a significant increase of migraine prevalence with age, and lower social class (24).
* Migraine co-morbidities
Migraine and epilepsy

The association between migraine and epilepsy has been extensively documented. The median prevalence of epilepsy in migraineurs is 5.9% (range, 1% to 17%), as compared with a usual overall prevalence of 0.5% to 1.0% in the general population.
Migraine and psychiatric diseases
Clinical observations in subspecialty clinics have suggested that patients with migraine frequently exhibit certain personality traits, such as rigidity, perfectionism, oversensitivity, competitiveness, and a tendency to become frustrated easily. The lifetime rates of affective and anxiety disorders are increased in individuals with migraine. Studies comparing migraine cases with non migraine controls have shown odds ratios of 4.2 for major depression, 6.1 for panic disorder, and 2.8 for any anxiety disorder.
Migraine and stroke
The relationship between migraine and stroke is particularly complex. In a variety of hospital series, 1% to 17% of strokes occurring in patients younger than 50 years of age were thought to be induced by migraine. stroke increase approximately fourfold in women younger than 45 years of age who have migraine. The association between migraine and stroke increases substantially in women who smoke or use oral contraceptives and particularly in women with both risk factors. (10)

Pathophysiology

The pathophysiology of migraine is not fully understood (25). Recent studies have shed light on the neuronal events mediating the aura and headache phases of migraine. Spreading Cortical depression (SCD) appears to underlie the aura phase in patients with migraine with aura (26, 27), and it may also precede headache in patients with migraine without aura. Recent evidence suggests that the pain of the headache phase is mediated by the trigeminal vascular system and its central projections. (28)
Mechanism of the aura
One fifth of migraineurs experience aura, predominantly visual in nature, before headache onset. (29) The mechanism mediating aura is considered a human analogue to the cortical phenomenon of spreading depression first observed by Leao in 1944(30,31) and Lashley (32)  who calculated  the growth of his own migrainous fortification spectrum corresponding to an event moving across the cortex at a rate of 2 to 3mm/minute.
Cortical stimulation initiates excitation followed by depression of normal neuronal activity that spreads slowly from the focal site of stimulation at rates between 2 and 6 mm per minute. the phase of oligemia  begins in one occipital pole and spreads forward over the ipsilat­eral hemisphere .Spreading depression does not follow vascular boundaries but crosses the areas perfused by the middle and posterior cerebral arteries while advancing with a distinct wave front until some major change in cortical cellular architecture is reached (e.g.; at the central sulcus)., although pial arterial and venous dilation occur simultaneously with the first activated neural activity. (33)
Olesen and Lauritzen (34,35,36), using Xe single photon emission tomography (SPECT) found 17% to 35% reductions in CBF in posterior regions of the brain, which spreads anteriorly across contiguous areas of cortex at a rate of about 2 to 3mm per minute. It crossed isolated vascular territories and is thus not due to segmental vasoconstriction. Reduced CBF persisted from 30 minutes to 6 hours, then slowly returned to baseline or even increased. Focal hyperemia at times preceded the hypoperfusion. The rates of progression of spreading oligemia are similar to those of migrainous scotoma and CSD, suggesting that these phenomena are related (37).
Additional studies using single photon emission tomography (38, 39, 40), positron emission tomography (41) and MRI (42) support the hypothesis that CSD is the basis for the migraine aura. (43)
Although the cerebral cortex is insensitive to pain, it initiates a painful phenomenon. This stimulated many research to study this point. Bolay et al (44) demonstrated increase in flow of the middle meningeal artery (MMA) after SCD, which was produced by trauma. To clarify the mechanisms underlying these events the trigeminal nerve was transected and demonstrated lack of the delayed phase of increased blood flow in MMA. Furthermore the expression of c-fos a surrogate marker of pain was increased in lamina I and II in trigeminal nucleus caudalis. There was also plasma protein extravasation noted in the experiment which was noted to be mediated by neurokinin I. This Important study clearly demonstrated the link between head pain of migraine and SCD( the putative mechanism of aura).
* Genesis of the headache syndrome
Stimulation of the large cranial vessels and dura mater has long been known to cause headache pain in humans (43). Afferent fibers from these intracranial sites project through the ophthalmic tract of the trigeminal nerve, with cell bodies in the trigeminal ganglion. The trigeminal ganglion neurons also project to the trigeminal nucleus caudalis of the brainstem and C1 and C2 regions of the spinal cord. Together, these trigeminal neurons and the innervated intracranial structures comprise the trigeminovascular system(45,46,47).The vasodilator peptides calcitonin gene-related peptide (CGRP), substance P, and neurokinin A are found in the cell bodies of trigeminal neurons. (48)
 Stimulation of the trigeminal ganglion in cats and humans treated for trigeminal neuralgia leads to an increase in release of these neuropeptides. (49) Venous concentrations of CGRP but not substance P increase during the headache phase of migraine. (50)
CGRP infusion triggers headaches, some migraine-like, in humans, (51) and stimulation of the pain-producing superior sagittal sinus results in release of CGRP, but not substance P. Furthermore, CGRP levels in humans decrease as headache subsides after administration of the antimigraine agent sumatriptan. (52) These observations indicate that venous levels of CGRP may be used as a marker for migraine. Further studies are needed to elucidate the CGRP-mediated mechanisms responsible for migraine headache (53).
          Stimulation of trigeminal sensory neurons induces inflammation and plasma protein extravasation (PPE). (54)The vasoactive peptides substance P and neurokinin A, released by the trigeminovascular system, cause PPE from the vessels, mast cell degranulation, platelet adherence and aggregation, endothelial activation, and formation of endothelial vesicles, microvilli, and vacuoles.(55) The result is meningeal inflammation that persists for minutes to hours. The antimigraine agents sumatriptan, ergotamine, dihydroergotamine, and methysergide have been shown to block this PPE, thereby reducing neurogenic inflammation. (54)
Although trigeminal ganglion stimulation elicits PPE in animals, it is not clear whether PPE and meningeal inflammation occur in humans during migraine. It is not possible to measure changes in PPE in humans directly. Studies of the pharmacology of sumatriptan and related 5-HT1B/1D receptor agonists question the role of PPE in migraine. (56)
The anatomy of the projections to the trigeminocervical complex can explain several clinical aspects of migraine. Patients with primary headache complain of pain that does not respect the cutaneous boundaries of either the trigeminal or the cervical nerves. The diffuse pattern of nerve activation in the trigeminocervical complex in response to superior sagittal sinus stimulation shows great anatomic overlap with innervation from other intracranial vessels (57)
          Brainstem activation occurs in attacks of spontaneous migraine without aura. Using PET, in patients with only right sided migraine headache, regional cerebral blood flow (rCBF) was increased bilaterally in the cingulate, auditory association, and visual association cortices, and on the left side only in the inferior anterocaudal cingulate cortex. There was increased rCBF in the left brainstem, anterior to the aqueduct, and posterior to the corticospinal tract. Sumatriptan relieved the headache and its associated symptoms and reversed the cerebral but not the brainstem increase in rCBF. Since the rCBF increase in the brainstem persisted despite resolution of the headache, it seems likely that the activation is due to factors other than, or in addition to, increased activity of the endogenous antinociceptive system in the periaqueductal grey and locus caeruleus. Activation of the brainstem may be inherent in the migraine process itself. (58)

Welch et al. (59) have proposed a theory of central neuronal hyperexcitability. Although the pathways mediating headache pain may be the same in all individuals, these pathways are thought to be more easily triggered in patients with episodic migraines. Several findings support this view. Interictal differences in brain activity between healthy individuals and migraineurs appears in  studies showing that the level of transcranial magnetic stimulation to the occipital cortex required to produce phosphene generation is substantially lower in patients with migraines with aura between their headaches than it is in healthy controls. (60, 61, 62)

Serotonin (5-HT) Receptors and Migraine
Serotonin (5-HT) receptors consist of at least three distinct types of molecular
Structures:
Ø  Guanine nucleotide G protein-coupled receptors,
Ø  Ligand-gated ion channels,
Ø  Transporters.
There are seven classes of 5-HT receptors: 5-HT1, 5-HT2, 5-HT3, 5-HT4,

5-HT5, 5-HT6, and 5-HT7. In humans, there are five 5-HT1 receptor subtypes: 5-HT1A, 5-HT1B, 5-HT1D, 5-HT1E, and 5-HT1F. (6)
The 5-HT1B receptor is located on intracranial blood vessels and CNS neurons. The 5-HT1D receptor is located on CNS neurons and trigeminal nerve endings. 5-HT1F receptors are located on trigeminal nerve endings.(64)The ergots and triptans act at the 5-HT1B, 5-HT1D, and in part at the 5-HT1F receptors. They can constrict extracerebral intracranial vessels, inhibit activity in peripheral trigeminal neurons, and block transmission in the trigeminal nucleus.
Triptans minimally constrict the human coronary artery. Triptans and ergots block neurogenic PPE, (65) presumably by activating prejunctional trigeminal 5-HT1D and 5-HT1F heteroreceptors, blocking neuropeptide release. Neurogenic PPE can be also be blocked by NSAIDs, GABA agonists (valproate). They also reduce activity of second order trigeminal neurons through 5-HT1D and/or 5-HT1B receptors. Dihydroergotamine (DHE) and the centrally penetrating triptans pass through the blood-brain barrier and label nuclei in the brainstem and spinal cord that are intimately involved in pain transmission and modulation. The caudal trigeminal nucleus is activated by stimulation of the sagittal sinus, and this activity is transmitted to the thalamus. Ergots and triptans suppress this activation. (66)

 

     * Migraine triggers

A migraine trigger is any factor that on exposure or withdrawal leads to the development of an acute migraine headache. Triggers may be categorized as behavioral, environmental, infectious, dietary, chemical, or hormonal. (67)
common migraine triggers(67)
Behavioral
Fasting
Emotions
Sleep disturbances
Stress
Exercise
Environmental
Bright light/visual stimuli
Odors
Weather changes
Cigarette smoke
Infectious
Upper respiratory infections
Dietary
Caffeinated beverages
Alcoholic beverages
Aged cheeses
Chocolate
Ice cream
Chemical
Monosodium glutamate
Tyramine
Nitrates
Aspartame
Hormonal
Menstruation

The typical migraine patient is exposed to a myriad of migraine triggers on a daily basis. These triggers potentially can act at various sites within the cerebral vasculature and the central nervous system to promote the development of migraine headache. The challenge to the physician is in the identification and avoidance of migraine trigger factors within patients suffering from migraine headache. (68, 69, 70)

     * Clinical picture
The migraine attack can be divided into four phases:

1.     The prodrome, which occurs hours or days before the headache;
2.     The aura, which immediately precedes the headache;
3.     The headache itself; and,
4.     The postdrome.(71)
The first phase or prodrome

Prodromal symptoms occur in 40% to 60% of migraineures. This phase consists of altered mood, irritability, depression or euphoria, fatigue, yawning, excessive sleepiness, craving for certain food (e.g., chocolate), and other vegetative symptoms (72, 73), all of which suggest origin of these symptoms in the hypothalamus, perhaps resulting from excessive dopamine stimulation (74). These symptoms usually precede the headache phase of the migraine attack by several hours or days, and experience teaches the patient or observant family that the migraine attack is near.
 Two types of migraine prodrome may occur non-evolutive ,which precedes the attack by 48 hours and evolutive which starts 6 hours before the attack, gradually increasing in intensity and culminating in the attack (73,78)
The second phase or the aura:
The migraine aura is comprised of focal neurological phenomena that precedes or accompany the attack. They appear gradually over 5 to 20 minutes and usually subside just before the headache begins.  Symptoms of migraine aura are usually sensory in nature (20, 76). They are visual in 99% and sensory in 31%. And may involve motor, language or brainstem disturbances (77). The aura symptoms usually precede the headache phase of the migraine attack but occasionally occur simultaneously. Sometimes, two aura symptoms occur in the attack, or may occur in isolation. Rarely, auras may occur repeatedly. This may be many times and as long as several months. These have been termed "migraine aura status" yet other organic causes should be considered   (78)
Visual aura is the most common of the neurological events. There is a disturbance of vision consisting usually of unformed flashes of white or, rarely, of multicolored lights (photopsia) or forma­tions of dazzling zigzag lines (arranged like the battlements of a castle, hence the term fortification spec­tra or teichopsia). Some patients complain of blurred or shimmering or cloudy vision, as though they were look­ing through thick or smoked glass. These luminous hallucinations move slowly across the visual field for several minutes and may leave scotomatous defects; the latter are usually bilateral and often homonymous (involving corresponding parts of the field of vision of each eye), pointing to their origin in the visual cortex. Visual abnormalities of retinal and optic nerve origin have also been observed (20, 79)
The somatosensory aura of migraine consists of digitolingual or cheiro-oral paresthesias, a feeling of pins-and-needles experienced in a hand and arm as well as in the ipsilateral nose-mouth area.. Paresthesia migrate up the arm, and then extend to involve the face, lips, and tongue. Paresthesias can become bilateral and may be followed by numbness and loss of positional sense.  More complex symptoms include difficulties in the perception and use of the body; speech and language disturbances; states of double or multiple consciousnesses associated with de ja vu or jamais vu; and elaborate dreamy, nightmarish, trancelike, or delirious states. Motor symptoms, when they occur, are usually associated with sensory symptoms, but true weakness is rare and usually unilateral. (79)
 Periodic neurologic phenomena, which may be the aura of migraine, can occur in isolation without the headache. these phenomena (scintillating scotoma, recurrent sensory, motor, and mental phenomena must  be differentiated from other neurologic disorders.(79)
The third phase: the headache
The typical migraine headache is unilateral, throbbing, moderate to   severe, and aggravated by physical activity (9). Not all of these features are required. The pain may be bilateral at the onset or start on one side and become generalized, usually alternates sides from one attack to the next. The onset is usually gradual. The pain peaks and then subsides, and usually lasts between 4 and 72 hours in adults and 1 and 48 hours in children. The frequency of attacks is extremely variable, from a few in a lifetime to several times a week, and the average migraineur experiences from one to three headaches a month. The head pain varies greatly in intensity. Pain is throbbing in 85 percent of cases, although throbbing pain is not diagnostic of migraine because it is often described in other headache types. (80, 75)
The pain of migraine is invariably accompanied by other features. Anorexia is common, and nausea occurs in almost 90 percent of patients, while vomiting occurs in about one third of patients. Many patients experience sensory hyperexcitability manifested by photophobia, phonophobia, and osmophobia, and seek a dark, quiet room. Blurred vision, nasal stuffiness, diarrhea, polyuria, pallor, or sweating may be noted during the headache phase. There may be localized edema of the scalp or face, scalp tenderness, prominence of a vein or artery in the temple, or stiffness and tenderness of the neck. Impairment of concentration and mood are common. Lightheadedness, rather than true vertigo, and a feeling of faintness may occur. The extremities tend to be cold and moist.(77,80)
Following the headache, during the postdrome phase, the patient may feel tired, "washed out," irritable, and listless, and may have impaired concentration, scalp tenderness, or mood changes. Some people feel unusually refreshed or euphoric after an attack, whereas others note depression and malaise (77).
* The International Headache Society (IHS) classification and diagnostic criteria
These criteria were developed by a committee of experts and have been widely accepted. The criteria provide a hierarchical classification of all headache disorders (9) and have been translated into more than 15 languages. They also provide explicit diagnostic criteria for all headache disorders. Most headaches can be classified using this system. Since the development of the IHS classification and diagnostic criteria, many studies have shown that they are a valid, reliable, and comprehensive diagnostic tool (81, 82)

table (3) International Headache Society Diagnostic Criteria for Migraine With Aura(9)
 At least 2 attacks fulfilling B

   1. At least 3 of the following characteristics:
         1. One or more fully reversible aura symptoms indicating focal brain dysfunction
         2. At least 1 aura symptom develops gradually over more than 4 minutes or 2 or more symptoms occur in succession
         3. No single aura symptom lasts more than 60 minutes
         4. Headache follows aura with a free interval of less than 60 minutes (it may also begin before or simultaneously with the aura)
   2. History, physical examination, and, where appropriate, diagnostic tests exclude a secondary cause


At least 5 attacks fulfilling B–D

   1. Headache lasting 4–72 hours (untreated or unsuccessfully treated)
   2. Headache has at least 2 of the following characteristics:
         1. Unilateral location
         2. Pulsating quality
         3. Moderate or severe intensity (inhibits or prohibits daily activities)
         4. Aggravation by walking stairs or similar routine physical activity
   3. During headache at least 1 of the following:
         1. Nausea, vomiting, or both
         2. Photophobia and phonophobia
   4. At least 1 of the following:
         1. History, physical, and neurologic examinations do not suggest one of the disorders listed in groups 5–11 (headaches secondary to organic or systemic metabolic disease)
         2. History, physical, and neurological examinations do suggest such disorder, but it is ruled out by appropriate investigations
         3. Such disorder is present, but migraine attacks do not occur for the first time in close temporal relation to the disorder.
* Migraine variants
Familial Hemiplegic Migraine (FHM)
FHM is an uncommon autosomal dominant form of migraine headache in which the aura has a “stroke-like” quality producing some degree of hemiparesis. The nosology is somewhat misleading since there is actually a wide diversity of symptoms and signs which can accompany this migraine variant beyond motor deficits.
The discoveries into the molecular genetics of FHM have broadened our understanding of the fundamental mechanisms of migraine and demonstrated the Overlap with other paroxysmal disorders such as acetazolamide-responsive episodic ataxia. Genetic linkage to chromosome 19p13 has been identified in half of the known FHM pedigrees and, more recently, a separate pedigree with linkage to chromosome 1q31 has been reported. The chromosomal 19 defect produces a missence mutation in a neuronal calcium channel gene providing an evidence that FHM represents a channelopathy(83,84).hemiplegic migraine is characterized by transient (hours todays) episodes of focal neurologic deficits which precede the headache phase by 30-60 minutes, but, occasionally, extend well beyond the headache itself. The headache is often, but notinvariably, contralateral to the focal deficit.
The IHS diagnostic criteria for FHM include the following:

1.     The presentation fulfills criteria for migraine with aura.
2.     The aura includes some degree of hemiparesis and may be prolonged.
3.     At least one first-degree relative has identical attacks.(9)
Alternating hemiplegia of childhood
The syndrome has  traditionally been considered a variant of hemiplegic migraine.  Initial symptoms begin before 18 months of life. Affected children have attacks of paralysis: hemiparesis, monoparesis, diparesis, ophthalmoparesis, bulbar paralysis which may be accompanied by variable tone changes (flaccid, spastic, or rigid). A variety of paroxysmal involunary movements including chorea, athetosis, dystonia, nystagmus and respiratory irregularities (hyperpnea) can be seen. (85)
Basilar Migraine (BM)
Also known as basilar artery, vertebro-basilar, or Bickerstaff migraine(86), this clinical entity is the most frequent of complicated migraine variants and is estimated to represent 3-19% of all migraine. This wide range of frequency relates to the rigorousness of the definition.

The I.H.S.(9) criteria require 2 or more symptoms and emphasizes bulbar and bilateral sensorimotor features. The age of onset of BM tends to be in the younger children with mean age being 7 years, although the clinical entity probably appears as early as 12-18 months as episodic pallor, clumsiness, and vomiting .(87)Affected children will have attacks of intense dizziness, vertigo, visual disturbances, ataxia and diplopia. These early transient features last minutes to an hour and are then followed by the headache phase. But unlike the more typical frontal or temporal location, the headache may be occipital in location. The quality of the pain may be difficult for the child to describe and the terms such as pulsing or throbbing may not be used. A small subset of children with BM will have their posterior fossa symptoms after the headache phase is well established.(88)
 Ophthalmoplegic Migraine (OM)
 One of the least common migraine variants. the epidemiological data suggest an annual Incidence of 0.7 per million. The two key features are ophthalmoparesis and headache, though the headache may be mild or a nondescript retro-orbital discomfort. While verbally sophisticated school aged children may describe blurred vision or diplopia, young children may simply rub their eye. Attacks of OM have been reported during infancy, as early as 5-7 months of age. Ptosis, adduction defects and skew deviations are the common objective findings.
acute treatment with steroids and prophylactic treatment must be considered.(89,90)
Retinal Migraine
Also referred to as ocular, ophthalmic or anterior visual pathway migraine, this variant is extremely uncommon in children and usually seen in young adults. Unlike the descending curtain-like onset of amauroses fugax, affected patients will report brief (seconds to <60 minutes), sudden, monocular black or gray "outs", or bright, blinding episodes (photopsia) of visual disturbance before, after, or during the headache. (90)
Benign Paroxysmal Vertigo
 Typically, an affected young child (median 18 months) child will be struck by a sudden unsteadiness on their feet. They will anxiously grab onto a nearby table, chair or adult for stability or fall to the ground. Consciousness will not be lost but astute observers may notice nystagmus. Vomiting may be vigorous. The spells usually last minutes and afterward the child will sleep. Upon awakening, the children return to their normal baseline. The spells will occur in clusters over several days, then subside for weeks or months. These spells probably represent the early evolution of basilar migraine and the differential diagnosis would be similar. During a long-term follow-up of 7 cases, Lanzi reported 5 of 7 BPV cases spontaneously resolved and 6 of 7 patients later developed migraine and other migraine-related symptoms. The authors suggest that BPV can be interpreted as a migraine precursor(91).

    * Investigations
Headache is a common disorder with many potential causes. The primary headache disorders, which include migraine, cluster, and tension-type headaches, account for the majority of headaches (108), while secondary headaches, which are those with underlying pathology (e.g., tumor, aneurysm, or giant cell arteritis) are far less common. Most patients presenting with headache in the primary care setting do not have serious underlying conditions. The relative rarity of secondary headaches, compared with the large number of patients with primary headache, raises concern about the wisdom of routine neuroimaging studies, either computerized tomography (CT) or magnetic resonance imaging (MRI), to exclude underlying causes of headache(109,110, 111).
In adult patients with recurrent headaches defined as migraine, including those with visual aura, with no recent change in headache pattern, no history of seizures, and no other focal neurologic signs or symptoms, the routine use of neuroimaging is not warranted. (110)
Reasons to consider neuroimaging in migraine
Unusual, prolonged, or persistent aura
Increasing frequency, severity, or change in clinical features
First or worst migraine
Basilar, confusional migraine
Hemiplegic
Late-life migraine accompaniments
Aura without headache
Headaches always on the same side
Posttraumatic
Patient or family and friends request
Meta-analysis of patients with migraine and a normal neurological examination found a rate of significant intracranial lesions of 0.18 % (2/1000); previously reported rates of finding intracranial lesions with CT and MRI ranged from 0.3% to 0.4%. Neuroimaging is thus unlikely to reveal an abnormality on MRI or CT scanning in patients with migraine and a normal neurological examination. MRI appears to be more sensitive in finding white matter lesions and developmental venous anomalies than CT. (110,111)
Blood tests generally are not helpful for the diagnosis of headaches. There are numerous indications, however, such as the following: erythrocyte sedimentation rate (ESR) or C-reactive protein to evaluate for temporal arteritis; ESR, rheumatoid factor, and antinuclear antibody in a patient with headaches and arthralgias to evaluate for collagen vascular disease such as lupus (111)
The electroencephalogram  is not useful in the routine evaluation of patients with headache. This does not exclude the use of EEG to evaluate headache patients with associated symptoms suggesting a seizure disorder such as atypical migrainous aura or episodic loss of consciousness. Assuming head imaging capabilities are readily available, EEG is not recommended to exclude a structural cause for headache. (112)
MR imaging or CT scan is performed before a lumbar puncture for the evaluation of headaches except in some cases in which acute meningitis is suspected and there are no focal findings. Lumbar puncture can be diagnostic for meningitis or encephalitis, meningeal carcinomatosis or lymphomatosis, SAH, and high (e.g., pseudotumor cerebri) or low CSF pressure diseases (111)
Treatment
Migraine is not always managed effectively by physicians and continues to be under-diagnosed and under-treated in clinical practice, about half of migraine patients stop seeking care for their headaches, partly because they are dissatisfied with therapy. Indeed, public surveys indicate that headache sufferers are among the most dissatisfied patients. (12)
Migraine is heterogeneous (among sufferers and between attacks) in frequency, duration, and disability. Some migraineurs have fewer than one attack a month while others have one or more attacks a week. (17)Some are quite disabled by their headaches, while others are not. Therefore, it is appropriate to stratify the care of the migraine population by headache frequency, severity, and level of disability, and to consider prevention for those patients whose migraine has a substantial impact on their lives. (92)
General principles of management (93)
·       Establish a diagnosis.
·       Educate migraine sufferers about their condition and its treatment. Discuss the rationale for a particular treatment, how to use it, and what adverse events are likely.
·       Establish realistic patient expectations by setting appropriate goals and discussing the expected benefits of therapy and how long it will take to achieve them. Empower the patients to be actively involved in their own management by encouraging patients to track their own progress through the use of diary cards, flow charts, headache calendars, and forms for tracking days of disability or missed work, school, or family activities. Treatment choice depends on the frequency and severity of attacks, the presence and degree of temporary disability, and associated symptoms such as nausea and vomiting.
·       Create a formal management plan and individualize management: consider the patient’s response to, and tolerance for, specific medications. Consider comorbidity/coexisting conditions. Coexisting conditions (such as heart disease, pregnancy, and uncontrolled hypertension) need to be ascertained as they may limit treatment choices.
·       Encourage the patient to identify and avoid triggers.
Treatment of acute attacks of migraine
The goals of migraine management are to treat attacks rapidly and consistently, restore the patient’s ability to function, minimize the use of back-up and rescue medications, optimize self-care and reduce subsequent use of resources, be cost effective for overall management, and have minimal or no adverse events.(93)
Analgesics and NSAIDs
Aspirin, ibuprofen, tolfenamic acid, naproxen sodium, the acetaminophen ,aspirin, and caffeine  combination, and acetaminophen and butalbital-containing(95) agents are effective in acute migraine treatment.(94)
Specific Medications
Ergotamine, DHE, and the triptans are potent agonists for the 5-HT1B/1D and in some cases the 5-HT1F receptors. The ergots have much greater receptor affinity at 5-HT1A, 5-HT2, adrenergic, and dopaminergic receptors than the triptans, leading to more adverse effects. All are indicated for acute migraine treatment. Patients with sepsis, renal or hepatic failure, and cerebral or peripheral vascular disease should avoid ergotamine and DHE. There is remarkably little consensus among physicians as to how many risk factors preclude the use of triptans and what constitutes an appropriate evaluation.(97,98)
Selective 5-HT1 Agonists (Triptans)
The first triptan was sumatriptan, followed by zolmitriptan, naratriptan, rizatriptan, almotriptan, frovatriptan, and eletriptan. All are more centrally penetrant than sumatriptan. Eletriptan’s central penetrance is usually limited, since it is a substrate for the p-glycoprotein (PGP) pump. Drugs that inhibit the PGP pump would allow higher central penetrance. All the triptans are effective.Patients whose migraine attacks are associated with moderate to significant disability or who fail to respond to other medications are candidates for treatment with a triptan.Triptans relieve head pain and nausea and vomiting. They are effective even if given after the onset of migraine, but are more effective when the pain is mild.
Seven triptans (sumatriptan, zolmitriptan, naratriptan, rizatriptan, almotriptan, frovatriptan, and eletriptan) are currently available. They are safe, effective, and appropriate first-line therapy for the patient who has a moderate to severe migraine headache or for whom analgesics have failed to provide adequate relief.(96)

 What form of triptan should be used?

 Headache severity, rapidity of onset, and duration are important factors when making treatment decisions. When the headache intensifies rapidly (<30 minutes), or nausea and emesis are early and severe associated symptoms, a non-oral route of administration is appropriate. Subcutaneous sumatriptan is the fastest and most effective triptan. The nasal spray formulation of sumatriptan or zolmitriptan may provide a faster onset of action than the oral triptans, but sumatriptan nasal spray is often associated with a disagreeable taste. The oral formulations can be divided into two classes. Sumatriptan, rizatriptan, zolmitriptan, almotriptan, and eletriptan have the highest 2-hour efficacy, can provide headache relief within 30 to 60 minutes (96, 97, 78)
Ergotamine and Dihydroergotamine
Ergotamine is used to treat moderate to severe migraine if cost is a factor.Some patients still respond preferentially to rectal ergotamine. DHE has fewer Adverse effects than ergotamine and can be administered intramuscularly, subcutaneously, or intravenously. The best efficacy evidence exists for DHE nasal spray. DHE is associated with a low headache recurrence rate (<20%), has fewer Adverse effects, and is less likely than ergotamine to produce rebound headache. Repetitive intravenous DHE has become the mainstay of acute symptomatic treatment for intractable headache (94, 99,113).
Preventive treatment
Prophylactic treatment should be considered only: (102)
1)    When attacks of migraine occur more than two or three times a month.
2)    When the attacks are severe and limit normal activity.
3)    When the patient is unable to cope with the attacks.
4)    When symptomatic therapies have failed or have had serious side effects.
5)    When attempts at non-pharmacological prevention have failed.
Beta-Blockers
Propranolol, nadolol, atenolol, metoprolol, and timolol are effective. Partial
Agonists and those with intrinsic sympathomimetic activity are not effective.
Their relative efficacy has not been established; choice is based on beta-selectivity, convenience of drug formulation, Adverse effects, and the patient's individual reaction. (21)

 Beta-blockers can produce behavioral adverse effects, such as drowsiness, fatigue, lethargy, sleep disorders, nightmares, depression, memory disturbance, and hallucinations; they should be avoided when patients have depression or low energy. Decreased exercise tolerance limits their use by athletes. Less common adverse effects include impotence, orthostatic hypotension, bradycardia. Beta-blockers are useful for patients with angina or hypertension. They are relatively contraindicated for patients with congestive heart failure, asthma, Raynaud's disease, and insulin-dependent diabetes. (101,78)
Antidepressants
Antidepressants consist of a number of different classes of drugs with different mechanisms of action:

A)    MAOIs.
B)    monoamine reuptake inhibitors.
(1)  nonselective tricyclic antidepressants (TCAs).
(2)  selective serotonin reuptake inhibitors (SSRIs).
(3)  selective serotonin and norepinephrine reuptake inhibitors (SNRIs).
C)   monoamine receptor targeted drugs:
(1) serotonin (2) norepinephrine; and (3) dopamine.
Amitriptyline is the only antidepressant with fairly consistent support for efficacy. Adverse effects from TCAs are common: antimuscarinic effects include dry mouth and sedation. They cause increased appetite and weight gain; cardiac toxicity and orthostatic hypotension occur occasionally.[129] There is one positive trial for fluoxetine. Sexual dysfunction is common with SSRIs. Antidepressants are especially useful for patients with comorbid depression and anxiety disorders.(102,78)
Calcium-Channel Blockers
The US Headache Consortium(102) analyzed 45 controlled trials of calcium channel blockers. Flunarizine was effective, nimodipine had mixed results, and nifedipine was difficult to interpret. Verapamil was more effective than placebo in two of three trials, but both positive trials had high dropout rates, rendering the findings uncertain. Constipation is the most common adverse effects of verapamil. Flunarizine is the most effective drug of this class, Adverse effects include Parkinsonism, depression and weight gain.
Anticonvulsant Medications
There is a strong, consistent(102) support for the efficacy of divalproex sodium and sodium valproate. . The most frequently reported. Adverse effects include nausea, infection , alopecia , tremor , asthenia, dyspepsia , and somnolence . Weight gain was reported in some patients. Hepatotoxicity is the most serious side effect, but irreversible hepatic dysfunction is extremely rare in adults. (103)

Gabapentin (1800 to 2400 mg), in a randomized, placebo-controlled, double-blind trial, was superior to placebo in reducing migraine attack frequency by 50% in about one-third of patients. The most common. Adverse effects were dizziness or giddiness and drowsiness. Relatively high patient withdrawal rates due to Adverse effects were reported in some trials.(104)
Topiramate, a derivative of the monosaccharide D-fructose, was effective in reducing migraine attack frequency by 50% in half of the patients.(93)
Divalproex and topiramate are useful in patients with epilepsy, anxiety disorder,
or manic-depressive illness. They can be used in patients with depression, Raynaud's disease, asthma, and diabetes, circumventing the contraindications to beta-blockers(78).
 Serotonin Antagonists
Methysergide is an effective drug for migraine prevention. Adverse effects include transient muscle aching, claudication, abdominal distress, nausea, weight gain, and hallucinations. The major complication is rare (1/2500) retroperitoneal, pulmonary, or endocardial fibrosis. To prevent this complication, a four week medication-free interval is recommended after six-months of continuous treatment(105). Pizotifen though  effective however Adverse effects are multiple they include drowsiness, increased appetite, and weight gain (94).
Natural products
Feverfew(107) (Tanacetum parthenium) is a medicinal herb whose effectiveness has not been totally established. Riboflavin (400mg) was also effective in migraine prophylaxis.
Newer treatments
Botulinum toxin type A (Botox R 0, 25, or 75U) was effective in one placebo-controlled, double-blind trial. It was injected into glabellar, frontalis, and temporalis muscles. The 25U treatment group was significantly better than the placebo group in reduction of mean frequency of moderate to severe migraines during days 31 to 60, incidence of 50% reduction in all migraine at days 61 to 90, and reduction in all migraine at days 61 to 90. (108)