Fisiopatología, manifestaciones clínicas y diagnóstico de migraña en adultos

Autores: F Michael Cutrer, MDZahid H Bajwa, Editor de MDSection: Jerry W. Swanson, MD, editor
MHPEDuty: John F Dashe, MD, PhD

Divulgaciones del colaborador

Todos los temas se actualizan a medida que hay nuevas pruebas disponibles y nuestro proceso de
revisión por pares está completo.

Revisión de literatura actual hasta: abr 2018. | Este tema se actualizó por última vez el 13 de
noviembre de 2017.

INTRODUCCIÓN - La migraña es un trastorno episódico, cuya pieza central es un dolor de cabeza

intenso generalmente asociado con náuseas y / o sensibilidad a la luz y al sonido. Es una de las
quejas más comunes encontradas por los neurólogos en la práctica diaria.

La fisiopatología, las manifestaciones clínicas, el diagnóstico y las complicaciones de la migraña

serán revisados aquí. Otros aspectos de la migraña se discuten por separado. (Consulte
"Tratamiento agudo de la migraña en adultos" y "Tratamiento preventivo de la migraña en
adultos" y "Migraña crónica" y "Migraña con aura del tallo cerebral (migraña de tipo basilar)" y
"Migraña hemipléjica" y "Migraña vestibular" y "Dolor de cabeza" , migraña y accidente
cerebrovascular ".)

FISIOPATOLOGÍA: el estado actual de los conocimientos sugiere que una disfunción neuronal
primaria conduce a una secuencia de cambios intracraneales y extracraneales que explican la
migraña [1], incluidas las cuatro fases de síntomas premonitorios, aura, dolor de cabeza y
posdromo.

La teoría vascular de la jaqueca, que alguna vez fue popular, que sugería que la migraña era
causada por la dilatación de los vasos sanguíneos, mientras que el aura de la migraña era el
resultado de la vasoconstricción, ya no se considera viable [2-4]. La vasodilatación, si se produce
durante los ataques espontáneos de migraña [4], es probablemente un epifenómeno resultante de
la inestabilidad en el mecanismo de control neurovascular central [5].

Depresión de propagación cortical: una asociación causal entre el aura de migraña y el dolor de
cabeza está respaldada por la evidencia de que ambos están relacionados con el fenómeno
conocido como depresión de diseminación cortical de Leão [2,6,7]. La depresión de propagación
cortical es una onda autopropagante de despolarización neuronal y glial que se propaga a través
de la corteza cerebral. La depresión de propagación cortical tiene la hipótesis de:

● Causa el aura de la migraña [8]

● Activar aferentes del nervio trigémino [9,10]

● Alterar la permeabilidad de la barrera hematoencefálica mediante la activación de la

metaloproteinasa de la matriz y la regulación positiva [11]

La activación de los aferentes del trigémino por la depresión cortical propagada a su vez provoca
cambios inflamatorios en las meninges sensibles al dolor que generan el dolor de cabeza de la
migraña a través de mecanismos reflejos centrales y periféricos [12]. La probable cascada
molecular de eventos por los cuales las neuronas aferentes trigeminales sensibles al dolor se
activan por la depresión cortical involucra la apertura de megacanal pannexin-1 neuronal y
posterior activación de caspasa-1, seguida de la liberación de los mediadores proinflamatorios,
activación del factor nuclear kappa -B en astrocitos y la transducción de la señal inflamatoria a las
fibras del nervio trigémino alrededor de vasos pianos [10]. Por lo tanto, esta vía vincula la
depresión cortical dispersa, el fenómeno que se cree subyace a la aura de la migraña, a la
activación prolongada de la nocicepción del trigémino, que genera el dolor de la migraña.

Se ha sugerido que la migraña sin aura puede ser causada por la aparición de una depresión
cortical dispersa en áreas del cerebro (p. Ej., Cerebelo) donde la despolarización no se percibe
conscientemente [13].

Sistema trigeminovascular: la fisiopatología de la migraña implica la activación del sistema

trigeminovascular, que consiste en neuronas sensoriales pseudounipolares de pequeño calibre
que se originan en el ganglio trigeminal y en las raíces dorsal del cuello uterino superior [14]. Estas
neuronas sensoriales proyectan inervar vasos cerebrales grandes, vasos piales, duramadre y
grandes senos venosos. La mayor parte de la inervación de las estructuras anteriores se realiza a
través de la división oftálmica del nervio trigémino con una mayor contribución de las raíces
cervicales superiores a las estructuras posteriores.

Hay convergencia de las proyecciones de las raíces nerviosas superiores del cuello uterino y el
nervio trigémino en el núcleo trigeminal caudalis [15,16]. Esta convergencia puede explicar la
distribución del dolor de la migraña, que a menudo incluye las regiones anterior y posterior de la
cabeza y la parte superior del cuello. Una vez transmitidos al núcleo ceudal del trigémino por los
axones del trigémino, las señales centrales pueden ser moduladas por proyecciones de los núcleos
del trigémino rostral [17], el gris periacueductal y el núcleo del rafe magnus [18] así como por los
sistemas inhibidores corticales descendentes [18]. 19].

A partir del núcleo caudal del trigémino, las fibras que participan en la localización del dolor
ascienden al tálamo (principalmente al núcleo medial ventroposterior del tálamo) y a la corteza
sensorial [20]. Otras neuronas de segundo orden del núcleo trigeminal caudalis proyectan a
numerosos sitios subcorticales incluyendo los segmentos más rostrales del complejo trigémino
[21], la formación reticular del tronco encefálico [22], el cerebelo [23,24], el mesencéfalo y núcleos
parabraquiales pontinos [25,26], el tálamo ventrobasal [21,24,27,28], el tálamo posterior [29,30] y
el tálamo medial [31]. A partir de núcleos del tronco encefálico más rostrales, la información
nociceptiva se transmite a otras áreas cerebrales (p. Ej., Regiones límbicas) implicadas en las
respuestas emocionales y vegetativas al dolor [25].

La estimulación del ganglio trigeminal da como resultado la liberación de neuropéptidos

vasoactivos, incluida la sustancia P, el péptido relacionado con el gen de la calcitonina y la
neurocinina A [32]. La liberación de estos neuropéptidos está asociada con el proceso de
inflamación neurogénica. Los dos componentes principales de esta respuesta inflamatoria estéril
son la vasodilatación (el péptido relacionado con el gen de la calcitonina es un vasodilatador
potente) y la extravasación de proteínas plasmáticas.

Se cree que la inflamación neurogénica es importante en la prolongación e intensificación del

dolor de la migraña. Se han encontrado niveles elevados de neuropéptidos vasoactivos en el
líquido cefalorraquídeo de pacientes con migraña crónica, lo que sugiere la activación crónica del
sistema trigeminovascular en estos pacientes [33]. La inflamación neurogénica puede conducir al
proceso de sensibilización.

Papel de la serotonina: aunque la activación de los receptores de la serotonina es de importancia

conocida en el tratamiento agudo de la migraña, su papel en la generación de la migraña no está
claro [43]. Algunos autores han sugerido que la serotonina (liberada de los núcleos
serotoninérgicos del tallo cerebral) desempeña un papel en la patogénesis de la migraña, quizás
mediada por su acción directa sobre la vasculatura craneal, por su papel en las vías centrales de
control del dolor o por proyecciones corticales cerebrales del tronco encefálico serotoninérgico
núcleos [44,45]. Tal papel para la serotonina está respaldado por el hecho de que los
antidepresivos tricíclicos, que bloquean la recaptación de serotonina, son agentes profilácticos
antimigraña efectivos. En contraste, sin embargo, los inhibidores de la recaptación de serotonina
más selectivos no son muy efectivos en la prevención de la migraña. Hay otra evidencia de que un
bajo nivel de serotonina puede dar como resultado un déficit en el sistema inhibidor del dolor
descendiente de serotonina, lo que facilita la activación de las vías nociceptivas
trigeminovasculares junto con la depresión cortical dispersa [44,45].

Papel del péptido relacionado con el gen de la calcitonina: el péptido relacionado con el gen de la
calcitonina (CGRP) también puede desempeñar un papel en la fisiopatología de la migraña. CGRP
es un neuropéptido de 37 aminoácidos que se expresa en los ganglios del nervio trigémino y es un
vasodilatador potente de los vasos cerebrales y durales [46].
CGRP puede mediar en la transmisión del dolor trigeminovascular desde los vasos intracraneales al
sistema nervioso central, así como también al componente vasodilatador de la inflamación
neurogénica. Sin embargo, la evidencia es conflictiva. La estimulación del ganglio trigeminal induce
la liberación de CGRP [32], y la infusión de CGRP puede desencadenar un ataque de migraña en los
migrañosos [47]. En sujetos sanos sin migraña, un ensayo cruzado controlado con placebo
encontró que la infusión CGRP exógeno causa vasodilatación de la arteria media meníngea
(extracraneal), pero no de la arteria cerebral media (intracraneal), mientras que la infusión de
sumatriptán causa vasoconstricción de la arteria meníngea media [48] . La falta de respuesta
vasodilatadora de la arteria intracraneal a la infusión de CGRP en este ensayo puede explicarse por
la incapacidad del CGRP exógeno para cruzar la barrera hematoencefálica. Aunque un estudio
encontró la elevación de los niveles de CGRP en la sangre venosa yugular externa durante el
ataque de migraña [49], este resultado no se reprodujo en un estudio posterior [50]. Además, el
CGRP no activó ni sensibilizó los nociceptores meníngeos en un modelo animal [51].

Los niveles elevados de CGRP se normalizan en pacientes con migraña después de la

administración de la serotonina 1b / 1d sumatriptan agonista del receptor [52], lo que sugiere que
los triptanos pueden actuar para controlar la migraña al menos en parte mediante el bloqueo de la
liberación de CGRP.

La modulación farmacológica de la actividad de CGRP ofrece la promesa de futuras opciones de

tratamiento para los ataques de migraña aguda. Esto se discute por separado. (Consulte
"Tratamiento agudo de la migraña en adultos", sección sobre "Antagonistas del receptor CGRP").

BASE GENÉTICA: la migraña es un trastorno sindrómico del cerebro que en la mayoría de los casos
se hereda. Al igual que con las enfermedades más comunes, la base genética de la migraña es
probable que sea compleja y en algunos individuos puede basarse en el efecto aditivo de más de
una fuente genética. Los individuos propensos a la migraña tienen un umbral genético que los
hace susceptibles a un ataque de migraña aguda dependiendo del equilibrio entre la excitación y
la inhibición en varios niveles del sistema nervioso. Las anormalidades sutiles, que involucran
canales de membrana, familias de receptores y sistemas enzimáticos se han relacionado con la
migraña en ciertos grupos e individuos.

La importancia de la herencia en la migraña ha sido reconocida desde hace tiempo [53]. Un

estudio temprano basado en la población general encontró que el riesgo de migraña en los
familiares de migrañosos era tres veces mayor que el de los familiares de sujetos control no
migrañosos [54]. Sin embargo, el análisis de segregación no identifica ningún patrón de herencia
mendeliano en las formas comunes de migraña [55]. Los grandes estudios gemelares basados en
el registro nacional han confirmado una concordancia constantemente más alta de migraña en
gemelos monocigóticos versus gemelos dicigóticos. En uno de esos estudios, utilizando un modelo
multifactorial poligénico, los investigadores estimaron que la herencia representa del 40 al 50 por
ciento de la susceptibilidad de un individuo a la migraña [56].
Genética de las formas comunes de la migraña: la base genética de las formas comunes de
migraña (migraña con aura y migraña sin aura) no se ha aclarado a pesar del aumento de la
investigación. Un número de genes candidatos se han relacionado con la migraña, una lista que
incluye el gen KCNK18 que codifica para TRESK, un canal de dos poros de potasio dominio [57], y el
gen CSNK1D, que codifica la caseína quinasa I isoforma delta [58]. Sin embargo, los hallazgos de
estudios genéticos en migraña generalmente no se han replicado en informes posteriores. Como
ejemplo, una reevaluación sistemática de 27 genes candidatos prometedores de migraña en un
gran conjunto de datos compilados a partir de estudios de asociación de genoma completo
(GWAS), con más de 5175 pacientes con migraña y 13.972 sujetos control, encontró que ninguno
de los genes candidatos alcanzó el umbral para la significación estadística [59]. Por lo tanto,
todavía no está claro qué loci candidatos y genes están verdaderamente implicados en la
patogénesis de la migraña.

Las formas comunes de migraña son probablemente trastornos genéticos complejos, lo que
significa que múltiples genes en diferentes sitios genómicos actúan en conjunto con factores
ambientales para conferir tanto la susceptibilidad como las características de la enfermedad en
individuos afectados. Una posible explicación de la falta de replicación en estudios genéticos de la
migraña es que algunos polimorfismos genéticos se prueban con frecuencia para la asociación en
poblaciones relativamente pequeñas en las que solo una parte de los sujetos presenta migraña
que surge de la variante estudiada, mientras que la migraña en otro los sujetos del caso tienen una
base diferente. Esto tendería a disminuir el poder de muchos de estos estudios para detectar una
diferencia significativa en los sujetos de los casos en comparación con los sujetos de control sin
migraña. La identificación eventual de los genes que subyacen a la migraña en un paciente
individual es extremadamente importante, ya que puede predecir el tipo de tratamiento
profiláctico al que responderá el paciente.

Migraña hemipléjica familiar: la migraña hemipléjica puede ocurrir en familias o solo en un

individuo (esporádica). Los primeros tres tipos de migraña hemipléjica familiar (FHM) son
canalopatías. FHM1 es causado por mutaciones en el gen CACNA1A, FHM2 por mutaciones en el
gen ATP1A2, y FHM3 por mutaciones en el gen SCN1A. Las mutaciones en el gen PRRT2 también
causan algunos casos de migraña hemipléjica familiar. Los tipos conocidos de migraña hemipléjica
familiar representan solo una pequeña proporción de casos. (Consulte "Migraña hemipléjica",
sección "Migraña hemipléjica familiar").

EPIDEMIOLOGÍA: la migraña es un trastorno común que afecta hasta al 12 por ciento de la

población general [60]. Es más frecuente en mujeres que en hombres, y los ataques ocurren en
hasta el 17 por ciento de las mujeres y el 6 por ciento de los hombres cada año [61,62]. La migraña
es más común en las personas de 30 a 39 años, un período de edad en el que la prevalencia en
hombres y mujeres alcanza el 7 y el 24 por ciento, respectivamente (figura 1) [62]. La migraña
también tiende a ser hereditaria.
La migraña sin aura es el tipo más común, representa aproximadamente el 75 por ciento de los
casos.

Los datos de varios estudios retrospectivos de cohortes nacionales en Taiwán, todos del mismo
grupo de investigadores, sugieren que la migraña es un factor de riesgo potencial para la parálisis
de Bell, la hipoacusia neurosensorial y las parálisis del nervio craneal oculomotor [63-65]; Se
necesitan informes independientes para confirmar estas asociaciones.

Derivación cardíaca de derecha a izquierda: la migraña con aura se ha relacionado con

cortocircuitos cardíacos de derecha a izquierda, generalmente en el caso de un foramen oval
permeable (FOP) o, con mucha menos frecuencia, un defecto del tabique auricular (TEA) [66]. -68]
o malformaciones arteriovenosas pulmonares.

Right-to-left cardiac shunt — Migraine with aura has been linked to right-to-left cardiac
shunts, usually in the setting of a patent foramen ovale (PFO) or, much less often, an atrial
septal defect (ASD) [66-68] or pulmonary arteriovenous malformations in hereditary
hemorrhagic telangiectasia (Osler-Weber-Rendu syndrome) [69]. (See "Clinical
manifestations and diagnosis of atrial septal defects in adults" and "Clinical manifestations
and diagnosis of hereditary hemorrhagic telangiectasia (Osler-Weber-Rendu syndrome)".)

Evidence regarding the association of migraine with PFO is conflicting.

●In a population-based study of 1101 stroke-free subjects (mean age 69) from the
NOMAS cohort who were evaluated for PFO using transthoracic echocardiography
with saline contrast and provocative maneuvers, there was no significant difference in
the prevalence of PFO among subjects who had migraine compared with those who
did not have migraine (14.6 versus 15.0 percent) [70]. The presence of PFO was not
associated with an increased prevalence of migraine (odds ratio [OR] 1.01, 95% CI
0.63-1.61) or an increased prevalence of migraine with aura (OR 1.01, 95% CI 0.71-
1.69) compared with no migraine.

●A systematic review of case-control studies published in 2008 concluded that

migraine with aura (but not without aura) is more common in patients with PFO than
in the general population, and that PFO is more prevalent in patients who have
migraine with aura than in the general population [71].

While definitive conclusions are not yet possible, the population-based NOMAS study
provides high-quality observational evidence that PFO is not associated with migraine [72].
In contrast, the association of PFO with migraine in the systematic review is supported by
low or low to moderate quality evidence [71].
The mechanism of any possible association between right-to-left cardiac shunt and
migraine is not known. One theory is that a genetic influence might predispose some
patients to a higher risk of developing both atrial septal abnormalities and migraine [73].
Other theories focus on the shunt pathway. As examples, one hypothesis is that the
venous circulation contains vasoactive substances capable of triggering migraine; these
are normally inactivated in the lungs but gain access to the cranial circulation in the
presence of a right-to-left shunt [74]. Another hypothesis is that the existence of the shunt
provides a pathway for paradoxical embolism and subsequent cerebral ischemia, which in
turn triggers migraine. (See "Atrial septal abnormalities (PFO, ASD, and ASA) and risk of
cerebral emboli in adults".)

CLINICAL FEATURES — Migraine is a disorder of recurrent attacks. The attacks unfold

through a cascade of events that occur over the course of several hours to days. A typical
migraine attack progresses through four phases: the prodrome, the aura, the headache,
and the postdrome [75].

Migraine prodrome — The prodrome occurs in up to 77 percent of migraineurs and

consists of affective or vegetative symptoms that appear 24 to 48 hours prior to the onset
of headache [76,77]. Frequently reported prodromal symptoms include increased yawning,
euphoria, depression, irritability, food cravings, constipation, and neck stiffness.

Migraine aura — About 25 percent of people with migraines experience one or more focal
neurologic symptoms in the second phase, called the migraine aura. Traditional teaching
is that migraine aura usually precedes the headache. However, prospective data suggest
that most patients with migraine experience headache during the aura phase [78].

Typical migraine auras are characterized by gradual development, duration no longer than
one hour, a mix of positive and negative features, and complete reversibility [79]. Positive
symptoms indicate active discharge from central nervous system neurons. Typical positive
symptoms can be visual (eg, bright lines, shapes, objects), auditory (eg, tinnitus, noises,
music), somatosensory (eg, burning, pain, paresthesia), or motor (eg, jerking or repetitive
rhythmic movements). Negative symptoms indicate an absence or loss of function, such
as loss of vision, hearing, feeling, or ability to move a part of the body. Auras are most
often visual, but can also be sensory, verbal, or motor disturbances.

The aura of migraine usually develops gradually over more than five minutes. Less often,
the aura develops more acutely (ie, in less than five minutes). The acute onset of aura
makes confusion with a transient ischemic attack (TIA) or stroke more likely. In one case
series, four patients (2 percent) had exclusively acute onset visual aura [80].

Visual aura — A visual aura classically begins as a small area of visual loss often just
lateral to the point of visual fixation. It may either appear as a bright spot or as an area of
visual loss. Over the following five minutes to one hour, the visual disturbance expands to
involve a quadrant or hemifield of vision. Along the expanding margin geometric shapes or
zigzagging lines often appear. The shapes account for one of the common names for aura,
the "fortification spectrum," because of the resemblance of the aura to the walls of a
medieval fortress. The positive visual phenomena may assume a sickle or C-shape,
expanding over time toward the peripheral visual field, leaving a scotoma or area of
complete visual loss in their wake. As the aura moves off into the peripheral visual field, it
often assumes a shimmering or scintillating quality. As the aura resolves, vision usually
returns first to the areas of central vision initially affected by the aura [81]. (See "Approach
to the patient with visual hallucinations", section on 'Migraine aura'.)

Sensory aura — The sensory aura is also common and typically follows the visual aura
within minutes, although it may also occur without the visual aura. A sensory aura usually
begins as a tingling in one limb or on one side of the face. As the tingling sensation
migrates across one side of the face or down the limb, numbness is left in its wake that
may last up to an hour. The sensory aura may also move inside the mouth, affecting the
buccal mucosa and half the tongue. The slow spread of positive symptoms (scintillations
or tingling) followed by negative symptoms (scotoma or numbness) is quite characteristic
of migraine aura and is not typical for an ischemic event [81].

Language aura — Less common than the visual and sensory auras is the language or
dysphasic aura. Language auras cause transient problems that may run the gamut from
mild wording difficulties to frank dysphasia with paraphasic errors.

Motor aura — In the rarest of auras, motor aura, the limbs and possibly the face on one
side of the body become weak. Because of information related to the genetic basis of the
motor aura, it has been separated from the other forms of aura and classified as
hemiplegic migraine (see "Hemiplegic migraine") [79]. The aura symptoms may occur
either singly or in sequence but they do not generally occur simultaneously.

Aura without headache — Some patients may experience aura without an associated
headache. Migraine aura without headache (also known as migraine equivalent and
acephalgic migraine) manifests as isolated aura unaccompanied by headache. In a Danish
case study, 38 percent of patients reported having both attacks of migraine aura without
headache as well as migraine aura with headache, and 4 percent had exclusively migraine
aura without headache [80]. Auras without headache may be confused with transient
ischemic attacks, especially when they first present in older patients as late-life migraine
accompaniments, which are described in the next section.

Late-life migraine accompaniments — Late-life migraine accompaniments are

symptoms related to the onset after the age of 50 years of migraine aura without headache
[82,83]. The most common symptoms are visual auras, followed by sensory auras
(paresthesia), speech disturbances, and motor auras (weakness or paralysis). The most
common presentation is gradual evolution of aura symptoms with spread of transient
neurologic deficits over several minutes and serial progression from one symptom to
another.
Migraine headache — The headache of migraine is often but not always unilateral and
tends to have a throbbing or pulsatile quality, especially as the intensity increases. As the
attack severity increases over the course of one to several hours, patients frequently
experience nausea and sometimes vomiting. Many individuals report photophobia or
phonophobia during attacks, leading such migraine sufferers to seek relief by lying down in
a darkened, quiet room. Additional migrainous features such as osmophobia and
cutaneous allodynia (see 'Cutaneous allodynia'below) may occur during attacks [75,84-
86].

In adults, an untreated headache can last as little as four hours and as long as several
days. Many attacks resolve in sleep.

Migraine postdrome — Once the spontaneous throbbing of the headache resolves, the
patient may experience a postdromal phase, during which sudden head movement
transiently causes pain in the location of the antecedent headache. During the postdrome,
patients often feel drained or exhausted, although some report a feeling of mild elation or
euphoria [87-89].

Precipitating and exacerbating factors — An evidence-based review concluded that

stress, menstruation, visual stimuli, weather changes, nitrates, fasting, and wine were
probable migraine trigger factors, while sleep disturbances and aspartame were possible
migraine triggers [90]. All of the probable and possible migraine triggers except aspartame
were also general headache triggers. There was evidence that monosodium glutamate
was a general headache trigger but unproven as a migraine trigger. Smoking, odors,
chocolate, and tyramine were unproven as triggers of migraine or general headache.

In a retrospective study of 1750 patients with migraine, approximately 75 percent reported

at least one trigger of acute migraine attacks [91]. In order of descending frequency these
included:

●Emotional stress (80 percent)

●Hormones in women (65 percent)

●Not eating (57 percent)

●Weather (53 percent)

●Sleep disturbances (50 percent)

●Odors (44 percent)

●Neck pain (38 percent)

●Lights (38 percent)

 ●Alcohol (38 percent)

●Smoke (36 percent)

●Sleeping late (32 percent)

●Heat (30 percent)

●Food (27 percent)

●Exercise (22 percent)

●Sexual activity (5 percent)

Sleep disturbances and migraine are often comorbid, but both disorders are fairly common
in the general population and their co-occurrence could be coincidental [92-95].
Nevertheless, the study cited above suggests that sleep disorders can exacerbate
migraine [91]. In addition, poor sleep quality has been associated with increased migraine
headache frequency and disability [96]. Obesity also has been associated with an
increased frequency and severity of migraine [97-99]. Migraine headaches are often
worsened by rapid head motion, sneezing, straining at stool, constant movement, or
physical exertion.

Cutaneous allodynia — Cutaneous allodynia is the perception of pain produced by

innocuous stimulation of normal skin and may result from sensitization of central pain
pathways in migraine [100]. (See 'Sensitization' above.)

As examples, brushing hair, touching the scalp, shaving, or wearing contact lenses may
trigger allodynic symptoms of pain during migraine. Additional symptoms include
tenderness or difficulty resting on the allodynic side.

Cutaneous allodynia occurs frequently with migraine, and it may occur even in the
absence of headache. In one study, allodynia was reported by 62 percent of 11,094
patients with migraine who completed a questionnaire [101]. In an earlier survey of 157
patients with migraine and allodynia, the most common locations of allodynia were pure
cephalic and cephalic plus extracephalic, occurring in 85 and 34 percent, respectively
[102]. Pure extracephalic allodynia occurred in 15 percent. Scalp allodynia was ipsilateral
to the predominant headache side in the majority of cases and occurred at the height of
headache. Trunk allodynia occurred in a few patients.

The true frequency of allodynia appears to be even higher when assessed by

measurement of mechanical and thermal pain thresholds of skin. In a case series of 42
subjects with migraine, 79 percent reported cutaneous allodynia on the head ipsilateral to
the migraine pain by quantitative sensitivity testing, and 67 percent experienced cutaneous
allodynia in additional regions such as the contralateral head or extracephalic sites [100].
The actual percentage of people with migraine spontaneously reporting cutaneous
allodynia is lower.

Severe or persistent cutaneous allodynia may respond to abortive and prophylactic

therapy. However, existing data suggest that abortive therapy with triptans is less effective
once cutaneous allodynia develops. (See "Acute treatment of migraine in adults", section
on 'Triptans'.)

MIGRAINE SUBTYPES — Although there are numerous references in the medical

literature to unexplained neurologic symptoms that are called migraine variant or migraine
equivalent, most of these are probably not related to migraine. Nevertheless, there are
several well-characterized subtypes of migraine, including migraine with brainstem aura,
hemiplegic migraine, retinal migraine, vestibular migraine, menstrual migraine, and chronic
migraine. Complications of migraine are characterized by prolonged symptoms or, rarely,
with infarction or seizures (ie, status migrainosus, persistent aura without infarction,
migrainous infarction, and migraine aura-triggered seizure) [79].

Recurrent painful ophthalmoplegic neuropathy, previously termed ophthalmoplegic

migraine, is discussed elsewhere. (See "Overview of craniofacial pain", section on
'Recurrent painful ophthalmoplegic neuropathy'.)

Migraine with brainstem aura — Migraine with brainstem aura, reviewed here briefly and
discussed in detail elsewhere (see "Migraine with brainstem aura (basilar-type migraine)"),
is an uncommon form of migraine with aura wherein the primary signs and symptoms are
referable to the brainstem without weakness. Migraine with brainstem aura was previously
called basilar-type migraine. It occurs more often in females than in males. Onset is
usually between ages 7 to 20. The auras consist of some combination of vertigo,
dysarthria, tinnitus, diplopia, ataxia, decreased level of consciousness, and hypacusis.
Attacks nearly always include two or more brainstem-related aura symptoms (table 1).
Attacks may evolve to more typical common forms of migraine with age.

The occurrence of decreased level of consciousness followed by headache sometimes

results in diagnostic difficulty. It is important to remember that migraine with brainstem
aura is rare and that there must be another brainstem symptom in addition to decreased
consciousness to make the diagnosis. In the absence of a second brainstem localizing
symptom, other causes of unexplained loss of consciousness such as seizure and
cardiogenic syncope must be considered and appropriately investigated. Migraine with
brainstem aura should be diagnosed only when weakness is absent, since a number of
patients with familial hemiplegic migraine have brainstem symptoms. (See "Migraine with
brainstem aura (basilar-type migraine)" and "Hemiplegic migraine".)

Hemiplegic migraine — The primary feature that separates hemiplegic migraine from
other types of migraine with aura is the presence of motor weakness as a manifestation of
aura in at least some attacks. In addition to motor weakness during the aura phase, which
is typically unilateral, the manifestations of hemiplegic migraine attacks may variously
include severe headache, scintillating scotoma, visual field defect, numbness, paresthesia,
aphasia, fever, lethargy, coma, and seizures. Hemiplegic migraine may occur either in
families or only in one individual (sporadic). (See "Hemiplegic migraine".)

Retinal migraine — Retinal migraine is a rare condition that is characterized by repeated

attacks of monocular scotomata or blindness lasting less than one hour, associated with or
followed by headache. The International Headache Society prefers the term retinal
migraine [79], but ocular migraine has been suggested as a more precise term, since both
retinal and ciliary circulations may be involved [103]. Occasionally the onset may be abrupt
and difficult to distinguish from amaurosis fugax [82]. (See "Amaurosis fugax (transient
monocular or binocular visual loss)".)

Irreversible visual loss may be a complication of retinal migraine, although the incidence is
uncertain. In one of the largest studies to date that reported 6 new cases and reviewed 40
from the literature, permanent visual loss was eventually present in 20 patients (43
percent) [104]. No predictors of irreversible visual loss could be identified, and no
consistent pattern of visual loss was observed among these patients. However, permanent
visual loss may be less frequent than suggested by these data, since it is likely that cases
with such a major complication are more apt to be identified and to be reported (ie,
reporting bias).

The authors speculated that permanent visual loss resulting from retinal migraine may be
a type of migrainous infarction, leading them to suggest the use of prophylactic migraine
therapy with antiepileptic or tricyclic medications for patients with this condition [104].
(See "Headache, migraine, and stroke", section on 'Migrainous infarction
definition' and "Preventive treatment of migraine in adults".)

Chronic migraine — Chronic migraine is defined as headache occurring 15 or more days

a month for more than three months, which has the features of migraine headache on at
least eight days a month [79]. The current classification scheme recognizes chronic
migraine as a separate subform because it may be impossible to distinguish the individual
episodes of headache in patients with such frequent or continuous headaches.
Furthermore, the characteristics of the headache may change from day to day or even
within the same day. (See "Chronic migraine".)

Complications of migraine — Complications of migraine are characterized by attacks

associated with prolonged symptoms or, rarely, with infarction or seizures. Prolonged
symptoms may last for the entire headache, for several days or weeks, or in some cases
leave a permanent neurologic deficit.

●Status migrainosus is a debilitating migraine attack lasting for more than 72 hours

●Persistent aura without infarction is defined by aura symptoms persisting for one
week or more with no evidence of infarction on neuroimaging
 ●Migrainous infarction is defined by a migraine attack, occurring in a patient with
migraine with aura, in which one or more aura symptoms persist for more than one
hour and neuroimaging shows an infarction in a relevant brain area (see "Headache,
migraine, and stroke", section on 'Migrainous stroke')

●Migraine aura-triggered seizure is a seizure triggered by an attack of migraine

with aura

Vestibular migraine — Vestibular migraine (also called migrainous vertigo) is reviewed

briefly here and discussed in detail elsewhere. (See "Vestibular migraine".)

Vestibular migraine is a term used to describe episodic vertigo in patients with a history of
migraines or with other clinical features of migraine (photophobia, phonophobia, visual
aura, etc). The association of headache with vertigo is variable, even in individual patients.
There are no confirmatory tests for vestibular migraine (table 2). Other disorders,
specifically Meniere disease and structural and vascular brainstem disease, must be
excluded in most patients.

Menstrual migraine — Menstrual migraine (also called menstrually associated migraine

or catamenial migraine) is defined as migraine headache that occurs in close temporal
relationship to the onset of menstruation; this time period usually encompasses two days
before through three days after the onset of menstrual bleeding [79]. Women with
menstrual migraine may also have migraine at other times during the month.
(See "Estrogen-associated migraine", section on 'Menstrual migraine'.)

The treatment of menstrual migraine is discussed separately. (See "Estrogen-associated

migraine", section on 'Menstrual migraine' and "Estrogen-associated migraine", section on
'Preventive therapies'.)

DIAGNOSIS — The diagnosis of migraine is a clinical task and is based upon a

compatible history, physical examination, and fulfillment of the diagnostic criteria listed
below. There are no diagnostic tests specific for migraine.

While the features of migraine and tension headache overlap, the clinical features that
appear to be most predictive of migraine include nausea, photophobia, phonophobia, and
exacerbation by physical activity [105]. Food triggers are also more common with migraine
than tension-type headache. (See "Tension-type headache in adults: Pathophysiology,
clinical features, and diagnosis".)

Diagnostic criteria — The International Classification of Headache Disorders, 3rd edition

(ICHD-3) specifies diagnostic criteria for migraine (table 3) [79].

The ICHD-3 criteria for migraine without aura are the following [79]:

●A) At least five attacks fulfilling criteria B through D

 ●B) Headache attacks lasting 4 to 72 hours (untreated or unsuccessfully treated)

●C) Headache has at least two of the following characteristics:

•Unilateral location

•Pulsating quality

•Moderate or severe pain intensity

•Aggravation by or causing avoidance of routine physical activity (eg, walking or

climbing stairs)

●D) During headache at least one of the following:

•Nausea, vomiting, or both

•Photophobia and phonophobia

●E) Not better accounted for by another ICHD-3 diagnosis

The ICHD-3 criteria for migraine with aura are as follows [79]:

●A) At least two attacks fulfilling criterion B and C

●B) One or more of the following fully reversible aura symptoms:

•Visual

•Sensory

•Speech and/or language

•Motor

•Brainstem

•Retinal

●C) At least two of the following four characteristics:

•At least one aura symptom spreads gradually over ≥5 minutes, and/or two or
more symptoms occur in succession

•Each individual aura symptom lasts 5 to 60 minutes

•At least one aura symptom is unilateral

•The aura is accompanied, or followed within 60 minutes, by headache

 ●D) Not better accounted for by another ICHD-3 diagnosis, and transient ischemic
attack has been excluded

The ICHD-3 criteria for migraine with typical aura require the following [79]:

●A) At least two attacks fulfilling criteria B through D

●B) Aura consisting of visual, sensory and/or speech/language symptoms, each fully
reversible, but no motor, brainstem, or retinal symptoms

●C) At least two of the following four characteristics:

•At least one aura symptom spreads gradually over ≥5 minutes, and/or two or
more symptoms occur in succession

•Each individual aura symptom lasts 5 to 60 minutes

•At least one aura symptom is unilateral

•The aura is accompanied, or followed within 60 minutes, by headache

●D) Not better accounted for by another ICHD-3 diagnosis, and transient ischemic
attack has been excluded

When the aura includes motor weakness, the disorder is diagnosed as hemiplegic
migraine [79]. When the aura symptoms arise from the brainstem, the disorder is
diagnosed as migraine with brainstem aura. When the aura involves documented
monocular visual phenomena (documented by clinical visual field examination or patient
drawing of a monocular field defect), the disorder is diagnosed as retinal migraine.

Diagnostic testing — Neuroimaging is not necessary in most patients with migraine.

Evidence-based guidelines issued by the American Academy of Neurology suggest
considering neuroimaging in the following patients with non-acute headache [106]:

●Patients with an unexplained abnormal finding on neurologic examination

●Patients with atypical headache features or headaches that do not fulfill the strict
definition of migraine or other primary headache disorder (or have some additional
risk factor, such as immune deficiency)

Patients with sudden severe headache also need neuroimaging because of the suspicion
of subarachnoid hemorrhage. (See "Evaluation of headache in adults", section on
'Indications for imaging'.)

The following clinical situations may warrant neuroimaging [107,108]:

●The "first or worst" headache

 ●Recent significant change in the pattern, frequency, or severity of headaches

●New or unexplained neurologic symptoms or signs

●Headache always on the same side

●Headaches not responding to treatment

●New-onset headaches after age 50 years

●New-onset headaches in patients with cancer or HIV infection

●Associated symptoms and signs such as fever, stiff neck, papilledema, cognitive
impairment, or personality change

A head CT scan (without and with contrast) is sufficient in many patients when
neuroimaging is deemed necessary [109]. An MRI is indicated when posterior fossa
lesions or cerebrospinal fluid (CSF) leak are suspected. Magnetic resonance angiography
(MRA) and magnetic resonance venography (MRV) are indicated when arterial or venous
lesions, respectively, are considered in the differential diagnosis.

No other diagnostic tests are typically necessary in patients with suspected migraine.

DIFFERENTIAL DIAGNOSIS — The differential diagnosis of migraine headache is broad

and includes other types of primary headaches, such as tension-type headache and
trigeminal autonomic cephalalgias such as cluster headache (table 4), and secondary
headaches (ie, headache caused by another disorder such as head or neck trauma,
cerebrovascular disorders, intracranial lesions, disorders of face, skull or adjacent
structures, or infection).

The differential diagnosis for migraine aura includes transient ischemic attack (TIA),
seizure, syncope, and vestibular disorders. Useful features for distinguishing these various
types of transient neurologic attacks include the nature of the symptoms, their progression,
duration and timing, associated symptoms during and after the attacks (table 5), and
presence of focal or nonfocal symptoms. The symptoms of TIA and migraine are fully
reversible, and neuroimaging is often unrevealing in both conditions. However, both a TIA
and an ischemic stroke typically have a sudden onset of symptoms rather than a gradual
progressive spread of one aura symptom after another. Ischemic events are also less
likely to have positive symptoms such as visual scintillations or paresthesia, and are less
likely to have migrainous symptoms such as nausea, vomiting, photophobia, and
phonophobia. (See "Differential diagnosis of transient ischemic attack and stroke".)

An exception might be brain ischemia caused by cervical artery dissection, which can have
both a progressive spread of symptoms and some migrainous features.
(See "Spontaneous cerebral and cervical artery dissection: Clinical features and
diagnosis".)
SOCIETY GUIDELINE LINKS — Links to society and government-sponsored guidelines
from selected countries and regions around the world are provided separately.
(See "Society guideline links: Migraine and other primary headache disorders".)

INFORMATION FOR PATIENTS — UpToDate offers two types of patient education

materials, "The Basics" and "Beyond the Basics." The Basics patient education pieces are
written in plain language, at the 5th to 6th grade reading level, and they answer the four or
five key questions a patient might have about a given condition. These articles are best for
patients who want a general overview and who prefer short, easy-to-read materials.
Beyond the Basics patient education pieces are longer, more sophisticated, and more
detailed. These articles are written at the 10th to 12th grade reading level and are best for
patients who want in-depth information and are comfortable with some medical jargon.

Here are the patient education articles that are relevant to this topic. We encourage you to
print or e-mail these topics to your patients. (You can also locate patient education articles
on a variety of subjects by searching on "patient info" and the keyword(s) of interest.)

●Basics topics (see "Patient education: Migraine headaches in adults (The

Basics)" and "Patient education: Headaches in adults (The Basics)")

●Beyond the Basics topics (see "Patient education: Migraine headaches in adults
(Beyond the Basics)" and "Patient education: Headache causes and diagnosis in
adults (Beyond the Basics)")

SUMMARY AND RECOMMENDATIONS

●Cortical spreading depression is hypothesized to cause the aura of migraine,

activate trigeminal nerve afferents, and alter blood-brain barrier permeability.
Activation of the trigeminovascular system plays a central role in the pathophysiology
of migraine, including the onset of neurogenic inflammation which is linked to the pain
of migraine. Sensitization, a process in which neurons become increasingly
responsive to nociceptive and non-nociceptive stimulation, is likely responsible for
many of the clinical symptoms of migraine. (See 'Pathophysiology' above.)

●The genetic basis of the common forms of migraine is likely complex and in some
individuals may be based on the additive effect of more than one genetic source. The
KCNK18 and CSNK1D genes have been implicated in the pathogenesis of migraine
with aura. Familial hemiplegic migraine is associated with mutations in four genes,
three of which encode for transmembrane ion channels. (See 'Genetic basis' above.)

●Migraine is a common condition that affects up to 12 percent of the general

population. It is more frequent in women than in men. (See 'Epidemiology' above.)

●Migraine is a disorder of recurrent attacks. The attacks unfold through a cascade of

events that occur over the course of several hours to days. A typical migraine attack
 progresses through four phases: the prodrome, the aura, the headache, and the
postdrome. (See 'Clinical features' above.)

•The prodrome consists of affective or vegetative symptoms that appear 24 to 48

hours prior to the onset of headache. (See 'Migraine prodrome' above.)

•About 25 percent of people with migraines experience one or more focal

neurologic symptoms in the second phase, called the migraine aura. Auras are
most often visual, but can also be sensory, verbal, or motor disturbances.
(See 'Migraine aura' above.)

•The headache of migraine is often but not always unilateral and tends to have a
throbbing or pulsatile quality. Accompanying features may include nausea,
vomiting, photophobia, or phonophobia during attacks. (See 'Migraine
headache' above.)

•Migraine trigger factors may include stress, menstruation, visual stimuli, weather
changes, nitrates, fasting, wine, sleep disturbances, and aspartame, among
others. (See 'Precipitating and exacerbating factors' above.)

●Subtypes of migraine include migraine with brainstem aura, hemiplegic migraine,

retinal migraine, vestibular migraine, menstrual migraine, and chronic migraine.
Complications of migraine are characterized by prolonged symptoms or, rarely, with
infarction or seizures (ie, status migrainosus, persistent aura without infarction,
migrainous infarction, and migraine aura-triggered seizure). Ophthalmoplegic
"migraine" is now considered a cranial neuralgia called recurrent painful
ophthalmoplegic neuropathy. (See 'Migraine subtypes' above.)

●The diagnosis of migraine is a clinical task and is based upon a compatible history,
physical examination, and fulfillment of the diagnostic criteria (table 3). Neuroimaging
is not necessary in most patients. However, we recommend neuroimaging for patients
with suspected migraine or nonacute headache who have either an unexplained
abnormal finding on neurologic examination, atypical headache features, headaches
that do not fulfill the strict definition of migraine or other primary headache disorder, or
some additional risk factor for secondary headache, such as immune deficiency.
(See 'Diagnosis' above.)

ACKNOWLEDGMENT — The editorial staff at UpToDate would like to acknowledge

Ashraf Sabahat, MD, who contributed to an earlier version of this topic review.