Current Neurology and Neuroscience Reports (2020) 20:17

https://doi.org/10.1007/s11910-020-01037-3

HEADACHE (R. B. HALKER SINGH AND J. VANDERPLUYM, SECTION EDITOR)

Migraine Aura: Updates in Pathophysiology and Management

Joshua Lai 1 & Esma Dilli 1

# Springer Science+Business Media, LLC, part of Springer Nature 2020

Abstract
Purpose of Review To provide an updated review of the pathophysiology, diagnosis, and management of migraine with aura.
Recent Findings Thalamic and other subcortical regions may play a role in the pathophysiology of migraine. There is inter-
patient and intra-patient attack variability in the characteristics of typical aura especially visual aura symptoms. Migraine with
brainstem aura may originate cortically. Migraine with retinal aura may be associated with structural and functional changes in
the retina.
Summary Although cortical spreading depression (CSD) continues to be the predominant theory surrounding the pathophysi-
ology of migraine with aura, the exact mechanism of action of CSD and its role in relation of all phases of migraine including
features of aura are not fully understood. Novel experimental models and newer diagnostic tools including neuroimaging are
currently being used to enhance of understanding of migraine with and without aura. Transient ischemia attacks, stroke, and
epilepsy should be considered in your differential diagnosis of migraine with aura. There are no specific therapies for migraine
with aura.

Keywords Pathophysiology . Migraine with aura . Aura features . Cortical spreading depression

Introduction patient’s experience of migraine, and offers a deeper under-

standing of how and where an attack might start and progress
Migraine aura is a transient, fully reversible visual, sensory, or [1]. This review will focus on the aura pathophysiology, clin-
other central nervous system symptom that classically pre- ical features of migraine aura and discuss updates on the man-
cedes migraine headache. It occurs in about 30% of patients agement of patients suffering from migraine with aura.
with migraine. Visual symptoms, the most common symptom
type, occur in over 90% of patients with migraine with aura.
Common exceptions to the classic progression of aura to
migraine—migraine without aura, aura without headache, Updates in Migraine Aura Pathophysiology
and a high degree of inter- and intra-patient variability in the
type, duration, and frequency of aura—have raised questions Does Cortical Spreading Depression Explain Aura?
about the pathophysiology of aura and its relation to headache.
Recent understanding of migraine pathophysiology has Cortical spreading depression (CSD) is an abnormal phenom-
moved towards describing migraine as an attack consisting enon characterized by a slowly propagating wave of depolar-
of four phases, including a prodrome, aura, headache, and ization of cortical neuronal and glial cells followed by a “de-
postdrome. Not all migraine attacks have all these phases. pression” or silence of electrical activity [2]. There is an ac-
This model, reviewed elsewhere, more closely describes the companying hyperemia followed by non-concentric spreading
oligemia [3••, 4••]. CSD spreads at a rate of 3–5 mm/min and
is associated with toxic alterations in transmembrane ion gra-
This article is part of the Topical Collection on Headache
dients. This results in a massive influx of Na, Ca, and water,
and efflux of K, proton, glutamate, and ATP [5]. There is also
* Esma Dilli
[email protected]
a release of other intracellular contents including neurotrans-
mitters and other substances with vasoactive and/or inflam-
1
Department of Medicine, Division of Neurology, University of matory properties. These changes are thought to propagate the
British Columbia, Vancouver, Canada wave contiguously by affecting adjacent cells, and possibly to
 17 Page 2 of 10 Curr Neurol Neurosci Rep (2020) 20:17

link aura to head pain via activation of perivascular trigeminal limbic system, brainstem reticular formation, and other
nerve endings [5]. Recovery from CSD starts within minutes brainstem nuclei [14]. These association nuclei and their con-
but may take hours [3••]. Although this process has been dem- nections may explain the connection between the prodromal
onstrated in humans during acute brain injury, subarachnoid symptoms and the aura as well as headache following the
hemorrhage, and ischemic stroke, this “canonical” CSD aura.
(spreading depression limited to the cerebral cortex) has not
been demonstrated during migraine aura in humans [3••] and Is Migraine Aura an Epiphenomenon?
there is debate as to whether the aura, from the CSD, triggers
the rest of the migraine attack including the head pain [4••]. Even though spreading depression is still widely accepted as
In experimental models, CSD may be triggered by mechan- the underlying substrate for migraine aura, it remains unclear
ical deformation of cortex, electrical stimulation, pinprick, whether CSD is a generator or epiphenomenon of a migraine
ischemia, microemboli, glutamate agonists, and extracellular attack. Although there is robust pre-clinical evidence suggest-
application of potassium and other depolarizing agents [5]. A ing that CSD may activate the trigeminovascular system me-
right to left shunt through a patent foramen oval (PFO) may be diating migraine pain, most patients still experience migraine
one source of microemboli that can trigger CSD [5]. Novel without aura [1, 3••]. This implies that cortical spreading de-
optogenetic methods have been developed to induce CSD in pression is either silent or absent during these attacks. “Silent”
awake behaving transgenic mice via transcranial stimulation CSD may occur in non-eloquent cortex, in limited fashion or
of specific ion channels in the visual cortex and non-invasive area, or produce symptoms not typically classified as aura [8,
recording with laser Doppler flowmetry [6, 7]. This new mod- 12].
el is currently being used to study CSD in transgenic mice Increasing evidence has pointed towards subcortical struc-
with high temporal and spatial resolution [7]. tures including the posterolateral hypothalamus, midbrain teg-
The case for CSD or CSD-like events underlying migraine mentum and periaqueductal gray, and dorsal rostral pons as
aura is strongest in the case of visual aura. Spreading visual the earliest sites of a migraine attack [4••]. Typical prodromal
aura has been mapped retinotopically to visual cortex at a rate state symptoms including yawning, food cravings, and fa-
corresponding to CSD [8]. Perfusion defects and changes in tigue, typical homeostatic triggers, and the circadian rhyth-
BOLD fMRI signal starting in posterior occipital cortex and micity of migraine attacks strongly suggest a role for the hy-
spreading anteriorly have corroborated the timing of this prop- pothalamus [4••]. In a seminal study, eight patients with mi-
agation [9]. Susceptibility to CSD in pre-clinical models is graine without aura who experienced frequent prodromal
higher in female rats and rats with FHM-1 knock-in mutation, symptoms were imaged using PET after nitroglycerin pro-
and is suppressed by migraine preventive drugs [3••, 10, 11]. voked attacks [15]. Activations were seen in hypothalamus,
This may explain why migraine is more common in females periaqueductal gray, and dorsal pons in the early prodromal
and a possible mechanism of action of some of the migraine phase compared to baseline. During the migraine headache
preventive drugs. However, recent reviews have called into phase, only dorsal pontine activation continued. In another
question whether canonical CSD can explain phenomena such seminal study, a single patient with episodic migraine without
as simultaneous aura types, bilateral aura, ipsilateral headache, aura underwent daily fMRI for 30 days, capturing 3 sponta-
and predominance of positive symptoms rather of negative neous attacks [16]. In 24 h preceding an attack, the authors
symptoms predicted by oligemia [3••]. Neuroimaging evi- observed increased hypothalamic activity and functional con-
dence of direct spread of changes associated with CSD from nectivity with spinal trigeminal nucleus. During the attack,
occipital cortex to somatosensory or language cortex has also there was increased functional connectivity between hypothal-
been lacking [12, 13]. Spreading depression in other brain amus and dorsal rostral pons. This phase-specific switch in
regions in addition to the cortex or CSD of the thalamus with functional connectivity led the authors to suggest that the hy-
disruption of normal thalamocortical oscillations by cortical pothalamus may be the true migraine generator. These data
depression has been recently suggested as an alternative mod- also highlight the importance of understanding how alter-
el to canonical CSD that may better explain the occurrence ations in network activity contribute to the pathophysiology
and spread of different aura types [3••]. The role of the thala- of the migraine attack [12].
mus in spreading depression may account for the predomi- Whether hypothalamus or other brainstem structures trig-
nance of positive symptoms in migraine. The loss of excitato- ger CSD to cause migraine aura, or whether CSD occurs in-
ry activity on thalamic reticular nuclei (GABAnergic) may dependently of these activations remains unclear. In addition,
lead to the increase sensory excitation and may explain the the pathophysiological link between aura and the onset of
cheiro-oral sensory features in migraine aura [3••]. Thalamic head pain has not been clearly established. One study of mi-
association nuclei such as the pulvinar modulate inputs and graine aura patients found increased functional connectivity
outputs to the association cortices (particularly the visual cor- between the pons (an area shown to be activated in headache
tex) and receive input from subcortical regions such as the phase in migraine without aura patients) and both
Curr Neurol Neurosci Rep (2020) 20:17 Page 3 of 10 17

somatosensory cortex and between the visual cortex during The “Typical” Auras
the headache phase following a visual aura [17].
Synaptic and network instability appear to play a role in Single-patient cases as well as aggregate data have defined
transient neurological conditions such as migraine. In partic- both the basic clinical characteristics of aura, as well as com-
ular, synaptic and network hyperactivity in brainstem-cortical mon exceptions to the International Classification of
and thalamocortical networks has been recently suggested as a Headache Disorders 3rd edition (ICHD-3) definition of aura
possible mechanism by which CSD may be triggered in hy- [20]. According to the ICHD-3 criteria of migraine with aura,
perexcitable but metabolically normal cortex [18]. Stress, a patient requires at least 2 attacks of aura with one or more
sleep deprivation, and hypoglycaemia are known triggers of fully reversible aura symptoms and at least 3 of the 6 follow-
migraine. These physiological changes may increase cortical ing typical features: (1) at least one aura symptom spreading
excitability via increase glutamate [5] and subsequently lead gradually over > 5 min, (2) two or more aura symptoms occurs
to synaptic and network hyperactivity in those regions. Recent in succession, (3) each individual aura symptom lasts 5–
fMRI studies have shown higher visual cortex responsiveness 60 min, (4) at least one unilateral aura symptoms, (5) at least
in patients with aura compared with patients without aura, one positive aura symptom, and/or (6) the aura accompanied
suggesting hyperexcitability [13]. A human provocation mod- or followed within 60 min by a headache (20). Aura symp-
el of migraine aura would be very useful to study its genesis toms are visual, sensory, speech/language, motor, brainstem,
and underlying pathophysiology, but no safe and efficient or retinal. The aura can last > 60 min if there are more than one
method currently exists [19]. aura symptoms. For example, if the patient has visual and
sensory symptoms, the maximum duration of the aura is
120 min. Motor symptoms may last up to 72 h. Examples of
positive symptoms include scintillations and paresthesia.
Updates in the Understanding of Migraine Speech (dysarthria and dysphasia) and retinal symptoms are
Aura Clinical Features less common. Migraine aura by ICHD-3 criteria is “probable”
when fewer than 2 attacks have occurred [20].
One of the recurring challenges in headache practice is deter- The best clinical studies of aura are prospective, as data
mining whether patients’ pre-headache symptoms represent have shown a high degree of intra-patient variability subject
migraine aura. Although many patients report typical visual to recall bias [21••]. Single cases are most useful to illustrate
symptoms, like spreading visual scintillations followed by aura in granular detail, which may elucidate new hypotheses
scotoma, others describe symptoms that are less well-defined, about aura pathophysiology. In a single patient with migraine
like visual blurring or distortion. Sometimes typical symptoms with visual aura, 1000 episodes of visual aura were hand-
follow an atypical spatial or temporal course. Some aura illustrated by the patient over 18 years [22]. Aura in this pa-
symptoms like aphasia are also often difficult to distinguish tient had multiple points of initiation within the visual field,
from word finding difficulty due to cognitive fogging. variable direction of spread, relatively constant velocity and
Defining aura frequency and separating aura from the prodro- path of spread, showed non-concentric retinotopic propaga-
mal state has treatment implications (Table 1). tion through visual cortex, and had variable duration and

Table 1 Features of migraine

aura versus prodromal state Migraine aura Prodromal state

~ 33% of migraine patients Prevalence Unknown (wide estimates of 9%–88%)1

Within 60 min of, or Timing Hours to 1–2 days before headache phase
accompanying headache phase
5–60 min (for each individual aura Duration Hours to 1–2 days
symptom)
Typical aura: visual, sensory, Symptoms Homeostatic: food craving, thirst, frequent yawning
language or urination, pallor, sleep disturbance
Complex aura: brainstem, retinal, Fatigue/cognitive symptoms: difficulty concentrating,
motor irritability, elation, depression
Sensory sensitivities: neck stiffness, photophobia,
phonophobia, osmophobia
Cortical or cortical-subcortical Localization Hypothalamus, limbic cortex, brainstem
interactions
1
Karsan N, Bose P, Goadsby PJ. The migraine premonitory phase. Continuum (Mineeap Minn). 2018;24(4,
Headache):996–1008
 17 Page 4 of 10 Curr Neurol Neurosci Rep (2020) 20:17

consistency. These data demonstrate the variability observed region, and precentral gyri, respectively, while ataxia could be
even within typical aura and illustrate important basic assump- due to abnormal processing of vestibular, visual, and sensory
tions about cortical spreading depression [8]. inputs by the parietal lobe [26]. A cortical localization better
In the only large, prospective diary-based evaluation of explains how spreading depression may underly brainstem
migraine aura, Viana et al. recently studied a cohort of 72 aura without consistently producing severe symptomatology
patients with typical (visual, sensory, or language) aura like respiratory depression expected of spreading depression
[21••, 23]. Patients prospectively recorded three consecutive occurring in the brainstem itself. The progression of typical
auras in detailed fashion. A strength of this study was verifi- aura symptoms to brainstem aura and the association between
cation of symptoms as aura rather than prodromal by a neu- brainstem aura and motor aura is also amenable to a cortical
rologist. Important conclusions from this cohort study include explanation [26].
(1) visual symptoms are reported in 98% of the auras, sensory Study of brainstem aura is hampered by inexact definitions
symptoms in 36%, and dysphasia in 10%, (2) 56% of patients and ascertainment of the included symptomatology, resulting
did not have a stereotyped aura across attacks, in terms of in variable prevalence from 1% to around 10% of patients
quality or combination of aura types, (3) the typical progres- with migraine with aura [25, 27]. A recent re-analysis of 79
sion of aura to headache occurs in only 46% of patients, (4) cases in the literature by experts at the Danish Headache
26% of patients experienced at least one prolonged aura (> Center showed that only 44 fulfilled ICHD-3 criteria [25].
1 h), and (5) 17% of the reported auras were prolonged with The authors demonstrated a prevalence of 1.37% (4/293
prolonged aura tending to include a higher number of non- cases) of brainstem aura within a cohort of patients with mi-
visual symptoms. This cohort study highlighted the inter- graine with aura when ascertained by face-to-face interview,
patient and intra-patient attack variability in the characteristics compared with a prevalence of 12.8% ascertained by tele-
of typical aura and suggested that typical aura lasting more phone interview. They proposed a stricter definition of mi-
than 1 h is not uncommon. In a systematic review of the graine with brainstem aura [25].
clinical features of migraine with visual aura symptoms, the
most common symptoms were flashes of bright light, flicker-
ing of light, phosphenes (small bright dots),“foggy vision” Retinal Migraine
zig-zag lines, scotoma and an illusion of heat waves or water
[24]. Since the manifestations of visual aura are multiple with Migraine with retinal aura is defined as repeated reversible
currently no pathophysiological explanation for this variance, monocular positive or negative visual symptoms following
a more comprehensive classification with definitions may an aura time-course, associated with headache. The preva-
help in the understanding of aura pathophysiology and in the lence of retinal aura is unknown but it is considered rare
diagnostic accuracy of migraine aura versus other transient [28]. Cases of prolonged or permanent vision loss have been
neurological conditions [24]. described, therefore leading to diagnostic uncertainty [28].
The pathophysiology is thought to be due to reversible retinal
The “Complex” Auras vasospasm, retinal spreading depression, or both [29].
Interestingly, recent optical coherence tomography (OCT)
Migraine with Brainstem Aura studies have shown that patients with migraine with aura have
decreased foveal and peripapillary vascular density compared
Migraine with brainstem aura, previously called basilar mi- with migraine without aura and healthy controls [30] and de-
graine, is currently defined in the ICHD-3 as (1) at least two creased retinal nerve fiber layer (RNFL) thickness compared
of the following: vertigo, dysarthria, tinnitus, hyperacusis, with healthy controls [30, 31]. The RNFL is thinner during the
diplopia, ataxia, or decreased level of consciousness (GCS < aura and improves after the aura but still is thinner than
13), (2) the absence of retinal and motor symptoms, and (3) healthy controls while the P100 visual evoked potentials
the typical aura characteristics noted in the ICHD-3 criteria for (VEP) is prolonged during the aura and was not significantly
migraine with aura [20]. However, the existence and localiza- different from healthy control in between attacks [31]. These
tion of migraine with brainstem aura has been a matter of studies suggest that retinal microangiopathy may accompany
debate [25]. A recent review has suggested cortical localiza- migraine with aura, which also carries higher risk of stroke
tion of “brainstem” aura symptoms to multimodal association [32]. Speculatively, retinal aura may occur in patients who
and limbic cortex including the parieto-insular region (so- carry more genetic or acquired risk factors for retinal
called vestibular cortex), temporo-parietal-occipital junction, angiopathy. More studies are required to clearly define the
posterior and superior parietal lobe, and temporal-insular re- clinical spectrum and epidemiology of retinal aura and wheth-
gions [26]. Cortical origins of vertigo, auditory symptoms er these retinal features on OCT and VEP are due to co-morbid
(tinnitus and hyperacusis), diplopia, and dysarthria could orig- factors independent of migraine or causal of migraine with
inate from vestibular cortex, auditory cortex, parieto-occipital retinal aura.
Curr Neurol Neurosci Rep (2020) 20:17 Page 5 of 10 17

Hemiplegic Migraine and anti-epileptic effect of some prophylaxis like topiramate.

Overlap of polygenic risk factors for migraine and epilepsy
Hemiplegic migraine has continued to offer insights into the and other co-morbidities may contribute to the occurrence of
pathophysiology and genetics of migraine aura. Patients with atypical aura symptoms.
sporadic or familial hemiplegic migraine have a higher inci-
dence of other migraine aura (90% visual, 98% sensory, 72%
dysphasia, and 69% brainstem), and a higher prevalence of
Updates in Diagnosis of Migraine with Aura
family members with migraine [33]. Gene mutations of
CACNA1A, ATP1A2, and SCN1A are associated with famil-
Misdiagnosis of Migraine Aura
ial hemiplegic migraine (FHM) type 1, type 2, and type 3,
respectively. Younger age of onset (< 10–16 years old),
The differential diagnosis of migraine aura is wide,
prolonged motor aura, severe attacks (more extensive motor
encompassing TIA/stroke, seizure, structural brain pathology,
weakness, additional brainstem features, confusion, brain ede-
ocular pathology, and non-organic etiology. The diagnosis of
ma), more often triggered by mild head trauma and associated
migraine is particularly challenging in patients with vascular
interictal ataxia or intellectual disability predict familial hemi-
risk factors, co-morbid epilepsy, aura without headache, and
plegic migraine with a defined mutation, versus the sporadic
atypical aura. Acute post-stroke headache, post-ictal head-
form [34]. These findings have led to the concept of migraine
ache, and headache due to structural pathology may also have
heritability according to genetic load [35]. On one end of the
migrainous features, with or without other red flags [41, 42].
spectrum are rare patients with rare monogenic variants that
Migraine with aura is also a risk factor for stroke and often
are highly heritable and produce severe aura phenotypes. On
overlaps with epilepsy (migraine-epilepsy spectrum) [32, 43,
the other end are the majority of patients with migraine with-
44]. Therefore, it is important not to use migraine as the de-
out aura that may carry common variants in genes that may
fault diagnosis in patients with transient neurological symp-
play a role in migraine pathophysiology, each with small ef-
toms with or without headache.
fect size but contributing to a “polygenic” risk. Migraine with
aura of variable complexity may exist between these two ex-
tremes with a “moderate” degree of polygenic risk. The largest Migraine Versus Stroke
genome-wide association study (GWAS) identified 44 single
nucleotide polymorphisms (SNPs) associated with migraine, A recent systematic review examined how often migraine aura
with enrichment in genes expressed in vascular and smooth mimics stroke in the acute stroke setting [45]. Migraine with
muscle tissue [36]. This study showed genetic overlap be- aura was responsible for 1.79% of stroke unit activations and
tween migraine with and without aura but was not powered was the third commonest stroke mimic after seizures and psy-
to detect loci that may be specific for migraine with aura. chiatric disorders [45]. Migraine aura also accounted for 18%
However, a recent meta-analysis suggested that polymor- of patients who were thrombolyzed without a final diagnosis
phisms in the MTHFR gene, predicted to result in hyperho- of stroke [45]. Fortunately, the reported adverse event rate in
mocysteinemia, may be important in migraine with and with- this group was low (0.01%) [45]. The DOUBT study
out aura [37]. In Caucasians, the C677T polymorphism with (Diagnosis of Uncertain-Origin Benign Transient
40% of wild-type enzyme activity increased migraine with Neurological Symptoms), a prospective cohort study (n =
aura susceptibility, whereas the A1298C polymorphism with 1028 patients, age > 40, no prior stroke, 7.8% with migraine
60% of wild-type enzyme activity increased susceptibility for with aura) recently evaluated patients with low-risk symptoms
migraine without aura. (non-motor and non-speech symptoms of any duration, or
motor/speech symptoms ≤ 5 min) with diffusion-weighted
Rare Aura Phenotypes MRI within 8 days of onset [46]. Final diagnosis was revised
from stroke mimic to minor stroke in 7.7% of patients [46].
Single cases or case series of rare aura phenomenology also DWI + changes were seen in 5.3% of patients who had an
expand the possible boundaries of ascribing symptoms to mi- initial clinical diagnosis of migraine phenomenon [47]. Age,
graine aura. Remote and recent reports include alien hand male sex, ongoing symptoms, abnormal neurologic exam, and
syndrome, gelastic aura, auditory hallucinations or paracusias, no prior identical event were risk factors for DWI-positive
and olfactory hallucinations [38–40]. These descriptions rely lesions. The authors suggest that slow progression of symp-
on “aura” symptoms following expected temporal course with toms lasting more than 10 min, a time-course in keeping with
headache, neuroimaging and EEG ruling out mimics, and re- aura, did not discriminate stroke from mimics. Although only
sponse of symptoms to migraine prophylaxis. Possible con- approximately 1/5 of the patients in this study were diagnosed
founders in these cases include contribution of behavioral and clinically with migraine phenomena, attention to these risk
psychiatric co-morbidities, the low sensitivity of surface EEG, factors is warranted.
 17 Page 6 of 10 Curr Neurol Neurosci Rep (2020) 20:17

A right-left shunt through a patent foramen ovale the seizure activity [20]. Isolated ictal headache without other
(PFO) may be a source of microemboli that can trigger seizure manifestations is rare [54].
cortical spreading depression [5] and be a possible mech- There is controversy as to whether migraine aura can trig-
anism of stroke in migraine patients [48]. A recent study ger epileptic seizure (so-called “migralepsy”) or whether the
of cryptogenic stroke in young patients (n = 68, age 18– evolution of migraine visual aura into an epileptic seizure is
60) demonstrated a high prevalence of PFO in migraine co-incidental in a patient with a tendency to have both condi-
(79%; 93% in migraine with frequent aura) compared tions [51, 54].
with no migraine (59%). This study also found PFO in The clinical and genetic overlap between migraine and ep-
18% of the general population without stroke [48]. PFO ilepsy is an ongoing subject of investigation [43].
with atrial septal aneurysm may be more strongly associ-
ated with migraine aura [49]. The PREMIUM trial, a ran-
domized double-blind, sham-controlled study, evaluated Migraine Versus Other Transient Neurological Conditions
the efficacy of PFO closure for migraine reduction [50].
Although the trial failed to meet its primary endpoint Alternative diagnosis should be considered in patients
(50% reduction in migraine attacks), several secondary with older age of aura onset or change in aura pattern
endpoints including reduction in migraine days, and oc- [42]. Focal structural lesions may lead to aura symptoms
currence of complete migraine cessation at 1-year follow- and the description of an aura as “classic” is not enough
up were encouraging [50]; however, neither PREMIUM evidence itself to discount a secondary cause in patients
trial nor MIST or PRIMA trials have provided evidence to with other risk factors or headache and aura red flags. As
support the use of PFO closure as preventive therapy in an example, a recent case report described a 54-year-old
migraine [50]. man with longstanding migraine without aura, who expe-
rienced Alice in Wonderland syndrome gradually over
10 min, followed by sensory aphasia and migrainous
Migraine Versus Epilepsy headache [55]. Neuroimaging demonstrated a left
temporal-occipital junction glioblastoma.
Focal seizure and migraine aura, especially without headache,
may be difficult to differentiate. This is well documented in
case reports of occipital lobe epilepsy misdiagnosed as visual
migraine aura [51, 52]. A small retrospective analysis (n = 27) Updates in Management of Migraine
identified epileptic visual aura as shorter duration (median with Aura
56 s in epilepsy vs. 20 min in migraine), more likely stereo-
typed (55% in epilepsy vs. 7% in migraine), and more likely Treatment Considerations in Migraine with Aura
restricted to one visual hemifield (74% in epilepsy vs. 30% in
migraine) [53]. No epileptic patients had centripetal or centrif- Migraine with aura is managed similarly to migraine without
ugal spread of visual symptoms [53]. aura, with some important distinctions (Table 2). Non-
Headache may occur in patients with seizures so the pres- pharmacological and pharmacological therapies are used to
ence of headache in patients with an aura is not synonymous reduce the frequency of the attacks and/or duration/severity
with migraine with aura. The ICHD-3 codifies ictal headache of the attacks. Currently, there are no specific therapies for
as occurring during a focal seizure and usually ipsilateral to migraine with aura.

Table 2 Diagnosis and management considerations in migraine with versus without aura

Migraine with aura Migraine without aura

~ 2× baseline risk Risk of stroke Baseline risk

Currently contraindicated Combined hormonal contraception Not contraindicated
Use with caution in complex aura Treatment with vasoconstrictors (triptans/ergots) No restrictions
(brainstem, retinal, motor aura)
Consider prophylaxis for bothersome aura Prophylaxis initiation Based on headache frequency, disability,
even in absence of headache factors use of acute medications
No specific recommendations Prophylactic agent Various different types of agents
Variable—not necessarily more severe Degree of disability Variable
More likely positive family history of migraine Heritability Less heritable than migraine with aura
Curr Neurol Neurosci Rep (2020) 20:17 Page 7 of 10 17

Risk of Stroke, Oral Contraceptives, and PFOs multiple territorial infarction, or cortical laminar necrosis, con-
sistent with these hypotheses [68, 69].
Migraine with aura approximately doubles the risk of ische- The presence of high-risk features in aura is a potential
mic stroke in meta-analyses (RR 2.16–2.27), whereas mi- rationale for more aggressive migraine treatment. In accor-
graine without aura is not clearly associated with an increased dance with the Canadian Headache Society guidelines, mi-
stroke risk [32]. The risk is higher for younger women (age < graine prophylaxis in patients with these aura features should
45, RR 2.76–3.65), and increases with concurrent smoking be considered, even if attacks are infrequent [70]. Frequent
and oral contraceptive use (RR 7.02–10) [32, 56]. The abso- attacks of brainstem or hemiplegic aura, even if mild in sever-
lute risk of stroke remains low in the absence of smoking or ity, are also an indication for the use of prophylactic migraine
other established stroke risk factors [57]. This data have led to therapy. Rapid abortion of prolonged or complex aura would
debate about the safety of oral contraceptives in migraine, be a rational strategy, but there are no established effective
particularly migraine with aura [58, 59]. The main critique treatments specific to aura. There is a debate surrounding trip-
of this data is that the meta-analyses include older studies with tan use in migraine with aura particularly in migraine with
patients who used higher dose combined hormonal contracep- brainstem aura and motor aura. Triptans are 5-HT1B/1D ago-
tives (CHCs) (> 50 μg estrogen) than those available now nists and the 1B receptor subtype has vasoconstrictive effects
(10–35 μg estrogen). However, a recent large cohort study on blood vessels. The triptan trials excluded brainstem and
(n = 1884) which did not report estrogen doses but might hemiplegic migraine aura patients. There is lack of evidence
reflect lower available dosages still found an OR of 6.1 for in the use of triptans in this population group. Small retrospec-
stroke in migraine with aura patients on CHC, compared with tive studies have not shown increased stroke risk associated
OR 1.77 in migraine without aura on CHC [60]. This is con- with triptan use in hemiplegic migraine patients, except for
sistent with the risk being driven by migraine subtype. More one patient with prolonged symptoms for months without as-
frequent aura may also increase stroke risk [56, 61]. Current sociated DWI change [71]. Although the triptan product
guidelines from the World Health Organization (WHO) and monograph states that migraine with brainstem aura and hemi-
the American Congress of Obstetricians and Gynecologists plegic migraine are an absolute contraindication to triptan use,
(ACOG) state that migraine with aura is as an absolute con- some headache specialists have used triptans in the headache
traindication to CHC use regardless of dose [62, 63]. phase of the migraine after the aura has resolved. However,
However, experts have called for more studies on low-dose caution is recommended for patients with prolonged or severe
estrogen CHCs and suggest an individualized assessment of brainstem or motor aura, or any history of acute reversible
risk and benefit [59, 64]. neuroimaging changes. The ditans (5HT1F agonists) which
have no vasoconstrictive effect, and the -gepants (small mol-
Patients with “Higher Risk” Aura ecule CGRP receptor antagonists) may present additional op-
tions as acute therapy for this patient group [72].
Although there is no standard definition of what constitutes
“higher risk” aura (those with higher risk of stroke), aura that Therapeutics in Migraine with Aura
is prolonged (≥ 1 h), frequent, complex (multiple subtypes,
brainstem, motor, or retinal aura), or severe (loss of conscious- Few studies have separated migraine with and without aura
ness, prolonged hemiplegia) may carry a higher risk of stroke with respect to efficacy of acute or prophylactic treatment.
or irreversibility. A “Migraine Aura Complexity Score” (0–9 Intranasal DHE has similar efficacy in migraine with and
points) was recently proposed, but only for typical aura [65]. It without aura [73]. However, a post hoc analysis of oral suma-
includes spatial factors (amount of cortex clinically involved, triptan showed that it was less effective in migraine with aura
and aura symptoms including higher cortical dysfunctions and compared with migraine without aura [73]. It is unclear when
presence of dysphasic or memory disturbances) but not tem- in the migraine phase (i.e., during aura or during headache) the
poral factors (duration, frequency). patients took the medication. Since early treatment improves
Migrainous infarction is a rare complication of prolonged response, in patients with migraine with aura waiting to take
migraine aura, comprising 0.5–1.5% of ischemic stroke [57, the medication in the headache phase may be a reason for the
66]. The largest retrospective cohort (n = 33, median age 39, poor response.
61% female) showed absence of traditional vascular risk fac- Currently, there are no approved therapies specifically for
tors, and a predilection for the posterior circulation (82%), migraine with aura. Tonabersat, an agent that blocks cortical
mostly in the occipital lobes [67]. Outcomes were generally spreading depression, has shown mixed results as a migraine
favorable [67]. The pathophysiology may involve prolonged prophylactic agent in patients with migraine with aura, and
oligemia following CSD, arterial vasospasm, and/or therefore has not been approved for migraine prophylaxis in
neurovascular uncoupling causing cortical cellular energy fail- the migraine with aura population [74, 75]. The evidence be-
ure [66]. Imaging may have the appearance of single or hind other acute and prophylactic therapies potentially
 17 Page 8 of 10 Curr Neurol Neurosci Rep (2020) 20:17

targeting migraine with aura, including ketamine, lamotrigine, Compliance with Ethical Standards
amiloride, aspirin, topiramate, levetiracetam, and magnesium
was recently summarized in an excellent review [76••]. The Conflict of Interest The authors declare that they have no conflict of
interest.
evidence for these agents is largely based on open-label stud-
ies or observational data, as randomized controlled clinical
Human and Animal Rights and Informed Consent This article does not
trials in migraine treatment have generally not separated pa- contain any studies with human or animal subjects performed by any of
tients based on aura status. The authors emphasize that it is the authors.
unknown whether patients with migraine aura, or individual
attacks including an aura phase, should be treated differently
[76••]. Greater occipital nerve block was effective in
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