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Migrainous scintillating scotoma and headache is ocular in origin: A new

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Medical Hypotheses (2006) 66, 454–460

http://intl.elsevierhealth.com/journals/mehy

Migrainous scintillating scotoma and headache

is ocular in origin: A new hypothesis
Vinod Kumar Gupta *

Dubai Police Medical Services, P.O. Box 12005, Dubai, United Arab Emirates

Received 31 October 2005; accepted 3 November 2005

Summary Brain neuronal dysfunction has been implicated in pathogenesis of migraine but direct evidence is lacking.
Scintillating scotoma of migraine is generally believed to originate at the visual cortex. While cortical spreading
depression is a relatively late physiological alteration in migraine, its protective role in neuronal ischaemia is
increasingly being recognized. Atenolol, nadolol, or verapamil prevent migraine but do not readily cross the blood–
brain barrier or critically influence any brain or peripheral neuronal function. Typical migraine headache, aura, or
scintillating scotoma has not been reported following enucleation or evisceration of the eye. In humans, pain and
temperature fibres from only the ophthalmic division of the trigeminal nerve reach the upper cervical spinal segments.
Pain in migraine attacks including occipital and nuchal discomfort reflects selective involvement of the ophthalmic
nerve. Photophobia is largely a retinal reflex involving the ophthalmic division of the trigeminal nerve. Key clinical
features of the migrainous scintillating scotoma are consistent with retinal origin. Spreading depression in the retina is
well-established. A subtle regional ocular sympathetic deficit prevails in migraine patients and possibly impairs
regulation of intraocular choroidal blood volume and intraocular pressure. Several first-line migraine prophylactic
agents lower the intraocular pressure. The neuro-ophthalmological basis for a monocular origin of migrainous
scintillating scotomata due to mechanical deformation of the posterior segment of the corneo-scleral envelope
consequent to choroidal venous congestion and rise in intraocular pressure is presented. Study of distribution and
displaceability of the migrainous scintillating scotoma can settle its site of origin. Headache of migraine possibly arises
from a similar mechanical deformation of the anterior eye segment followed by antidromic discharge in the
trigeminovascular system. Lateralizing negative deficits such as homonymous hemianopia probably reflect vasospastic
complications of migraine. A rational explanation for the most characteristic clinical features of migraine and a new
template to elucidate the pharmacological basis of anti-migraine drugs is offered.
c 2005 Published by Elsevier Ltd.

Abbreviations: ANS, autonomic nervous system; BBB, blood–
brain barrier; CSD, cortical spreading depression; IOP, intraocular
pressure; NO, nitric oxide; RSD, retinal spreading depression.
* Tel.: +971 43355954.
E-mail addresses: dr_vkgupta@yahoo.com, vinodkgupta9@
gmail.com, docgupta@emirates.net.ae.
Introduction
Migraine is a painful, incapacitating disease with a
substantial economic burden on society [1,2]. Cen-
tral brain or thalamic or brain stem neuronal dys-
function possibly related to cortical spreading
depression or involvement of the midbrain periaqu-


0306-9877/$ - see front matter c 2005 Published by Elsevier Ltd.
doi:10.1016/j.mehy.2005.11.010
Migrainous scintillating scotoma and headache is ocular in origin
eductal gray is currently believed to underlie both
the aura as well as the headache in migraine pa-
tients [1–5]. The occipital cortex is generally be-
lieved to generate the symptoms of migraine aura
[6].
A large body of evidence appears to support the
role of brain cortical spreading depression (CSD) as
a key component of the migraine pathogenetic cas-
cade [2,3,6,7]. Critical limitations, however, per-
sist in the link between CSD and migraine: (i)
Given the significant interval between the head-
ache-provoking stimulus and the onset of the pro-
drome of migraine as well as the prolonged
prodrome itself, CSD cannot be considered as the
initiating physiological event [8,9]. (ii) There is a
prominent theoretical gap between experimental
CSD in animals [9,10] and spreading cerebral oliga-
emia in migraine patients [11,12]. (iii) In unanaes-
thetized rats, CSD does not induce aversion as an
immediate or delayed reaction [13]. (iv) Dihydroer-
gotamine, acetylsalicylic acid, metoprolol, or val-
proate do not affect CSD in the cat [14]. (v) In
cats, CSD is not associated with release of calcito-
nin gene-related peptide [15]. (vi) CSD by itself
does not affect ATP levels, mitochondrial aconitase
activity, or induce neuronal injury [16]. (vii) CSD
cannot explain selective involvement of the oph-
thalmic division of the trigeminal nerve in mi-
graine, as discussed subsequently in this paper.
(viii) A large and growing body of evidence indi-
cates that CSD is biologically adaptive or neuropro-
tective. CSD influences the expression of many (to
date, over 40) genes associated with inflammation
and induces a long-lasting ischemic tolerance that
results in smaller subsequent infarcts and stimu-
lates persistent neurogenesis [17,18].
Key facets of basic sciences further challenge
the link between a primary visual cortex neuronal
dysfunction or CSD and migraine. Neurophysiologi-
cally, a recent transcranial magnetic stimulation
shows that two-thirds (64.86%) of patients affected
by either migraine with aura or without aura pres-
ent an increased phosphene threshold in the inter-
ictal period, suggesting that their visual cortex is
hypoexcitable; in such a state, occurrence of CSD
becomes quite unlikely [19]. Previous studies,
however, have reported increased visual cortex
excitability between migraine attacks [20]. Con-
versely, amitriptyline, a well-established migraine
preventive agent, can provoke seizures and unam-
biguously increases excitability of the brain [21].
Cortical excitability in migraine patients funda-
mentally depends on trait- and state-related highly
variable levels of arousal, whether during or be-
tween attacks; different migraine cohorts are,
therefore, likely to present contrasting results in
455
studies of cortical excitability [21]. Furthermore,
photophobia is a pathognomonic and diagnostic
feature of migraine [22]. Photophobia, is a reflex
involving the trigeminal nerve; vasodilatation in
the ciliary muscle is probably involved as photo-
phobia generally disappears when cycloplegia is in-
duced [23]. In photophobia, light falling on the
retina causes constriction of the pupil and pain;
photophobia is reinforced by a reflex from the ret-
ina [23–25]. Although visual cortex excitability has
been proposed to explain migrainous photophobia
[26], this theory, as discussed previously, is contro-
versial. In migraine, anterior eye segment uveal
sensitization following antidromic neuropeptide
release at the level of iridial ophthalmic fibres
might underlie photophobia during and between
attacks [26,27]. Remarkably, occipital lobe seizure
disorders and mass lesions such as arteriovenous
malformations are generally not associated with
photophobia [28]. Also, a MEDLINE search does
not show any association between photophobia
and occipital seizures. Finally, CSD-induced neuro-
genic inflammation is believed to activate trigemi-
nal-C fibres and cause pain of migraine [29] but a
positive correlation was not seen between the
number of CSDs and the extent of c-fos expression
in Trigeminal Nucleus Caudalis in rats [30].
Neuroanatomically, pain in migraine is not – as
has been generally assumed – distributed through-
out the trigeminal nerve but is principally confined
to the ophthalmic division of the trigeminal nerve.
While selective or isolated involvement of the max-
illary or mandibular divisions does not appear to
occur in migraine attacks, spread of pain to the
back of the head as well as to the neck has been
attributed to a diffuse involvement of the trigemi-
nal nerve and upper cervical spinal segments [31].
The primary afferent fibres of the three divisions of
the trigeminal nerve are arranged in a complex
manner at the spinal nucleus with only pain and
temperature fibres from the ophthalmic area
descending to the lower limit of the first cervical
spinal segment; this long held view, although con-
troversial, is supported by sectional studies in hu-
mans at and below the obex for severe trigeminal
neuralgia [32]. Occipital and nuchal pain in mi-
graine attacks probably involves predominantly
the link between ophthalmic trigeminal fibres and
the upper cervical spinal segments. Moreover, a
typical migraine attack – with scintillating sco-
toma or pulsating headache or both – has not been
reported following enucleation or evisceration of
the eye [33,34], reinforcing the pathogenetic role
of the ophthalmic division of the trigeminal nerve.
Neuropharmacologically, drugs that do not
freely cross the intact blood–brain barrier (BBB)
456
or critically influence brain or any other – central
or peripheral – neuronal function offer effective
migraine prophylaxis (e.g., atenolol, nadolol, or
verapamil) or instantaneously abort the migraine
aura (e.g., nifedipine or isoproterenol) [21]. Aten-
olol, like propranolol, is accepted by a broad con-
sensus as a first-line migraine prophylactic agent
[35]. Also, some therapists prefer to use verapamil
prophylactically in patients with migraine aura,
with or without headache, particularly when auras
are frequent or associated with hemiparesis [36];
verapamil, however, does not directly alter brain
neuronal function [21]. Since migraine prophylactic
agents unarguably modulate primary pathophysio-
logical disturbance(s), poor brain penetrability of
several such agents is a pharmacokinetic absolute
that strongly indicates that the origin of migraine
might not be primarily or exclusively related to
brain or central neuronal dysfunction [21]. More-
over, between migraine attacks, headache-related
alterations in BBB permeability or cerebral blood
flow or release of neuropeptides/second messen-
gers is not envisaged; the actions of migraine pro-
phylactic agents are unlikely to involve such
mechanisms. Next, overall relevance of ion chan-
nel disorders to pathogenesis of migraine remains
uncertain. A double-blind, placebo-controlled, par-
allel study of lamotrigine in 53 migraine with aura
and without aura patients found the drug ineffec-
tive for prophylaxis [37]. Two, topiramate is not
effective in preventing aura in migraine patients
[38] while it can prevent recurrences of episodic
and chronic cluster headache [39]. CSD, however,
has not been envisaged as a pathogenetic mecha-
nism in cluster headache. Three, acetazolamide
appears to have a preventive role in migraine pa-
tients with aura [40]. Acetazolamide, however,
neither has a direct action on the P/Q type calcium
channel [41] nor does it alter penetration of sodium
ions into the parietal cortex [42]. Finally, periphe-
ral fronto-temporal scalp application of nitroglyc-
erine ointment can precipitate migraine attacks
[43]; again, no alteration of brain neuronal func-
tion appears to be involved [21].
In contrast to the origin of migraine-related neg-
ative scotomata – the commonest being homony-
mous hemianopia – that clearly originate at the
level of the visual cortex, the site of origin of the
migrainous scintillating scotoma is uncertain. While
retinal lesions are monocular, visual cortex lesions
are binocular in distribution; even an astute obser-
ver, however, might be unable to pinpoint monocu-
lar or binocular origin of visual field disturbances
[28]. Currently, whereas in retinal migraine or
‘‘ocular migraine’’ or ‘‘typical aura without head-
ache’’ monocular visual impairment is the rule
Gupta
[22,28,44], it is uncertain whether the scintillating
scotoma of migraine is a monocular or binocular
phenomenon. Although the migrainous scintillating
scotoma is usually hemianopic and many patients
maintain that it involves one eye only [28], the issue
appears controversial as most investigators regard it
as a homonymous binocular phenomenon consistent
with origin at the visual cortex [45]. Several critical
limitations of visual cortex origin of the migrainous
scintillating scotoma merit attention: (i) The nega-
tive visual auras of migraine including homonymous
hemianopia have never been clinically associated
with the scintillating scotoma [28,45–47]. (ii) As a
rule, the occipital cortex is the most likely source
of visual phenomena occurring in the peripheral vi-
sual field whereas deficits of central vision are gen-
erally due to retinal involvement [28]. Migrainous
visual field deficits, however, usually involve the
central vision [28,44,45,47]. (iii) While the link be-
tween metamorphopsia, visual cortex dysfunction,
and migraine is nebulous [28,46], macular retinal le-
sions are well known to be associated with visual
distortions [48]. (iv) Occipital ischemia-associated
scintillating scotomata due to posterior cerebral ar-
tery insufficiency are not associated with the
‘‘build-up’’ phenomenon [28]. Additionally, sei-
zure-related scintillating scotomata of occipital vi-
sual cortex origin differ clinically from the classic
scintillating scotoma of migraine in several impor-
tant ways; with occipital lobe mass lesions, particu-
larly arteriovenous malformations, recurrent
headache occurs almost always on the same side
and generally precedes the visual symptoms [28].
Conversely, migrainous aura, including the scintil-
lating scotoma, is not consistently associated with
neurologically lateralizing headache [8,9]. (v) The
intrinsic property of the retina to manifest a gluta-
mate- or potassium-release based excitatory wave-
front similar to the CSD of Leão has been extensively
investigated [49–51]. Also, anti-migraine agents
such propranolol, sumatriptan, methysergide, para-
cetamol and acetylsalicyclic acid decrease the
propagation velocity of retinal spreading depression
(RSD) waves, accelerate the recovery of the optical
and electrical signal and reduce the amplitude of
the negative potential shift that accompanies RSD
[52,53]. Furthermore, sumatriptan can attenuate
migraine aura [54], although the issue remains
unsettled [55]. The retina is an avascular tissue
and pharmacological modulation of RSD appears to
be a neuronal action [52,53]; however, it is impor-
tant to underscore that the isolated retina in animal
experiments is not representative of the human eye
in vivo as the influence of the highly vascular cho-
roid is eliminated in the laboratory. Fourthly, in
RSD, spiral wavefronts perform a complex motion
Migrainous scintillating scotoma and headache is ocular in origin
across the retina [56] that can mimic propagation of
the migrainous scintillating scotoma in humans. Fif-
thly, ischemic RSD has been suggested to underlie
visual deficits in retinal migraine [44] as well as scin-
tillating scotomata following internal carotid artery
dissection [57]. Finally, involvement of ocular
retinal and choroidal vessels by neurogenic inflam-
mation does not appear to be a major factor in mi-
graine headache attacks [58]. A non-inflammatory,
non-ischaemic, and non-neuronal retinal origin
for the migrainous scintillating scotoma appears
plausible [21,59].
Hypothesis
RSD mimics the CSD of Leão. In migraine patients, a
mechanical deformation of the posterior pole of
the eye consequent to choroidal congestion and
associated rise in IOP might trigger an activating
wavefront in the retina that results in monocular
scintillating scotomata. A similar mechanical acti-
vation of the anterior segment of the eye might
underlie photophobia and headache of migraine.
A hitherto unknown altered biomechanical prop-
erty of the corneo-scleral envelope may render mi-
graine patients particularly susceptible to periodic
self-limited mechanical deformations of the eye.
Migraine-glaucomatous visual
dysfunction-IOP nexus: a new hypothesis
A close relation exists between migraine and the vi-
sual system [24,28,44–47]. McKendrick and Bad-
cock [60,61] recently recorded visual field
dysfunction in migraine manifest as a generalized
decreased sensitivity across the visual field and
localized deficits, confirming earlier studies
[62,63]. Between 30% and 60% of migraine patients
have visual field deficits during the interictal peri-
ods, and the dysfunction worsens in the first 7 days
following an attack [60,61]. This consensus has
been recently challenged by Harle and Evans [64].
Nevertheless, frequency of migraine attacks and
length of time for which patients suffer might ex-
plain the variability seen in visual field deficits be-
tween cohorts. Also, differences in visco-elastic
properties of the eye, including dynamic ocular
rigidity, ocular tissue creep, and corneo-scleral dis-
tensibility probably modulate and determine the
clinical outcome of episodic elevations of IOP on
retinal/optic nerve head barotrauma in migraine.
The link of such visual deficits in migraine to cere-
bral ischaemia is limited by lack of neuroanatomi-
cal lateralization as well as by occurrence of
457
bilateral glaucomatous deficits and retinal impair-
ment in patients with unilateral headache [65–
67]. Diffuse depression of retinal sensitivity as well
as mild reduction in the central vision may precede
characteristic visual field changes in glaucoma
[68]. Importantly, abnormalities in visual evoked
potentials have been seen pre-ictally in a cohort
of migraine without aura patients [69]. Both mi-
graine with aura patients as well as migraine with-
out aura patients can manifest retinal deficits not
consistent with ischaemic aetiology.
A subtle sub-clinical general as well as regional
ocular autonomic nervous system (ANS) dysfunc-
tion prevails in migraine between attacks [70,71].
Occurrence of both glaucomatous visual field defi-
cits in migraine patients with aura or without aura,
as discussed previously, as well as the ocular hypo-
tensive effect of several migraine prophylactic
agents, including propranolol, atenolol, metopro-
lol, nadolol, clonidine, flunarizine, and verapamil
[24,65,66,68,72,73] indicate that a strong link ex-
ists between migraine and dysregulation of the
intraocular pressure (IOP). The ocular choroid pos-
sesses the greatest blood supply in the human
body, with a circulation volume 10–20 times that
of the cerebral cortex; the sympathetically inner-
vated choroidal venous circulation is capable of
vigorous autoregulation [74,75]. An intrinsic or
trait regional ocular ANS hypofunction possibly pre-
disposes migraine patients to develop episodic cho-
roidal congestion and transient elevations of the
IOP in a variety of stressful circumstances and clin-
ical situations [65,66].
I propose that the headache and the scintillating
scotoma of migraine is the outcome of an episodic
intraocular pressure-related mechanical distortion
of the corneo-scleral envelope in genetically pre-
disposed individuals with regional ANS hypofunc-
tion. Acute experimental IOP elevations discharge
impulses in iris, corneo-scleral, and whole nerve
ocular trigeminal fibres probably involving mechan-
ical distortion of iris and chamber angle, suggesting
production of painful antidromic impulses [24,76].
Selective involvement of the ophthalmic division
of the trigeminal nerve in pain of headache and
photophobia of migraine is likely based on mechan-
ical activation of nerve fibres in the anterior seg-
ment of the eye. Migraine is characterized by
typical precipitating and relieving factors besides
longer-term periods of exacerbations and remis-
sions [9,45]. The physiological system of IOP is sub-
ject to a very large spectrum of variations, both
from within the internal milieu as well from the
environment [24,68]. Using the IOP as the template
for the primary physiological system involved in mi-
graine, it will be seen that several precipitants of
458
migraine raise the IOP while a number of relieving
factors lower the IOP. Fasting, sleep, alcohol con-
sumption, histamine, glyceryl trinitrate and other
well-known precipitating and relieving factors for
migraine have central neuronal or local ocular or
both influences that can affect the IOP [24,68].
Of particular relevance to migraine pathophysiol-
ogy is the unexplained tendency of any activity that
raises the cardiac output (pulse rate or blood pres-
sure or both) or central venous pressure to increase
the severity of headache and to induce a pulsatile
quality for a few seconds [45]. While rise of central
venous pressure instantaneously increases choroi-
dal venous congestion and IOP, as with cough or
the Valsalva manoeuvre [24,68], beat-to-beat in-
crease in arterial input into a relatively stretched
eyeball might contribute to pulsatile aggravation
of migraine headache. Phasic exacerbations and
remissions of attacks in migraine possibly relate
to individual handling of stress or to alteration in
corneo-scleral envelope distensibility or both.
Complex variations in visco-elastic properties of
the eye and their alterations with age, genetic
influences, hydration, systemic blood pressure,
hormones, menstrual cycle, and pregnancy might
determine the highly variable onset or offset,
aggravation or remission of migraine as well as
the typical difference in incidence that prevails be-
tween the sexes. Post-stress headache is a charac-
teristic manifestation of migraine [9]. Sympathetic
hyperfunction during stress probably prevents cho-
roidal congestion and rise of IOP. A full discussion
of these influences is beyond the scope of this pa-
per but the abstract of an attempted synthesis
has been published [77].
While migraine headache possibly results from
involvement of the anterior eye segment, scintil-
lating scotoma might be the outcome of a choroi-
dal congestion induced mechanically propagated
wave in the posterior segment of the eye. Physio-
logically, the retina is sensitive to mechanical
stimulation. A RSD-like phenomenon has been
clearly established to propagate as a wavefront
[49–51,56] that can resemble migrainous scintil-
lating scotomata. On different occasions, a pa-
tient with migraine might experience either
headache with aura or headache without aura or
aura alone [22]; such clinical overlap is a common
feature and there are no significant differences in
characteristics of either the attacks or the sub-
jects between these groups [78]. The concurrence
of scintillating scotoma with migraine headache
probably indicates involvement of both posterior
and anterior eye segments, with the mechanical
wave commonly but not always beginning at the
posterior pole of the eye. Segmental or patchy
Gupta
mechanical deformation of the corneo-scleral
envelope may underlie occurrence of migraine
without aura, scintillating scotoma without head-
ache or monocular migraine with transient or per-
manent visual loss or defect. A conceptual
pathogenetic divide needs to be developed be-
tween migrainous scintillating scotoma that is usu-
ally hemianopic (monocular) and migrainous
negative visual deficit such as homonymous hemi-
anopia that is clearly binocular and probably vaso-
spastic in origin [59]. It appears particularly
relevant that nitric oxide (NO) directly inhibits
propagation of retinal spreading depression in a
concentration- and time-dependent manner; also,
NO speeds up the recovery of the intrinsic optical
signal after the wavefront [79]. With this hypoth-
esis, it becomes possible to understand how nitro-
glycerine [28,36] – a NO donor – might swiftly
resolve migrainous scintillating scotomata [59].
Importantly, ocular autonomic hypofunction or
choroidal venous congestion is not a feature of
glaucoma, which probably explains why the
migrainous scintillating scotoma does not develop
in acute congestive glaucoma. Additionally, the
possibility of an intrinsic difference in the visco-
elastic properties of the corneo-scleral envelope
between migraine and glaucomatous patients
may be relevant. Future studies of migrainous
scintillating scotomata must focus on its distribu-
tion (monocular or binocular) and displaceability;
a monocular, displaceable positive visual phenom-
enon can only originate at the retina [28]. Serial
measurements of IOP between attacks rather than
during headache attacks – when pain-related
arousal mediated autonomic hyperfunction likely
prevails – can reveal a sub-clinical physiological
disturbance; home tonometry might be particu-
larly useful.
Conclusion
Origin of migraine directly due to brain neuronal
dysfunction is debatable. It is proposed that the
migrainous scintillating scotoma and headache re-
sult from a mechanical deformation of the cor-
neo-scleral envelope. With this hypothesis, it is
possible to explain the particular involvement of
the ophthalmic division of the trigeminal nerve as
well as to rationalize the phenomenology and the
prophylactic pharmacotherapy of migraine. Studies
of mechanical visco-elastic properties of the cor-
neo-scleral envelope in migraine patients might
lead to a unifying hypothesis that further rational-
izes its protean manifestations and pathogenesis.
Exploration of the potential therapeutic role of
Migrainous scintillating scotoma and headache is ocular in origin
topical ocular hypotensive agents for migraine pro-
phylaxis might prove useful.
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