Curr Pain Headache Rep (2015) 19:21
DOI 10.1007/s11916-015-0492-1
CHILDHOOD AND ADOLESCENT HEADACHE (S EVERS, SECTION EDITOR)
From Ophthalmoplegic Migraine to Cranial Neuropathy
Stefanie Förderreuther & Ruth Ruscheweyh
# Springer Science+Business Media New York 2015
Abstract Ophthalmoplegic migraine (OM)/recurrent painful
ophthalmoplegic neuropathy (RPON) is a rare disease
consisting of recurrent unilateral headache accompanied or
followed by ipsilateral ophthalmoplegia. Because MRI find-
ings suggest neuropathy and the relationship to typical mi-
graine remains unclear, the disease has been renamed from
“ophthalmoplegic migraine” to “recurrent painful oculomotor
neuropathy” in the third edition of the International
Classification of Headache Disorders (ICHD). However, it
remains a fact that most cases of OM/RPON described in
the literature have a history of migraine and that the headache
during OM/RPON often has migrainous features. A more de-
tailed clinical description of the headache during OM/RPON
and additional results from imaging and possibly histology
will be needed to better understand the pathophysiology of
the disease and its relationship to typical migraine.
Keywords Ophthalmoplegic migraine . Cranial neuropathy .
Periorbital pain syndrome . Ophthalmoplegia
Introduction
Ophthalmoplegic migraine (OM), which has been renamed
“recurrent painful ophthalmoplegic neuropathy” (RPON) in
This article is part of the Topical Collection on Childhood and Adolescent
Headache
S. Förderreuther : R. Ruscheweyh
Department of Neurology, Klinikum Großhadern,
Ludwig-Maximilians University, Munich, Germany
S. Förderreuther (*)
Neurologischer Konsiliardienst, Ludwig-Maximilians-Universität,
Ziemssenstr.1, Munich 80336, Germany
e-mail: steffi.foerderreuther@med.uni-muenchen.de
the third edition of the International Classification of
Headache Disorders (ICHD) [1] is a rare headache disorder
of unknown origin. It typically starts in childhood, but adult-
onset cases have also been reported. Hallmarks of the disorder
are recurrent episodes of migraine-like unilateral headaches
with a periorbital maximum of pain accompanied or followed
by transient ipsilateral extraocular muscle paresis. The oculo-
motor nerve is most frequently affected, followed by the
abducens and in rare cases the trochlear nerve. Both, headache
and ophthalmoplegia, resolve spontaneously, but
ophthalmoplegia typically outlasts the headache phase over
days or weeks.
The term ophthalmoplegic migraine was coined in 1890 by
the publication of Charcot with the title “Sur un cas de mi-
graine ophthalmoplegique” [2]. This publication was the basis
to classify the coincidence of migrainous headaches and
ophthalmoplegia as a subtype of migraine.
Here, we summarize the key findings published on OM/
RPON and discuss the pathophysiological hypotheses regard-
ing the different facets of the syndrome.
Clinical Picture
OM/RPON usually, but not exclusively, starts in childhood. The
youngest published patient suffered from his first OM attack at
the age of 3 months [3]. A review of 84 cases reported that the
median age at the time of the first ophthalmoplegic migraine
attack was 8 years, with a range from 7 months to 50 years
[4••]. OM/RPON attacks in adult persons are not limited to youn-
ger age groups [5].
Information on the gender ratio of OM/RPON varies: In a
series with predominance of children, about two third of OM/
RPON cases were females and one third males [4••]. In a
series of adult patients with OM/RPON published by Lal,
the gender ratio was balanced [5]. Another summary of 121
21 Page 2 of 6
OM/RPON cases of all age groups reported a slight prepon-
derance of female patients [6].
In typical cases, headache is the first clinical sign and usu-
ally lasts for several days up to a week. The headache is uni-
lateral with a maximum intensity in the periorbital and/or
retro-orbital region. A “migrainous” pain character is reported
in the majority of published cases, but often, the meaning of
migrainous is not strictly defined. According to the analysis of
84 OM/RPON cases by Gelfand, information about associated
symptoms was available in less than half of cases. Of these,
photophobia was noted in 65 %, phonophobia in 56 %, nausea
in 66 %, and vomiting in 69 %. These numbers illustrate that
migrainous features are present in many patients, but it is not
possible to determine the number of patients that definitively
fulfill the International Headache Society (IHS) criteria for
migraine. There is no doubt that in a number of patients, head-
ache fulfills the IHS migraine criteria. However, nausea and
vomiting are unspecific autonomic signs that, for example,
also can be found in a headache attack caused by acute glau-
coma. Photophobia might also be attributed to mydriasis, if
present, and phonophobia is another frequent and unspecific
complaint of patients suffering from a severe headache.
Aura symptoms would be much more specific for mi-
graine. But to the best of our knowledge, visual (fortification
spectra) and/or sensory and/or speech/language symptoms
characterized by gradual development and complete revers-
ibility within 60 min preceding the headache phase of OM/
RPON are not mentioned in any published case, even not in
the rare cases who were diagnosed with migraine with aura in
addition to OM/RPON [5, 7].
Diplopia usually develops during or after the headache
phase. In most cases of OM/RPON, the oculomotor nerve is
affected [4••], and mydriasis is present in part of the cases [8,
9]. Paresis of the abducens nerve occurs in 10 % of cases.
Trochlear nerve palsy is even rarer. There are only few cases
with combined nerve palsies in the literature [4••, 5].
The publication of Lal holds a special position in the liter-
ature [5]: In his series, the findings in 62 consecutive adult
patients from India with “OM” were analyzed, but only 14
patients strictly fulfilled the OM/RPON criteria with recurrent
painful ophthalmoplegia, since 48 had only a single attack. In
this cohort, isolated abducens palsy was most frequent
(56.5 %), followed by oculomotor and trochlear nerve in-
volvements in 33.9 and 8.1 % patients, respectively. One pa-
tient had simultaneous involvement of the third and sixth
nerves. In contrast to the majority of recently published case
series [4••, 9–12], none of the 62 Indian cases had any nerve
enhancement in MRI. All patients had a history of migraine,
and 51 (82.3 %) exhibited an antecedent worsening in severity
of migraine. However, these numbers cannot serve as proof
for the strong association of OM/RPON with typical migraine,
since in this cohort of patients, a history of headache consis-
tent with the IHS criteria of migraine (1988 and 2004) was an
Curr Pain Headache Rep (2015) 19:21
inclusion criterion. In these patients, ophthalmoplegia devel-
oped during (59/95.2 %) or within 24 h (3/4.8 %) of a severe
migraine attack.
In many published cases, ophthalmoplegia develops during
or immediately after the headache phase [3, 4••, 5–7, 10, 11,
13–16], but there are also reports on patients who developed
diplopia with a latency period between the beginning of head-
ache and diplopia of up to 11 days [3, 7–9, 17–20]. A reverse
order of symptoms starting with diplopia followed by head-
ache occurs only exceptionally [21]. The duration of diplopia
varies: In rare cases, diplopia resolves within hours [22, 23]. In
the majority of the reported cases, diplopia resolves over days
to weeks or even months. Patients suffering from frequent
episodes sometimes only show incomplete recovery [4••, 8,
24]. The interval between the first attack and recurrence of
ophthalmoplegia varies from as little as a week to up to 5-
7 years [23, 25–27].
Treatment response is generally difficult to estimate, as the
natural course of OM/RPON is variable: duration of a single
attack ranges between days and months. Under treatment with
steroids, some patients show improvement of headache and a
presumably faster remission of double vision, but the effect of
steroids is not as prompt and clear as, for example, in Tolosa-
Hunt syndrome or temporal arteritis [5, 9, 11, 28•]. There are
also clear steroid non-responders and patients with uncertain
response to steroids [4••]. Controlled studies are lacking.
Acute headache treatment with NSAR and even with triptans
is often unsatisfying [10, 11, 17]. For long-term treatment, the
following drugs with more or less well-established migraine
prophylactic effects have been used: pizotifen, flunarizine,
amitriptyline, verapamil, propranolol, sodium valproate, and
cyproheptadine [3, 5, 6, 11, 18, 21, 23]. A review of the liter-
ature gives no convincing arguments to initiate migraine pro-
phylactic treatment in OM/RPON, except if there is also clear-
cut typical migraine with frequent attacks.
Pathophysiology
The key pathophysiological questions regarding OM/RPON
are which mechanism is responsible for the pain, and is the
nerve palsy caused by the same mechanism? Furthermore, the
relationship of typical migraine has to be accounted for. Do
both disorders share a common pathophysiology? Do patho-
physiological mechanisms of migraine headache predispose
to develop OM/RPON or is there just a comorbidity of OM/
RPON with migraine, a frequent headache disorder?
In an attempt to explain the underlying pathophysiology,
Walsh and O’Doherty in 1960 pointed out that an edema of the
wall of the internal carotid artery generated during migraine
headache could compress the oculomotor, the trochlear, and
the abducens nerve in the carotid sinus [29]. However, since
compression of the oculomotor nerve typically results in
Curr Pain Headache Rep (2015) 19:21
mydriasis as the first clinical sign and since parasympathetic
fibers can be spared in OM/RPON [8, 9], other pathophysio-
logical mechanisms have been discussed. Vijayan pointed out
the similarities between OM/RPON and painful diabetic neu-
ropathy which typically spares the parasympathetic fibers of
the oculomotor nerve. He proposed that ischemia of the nerve
might be a better explanation [30].
The first classification of headache disorders was published
in 1988, years before cranial magnetic resonance imaging re-
vealed the morphological changes that can be found in part of
the patients with OM/RPON [1]. Therefore, it is coherent that
ophthalmoplegic migraine was classified by phenomenology
as a migraine variant. However, it is interesting that the first
classification criteria not even required typical migrainous
characteristics of the headache to diagnose OM. Only at least
two headache attacks overlapping with paresis of one or more
of cranial nerves III, IV, and VI and the exclusion of a
parasellar lesion were required for the diagnosis. Already,
the first IHS classification committee was in doubt whether
OM has anything to do with migraine since the headache often
lasts for a week or more. Probably one of the key features to
classify OM as a migraine variant was the observation that
there is an association of OM with other forms of migraine
in many patients.
In 1992, Mark et al. were the first to describe a patient with
ophthalmoplegic migraine with reversible contrast enhance-
ment of the oculomotor nerve on magnetic resonance imaging
[31]. In the following years, several cases of ophthalmoplegic
migraine were published with a striking similarity of MRI
findings: a localized thickening and reversible contrast en-
hancement of the oculomotor nerve in the intracisternal por-
tion, especially the root entry zone, of the affected oculomotor
nerve [31, 32]. This MRI finding is the main reason to favor
the theory of a painful neuropathy as a cause of OM/RPON.
However, since contrast enhancement is an unspecific finding
that can reflect vascular damage, demyelinization, inflamma-
tion, or tumor, the pathophysiology underlying OM/RPON is
still under discussion. Indeed, some case histories give argu-
ments that endorse the migraine theory and others that give
arguments for an independent neuropathic pain syndrome.
Changes in the ICHD reflect the pathophysiological discus-
sion. In its second edition, OM no longer was classified as a
migraine variant but reassigned to the section of cranial neu-
ralgias and central causes of facial pain. However, the head-
ache characteristics were required to be “migraine like,” and
the term “ophthalmoplegic migraine” was retained [33]. The
third edition of the ICHD no longer specifies headache quality,
but requires headache only to be unilateral and ipsilateral to
the nerve palsy and redefines ophthalmoplegic migraine as
recurrent painful ophthalmoplegic neuropathy [34]. The key
arguments to justify this change were the time course in the
development of the clinical signs and symptoms of the disor-
der and the MRI findings: Many case reports document that
Page 3 of 6 21
headache can develop up to 14 days prior to ocular motor
paresis and that gadolinium enhancement and nerve thicken-
ing are more probably the correlate of a peripheral nerve le-
sion than of migraine. Furthermore, the good response to treat-
ment with corticosteroids in some patients does not favor a
migrainous pathomechanism.
Today, there is general consent that other causes of
periorbital pain syndromes like Tolosa-Hunt syndrome, pain-
ful diabetic neuropathy, or any tumor arising from the affected
nerve or a space-occupying lesion compressing the nerve, like
an aneurysm or a meningioma, have to be excluded by appro-
priate investigations. Besides, a cranial MRI or at least a CT
scan, a lumbar puncture, and blood tests to exclude diabetes
and other systemic disorders with CNS or PNS involvement
are obligatory.
Right now, there are more arguments favoring a neuropath-
ic disorder, but it is difficult to explain all features of OM/
RPON by neuropathy, and there are still some arguments left
to favor migraine at least as a possible pathophysiological
cofactor. Therefore, there is an ongoing discussion in the lit-
erature on the pathophysiological mechanisms of headache
and ophthalmoplegia in OM/RPON. The arguments pro and
contra migraine and neuropathy as the primary cause of OM/
RPON are listed below.
Arguments Pro Migraine
With a striking frequency, published cases of OM/RPON have
a history of typical migraine or recurrent headaches outside
the ophthalmoplegic bouts (e.g., 83 % of 41 mainly pediatric
patients [4••]). In addition, many of these patients point out
that the headache in OM/RPON is more intense and
prolonged, but otherwise not different from their typical mi-
graine headaches. However, it must be taken into account that
a history of typical migraine was part of the ophthalmoplegic
migraine criteria initially proposed by Walsh and O’Doherty
in 1960 [29]. Therefore, when assessing a patient with painful
ophthalmoplegia and normal complementary investigations,
clinicians may have been biased to diagnose OM/RPON in
p at i e nt s w i t h a h i s t o r y o f m i g r ai ne a n d pa i n f u l
ophthalmoplegia of unknown cause in other cases. For exam-
ple, in the series of Lal et al., a history of migraine was an
inclusion criterion [5]. A family history of migraine or recur-
rent headaches are also frequently reported, e.g., in 49 % of 40
pediatric OM/RPON cases [9], in 62 % of 47 mostly pediatric
OM/RPON cases [4••], and in 42 % of 62 adult onset [5]. In
addition, the headache in OM/RPON is often (but not always)
described as migrainous and unilateral (ipsilateral to
ophthalmoplegia) [4••, 5]. Unfortunately, as explained above,
a thorough classification of the headache according to the IHS
migraine criteria is not available in most studies. OM/RPON
by definition includes at least two episodes of painful
21 Page 4 of 6
ophthalmoplegia, and in typical cases, OM/RPON presents
with recurrent episodes [4••, 9]. This fits well with migraine
which is a recurrent disorder, too. However, it would also fit
with an immune-mediated relapsing-remitting demyelinating
neuropathy. In addition, during OM/RPON attacks, headache
usually precedes ophthalmoplegia by several days [4••, 8],
establishing a time sequence consistent with migraine causing
the ophthalmoplegia. However, headache can even develop
up to 14 days prior to ocular motor paresis—a time course
not consistent with typical migraine. In addition, pain preced-
ing ophthalmoplegia has also been described in other types of
painful ophthalmoplegia, e.g., diabetic ophthalmoplegia or
herpes zoster ophthalmicus [35–38].
CSF examinations are normal in the vast majority of cases,
with unspecific abnormalities in the remainder [4••, 5, 16].
Therefore, CSF findings cannot endorse the theory of an au-
toimmune or other inflammatory-mediated pathomechanism.
Although pathologic MRI findings in OM/RPON patients
have received much attention, between 25 and 81 % of the
cases have normal MRI in the acute period [4••, 6]. Normal
CSF and MRI findings would be consistent with migraine.
Regarding pathophysiological considerations, several
mechanisms have been proposed to explain how migraine
might cause ophthalmoplegia. Migraine-related swelling of
the internal carotid artery or posterior cerebral artery vessel
walls has been proposed to lead to occlusion of arterial
branches supplying the cisternal portion of the oculomotor
nerves. Ischemic breakdown of the blood-nerve barrier would
then lead to vasogenic edema, explaining both
ophthalmoplegia and thickening and contrast enhancement
of the nerve [39••]. Alternatively, it has been proposed that
release of neuropeptides such as calcitonin-gene-related pep-
tide (CGRP) from trigeminal nerve fibers terminating on the
circle of Willis during a migraine attack might induce a neu-
rogenic inflammation of the blood-nerve barrier and/or the
oculomotor nerve, also accounting for both ophthalmoplegia
and the MRI findings [5, 8, 11]. Regarding the latter theory,
one might critically discuss that no OM/RPON cases have
been reported in patients with cluster headache, who have a
massive release of CGRP during their headache attacks [40,
41] and who also show increased blood CGRP levels between
attacks during the active cluster headache episode [40].
Similarly, peripheral blood CGRP levels in chronic migraine
are even higher than in episodic migraine [42]. However, most
OM/RPON cases seem to have a history of rather infrequent
episodic migraine, although worsening of migraine in the
weeks preceding the OM/RPON has been reported [5].
Arguments Pro Neuropathy
The main argument in favor of neuropathy as the primary
cause of OM/RPON are the MRI findings that have been
Curr Pain Headache Rep (2015) 19:21
reported in part of the OM/RPON cases [6, 8, 15, 31, 32].
Nerve thickening with contrast enhancement in the root entry
zone of the symptomatic nerve is the morphological correlate
of ophthalmoplegia. These findings are most prominent dur-
ing the acute period and show partial or complete resolution
during remission. This clearly is not a typical feature of mi-
graine. Together with ophthalmoplegia, it strongly suggests a
structural neuropathy, which might be of ischemic or inflam-
matory (infectious or non-infectious) origin. A structural
nerve damage would also explain the prolonged time course
of ophthalmoplegia, which usually outlasts headache for sev-
eral days or weeks, and the observation that after repeated
episodes of OM/RPON, there may be incomplete recovery
of ophthalmoplegia [4••, 8, 9].
If neuropathy is the primary cause of OM/RPON, neurop-
athy must also explain the headache. Most cases of OM/
RPON affect the oculomotor nerve, which has been shown
to conduct a number of afferent first division trigeminal nerve
fibers [43]. Therefore, irritation of the oculomotor nerve might
result in ipsilateral periorbital and frontal pain. Indeed, diabet-
ic ophthalmoplegia affecting the oculomotor nerve is also fre-
quently associated with periorbital pain demonstrating that
oculomotor lesions can be painful [36]. To explain the time
lag between onset of pain and onset of ophthalmoplegia in
OM, one has to assume that trigeminal afferent fibers are more
sensitive to irritation than motor fibers in the oculomotor
nerve. Indeed, a time lag between pain and ophthalmoplegia
has also been reported in other types of ophthalmoplegia, al-
though less frequently [35, 36]. The headache has migrainous
features in many OM/RPON cases. However, most reported
OM/RPON cases have a history of migraine [4••, 5]. One
might speculate that migraine patients have a tendency to react
with migrainous headache to various external and internal
stressors. Therefore, irritation of trigeminal nerve fibers dur-
ing oculomotor neuropathy might well induce a migrainous
headache in patients with a migraine history.
Another much cited argument contra migraine as the pri-
mary cause of OM/RPON is the duration of headache, which
often exceeds the typical duration of a migraine attack (≤72 h),
lasting up to a week [4••]. This might indeed support the
hypothesis of neuropathy and not migraine causing the head-
ache in OM. However, migraine attacks lasting longer than
72 h (status migrainosus) are a typical complication of mi-
graine [34]. Maybe more severe or prolonged migraine attacks
are especially prone to induce an OM/RPON attack.
Alternatively, headache might start as a typical migraine at-
tack, and then be prolonged by migraine-induced
ophthalmoplegic neuropathy. From our point of view, a stron-
ger evidence against migraine causing ophthalmoplegia is the
fact that no case has been reported where a migraine attack
with aura was associated with ophthalmoplegia. The presence
of a typical migraine aura would corroborate that the headache
is indeed due to a migraine attack. However, headache
Curr Pain Headache Rep (2015) 19:21
characteristics are often poorly reported in the published cases
of OM, so the presence of aura may not have been described.
From a pathophysiological point of view, it has been pro-
posed that a recurrent viral infection [31] or immune-mediated
inflammation, e.g., similar to chronic inflammatory demyelin-
ating neuropathy (CIDP) [3], might explain both, recurrent
ophthalmoplegia and the typical MRI findings in OM/
RPON. However, CSF results in OM/RPON are typically
normal and have not shown evidence of viral infection or
immune-mediated neuropathy [4••, 5, 16]. In addition, the
MRI findings in Miller-Fisher syndrome, zoster ophthalmicus
with ophthalmoplegia, and CIDP exhibit a different pattern
from those seen in OM/RPON, with a more linear enhance-
ment and/or thickening of the oculomotor nerve along its cis-
ternal and more distal trajectory, not limited to the root entry
zone [44–48].
In conclusion, although pathological MRI findings are
highly suggestive of neuropathy in OM, it remains unclear if
neuropathy is caused by migraine, facilitated by a migraine
predisposition, or caused by an independent disease, with mi-
grainous headache being secondary to neuropathy. The high
incidence of a personal or family history of migraine in the
reported cases suggests that even if migraine may not be the
cause of neuropathy, it might constitute at least a predisposi-
tion for developing this kind of neuropathy.
What We Need to Know from Future Cases
To better understand the pathophysiology underlying OM/
RPON and its relationship to migraine, it might be useful to
obtain more detailed clinical and additional information from
future cases that fulfill the criteria of OM/RPON.
Histology would be helpful, but cannot be expected due to
the benign course of the disease. The few autopsy cases pub-
lished between 1885 and 1911 are in part limited by
concurring diseases and contribute little to understand
the disease [49].
However, some hints regarding the relationship of OM/
RPON to migraine could be gained by a more thorough clin-
ical description of the headache and—if present—aura symp-
toms. It would be of interest to know (1) if the typical migraine
headaches are side locked or at least have a side preference
corresponding to the side affected during the OM/RPON at-
tacks, (2) if the headache during OM/RPON attacks fulfills the
IHS criteria for migraine or status migrainosus, (3) if the head-
ache during OM/RPON is undistinguishable from the typical
migraine attacks of the respective patient, and (4) if the head-
ache during OM/RPON attacks responds to early treatment
with migraine-specific drugs or to the analgesic drugs usually
effective in the respective patient. If these points are regularly
fulfilled, this would strengthen the view that there is a patho-
physiological relationship between migraine and OM/RPON.
Page 5 of 6 21
It would be of special interest to know at what point during
an OM/RPON attack the typical MRI findings develop. If they
are present early during the attack, before the development of
ophthalmoplegia, this might be an argument in favor of neu-
ropathy. Therefore, it would be useful to perform MRI in
patients with known OM/RPON in prolonged migraine at-
tacks before the development of ophthalmoplegia if the op-
portunity arises.
Compliance with Ethics Guidelines
Conflict of Interest Dr. Stefanie Förderreuther reports personal fees
from Boehringer Ingelheim, Hormosan, and Pharm Allergan.
Dr. Ruth Ruscheweyh reports personal fees from Allergan, MSD,
Mundipharma, and Pfizer.
Human and Animal Rights and Informed Consent This article does
not contain any studies with human or animal subjects performed by any
of the authors.
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