Here we have systematically reviewed and analyzed published cases of ophthalmoplegic migraine, including both pediatric and adult cases, and added illustrative cases from our practices. The most notable findings in this review were the following: (1) in up to one-third of cases the associated head pain was not migrainous in quality nor were there associated migrainous symptoms, such as nausea or vomiting; (2) the symptoms were overwhelmingly side locked; (3) there was a marked time lag between headache onset and ophthalmoplegia extending up to 14 days; and (4) there was focal third nerve enhancement and thickening on contrast-enhanced brain MRI in more than three-quarters of cases involving the third nerve. Taken together, these data suggest that this syndrome is a not a migraine variant but rather a form of cranial neuropathy that triggers headache secondarily. Ophthalmoplegic Cranial Neuropathy may be a more suitable diagnostic term.
Lal and colleagues published a review of 62 adult patients with painful ophthalmoplegia32
; the majority had only a single episode, and it is possible that some of these cases represented other etiologies. Their case mix was very different from ours, and indeed to what we have typically seen reported in the literature, with onset in adulthood and not a single case of third nerve enhancement. It seems likely the entity classically known as ophthalmoplegic migraine, and classified by the International Classification of Headache Disorders (second edition), is different from that described in that series. The difference is so striking that perhaps there is a genetically based difference seen more obviously in the Indian subcontinent.
While the pathophysiology of ophthalmoplegic migraine is unclear, these data provide some clues about what the syndrome is not. By International Classification of Headache Disorders (second edition) criteria, there can be no apparent structural lesion to account for the findings. In our analysis, only 3 cases had associated vascular findings on imaging and these were unlikely to be etiologically significant.25,27,31
If such abnormal vascular contact is functionally meaningful, it likely occurs in only a small percentage of ophthalmoplegic migraine cases. This is in contrast to trigeminal neuralgia—a prototypical cranial neuralgia characterized by much briefer and more frequent painful episodes—in which abnormal contact between vessel and nerve is a more common association.
There was no evidence to suggest a systemic inflammatory process associated with ophthalmoplegic migraine in this analysis. There was also no evidence of intrathecal inflammation in any of the cases involving the third cranial nerve. Possibly inflammatory cerebrospinal fluid abnormalities were reported in only 2 cases, which happened to be the only 2 patients with fourth nerve involvement: one with an elevated IgG index, without oligoclonal bands, and the other with a single oligoclonal band. This raises the question of whether this rarest variant of ophthalmoplegic migraine, involving the fourth nerve, may be different etiologically from typical ophthalmoplegic migraine. More data are required to clarify this issue.
Virologic studies on cerebrospinal fluid and serum were rarely reported, but there is no clear evidence to date of an association between viral infection and ophthalmoplegic migraine. A single report claiming an association between ophthalmoplegic migraine and a positive cytomegalovirus IgG, but not IgM,33
is of doubtful significance without definitive evidence of acute infection given the high prevalence of cytomegalovirus seropositivity in the general population.34
Familial cases with recurrent bouts of facial palsy and ophthalmoplegia preceded by head pain have been reported,35
and several of the ophthalmoplegic migraine cases in this analysis had personal or family histories of Bell’s palsy,1,36–38
which could suggest an abnormal response to neurotropic viral infection in these patients given the association between herpes simplex virus and varicella zoster virus with Bell’s palsy,39
but this remains to be proven. Of note, facial nerve enhancement can be seen on gadolinium-enhanced MRI in Bell’s palsy as well.40
The oculomotor nerve does not normally enhance on MRI following the administration of gadolinium, which makes the observation that up to three-quarters of all ophthalmoplegic migraine cases with third nerve involvement had nerve enhancement on MRI striking.41
The differential diagnosis for enhancement of the cisternal portion of the oculomotor nerve includes neoplastic, inflammatory, and infiltrative conditions; however, most of these would not be expected to resolve spontaneously as occurs in ophthalmoplegic migraine.20,42
One diagnostic possibility raised by the authors in several cases is an oculomotor nerve schwannoma, although there is only 1 pathology-proven case in the literature initially mistaken for ophthalmoplegic migraine.43
Two additional cases where schwannoma was implicated were not pathology proven.44,45
A schwannoma would be expected to cause a persistent or progressive nerve palsy. The observation that nerve enhancement in ophthalmoplegic migraine is often markedly diminished on follow-up imaging weeks to months later argues against schwannoma as a common etiology in ophthalmoplegic migraine.1–3,7,10,14,17,20,30,41,46
A recurrent demyelinating cranial neuropathy has gained favor in recent years as a possible explanation for ophthalmoplegic migraine, with some authors drawing the analogy to the nerve swelling seen in chronic inflammatory demyelinating polyradiculopathy.2
If demyelination is indeed on the pathophysiological pathway, however, what initiates the demyelination remains unclear. Unlike chronic inflammatory demyelinating polyradiculopathy, the cerebrospinal fluid tends to be bland in ophthalmoplegic migraine. Moreover, repeated attacks of a single unilateral cranial nerve would be highly unusual for a primary antibody-mediated attack. In several cases, the ophthalmoplegia persisted longer with subsequent bouts,1,38,47–49
which could be consistent with recurrent bouts of demyelination leading to cumulative axonal damage. Repeated episodes of demyelination with remyelination may also help explain the observation of focal enlargement of the oculomotor nerve in ophthalmoplegic migraine.41
There are no autopsy cases of ophthalmoplegic migraine from the post-MRI era. Carlow reviewed 5 historical cases that fulfill “the generally accepted clinical criteria for ophthalmoplegic migraine.”50
Excluding 1 patient who had tuberculous meningitis and granulomatous involvement of the cranial nerve, 3 of the remaining 4 cases showed thickening of the oculomotor nerve at or near the midbrain exit.
There have been no published treatment trials for ophthalmoplegic migraine, and the level of evidence for evaluating effective treatments is entirely observational. Nevertheless, oral steroids may be of possible benefit in treating acute exacerbations based on available case series. Given that ophthalmoplegic migraine is not a variant of migraine pathophysiologically, migraine-specific acute and preventive therapies probably do not have a role in treating ophthalmoplegic migraine. Injection of botulinum toxin or strabismus surgery may be considered for patients with persistent eye misalignment.51
Only cases of ophthalmoplegic migraine published in the literature could be reviewed, which is the main limitation of this type of analysis. There may be a publication bias wherein authors are more likely to submit cases with classic imaging findings, risking overestimation of characteristic MRI findings or other clinical or demographic variables.
Ophthalmoplegic migraine is currently classified as a cranial neuralgia in the International Classification of Headache Disorders (second edition).5
This analysis suggests the classification criteria, and even the name of the disorder, improved upon to allow for greater clarity and diagnostic accuracy. The findings here suggest the current classification criteria, which require the headache to be “migraine-like,” are too restrictive as the headache quality was not “migraine-like” in roughly a third of the patients, a critique also raised by other authors.26,30,33,52
In addition, while the current criteria require that ophthalmoplegia develop within 4 days of headache onset, these data indicate that ophthalmoplegia can take up to 14 days to develop following headache onset. The cases with long latencies between headache onset and cranial nerve deficits were indistinguishable from those with shorter latencies. Lastly, the term “ophthalmoplegic migraine” itself is misleading diagnostically and could encourage the inappropriate use of migraine-specific preventive therapies. A more appropriate name might be “recurrent ophthalmoplegic cranial neuropathy.” Further research is needed to understand more about the underlying biology of this unusual condition.