Ophthalmoplegic migraine: Migraine variant or cranial neuralgia?

Ophthalmoplegic migraine (OM) is a rare headache disorder, which usually starts in childhood but sometimes first appears in adulthood. The typical clinical presentation is migraine-like headache accompanied or followed by transient extraocular muscle paresis, mostly involving the oculomotor nerve but sometimes the abducens or trochlear nerves. Ophthalmoplegia recovers spontaneously within weeks. OM was initially classified as a migraine variant in the International Classification of Headache Disorders, 1st edition (ICHD-1) (1). In 1992, Mark et al. (2) described the first OM patient with reversible gadolinium enhancement of the oculomotor nerve on magnetic resonance imaging (MRI). Thereafter, several case reports followed. Because of the self-limiting clinical characteristics, the disease was suspected to be related to recurrent demyelinating neuropathy. In 2004, the International Headache Society (IHS) Classification Committee moved this headache disorder to the group of ‘cranial neuralgias’ in the International Classification of Headache Disorders, 2nd edition (ICHD-2) (3); nonetheless, the terminology of ‘ophthalmoplegic migraine’ remained in use (Table 1).

Table 1.

ICHD-2 diagnostic criteria of ophthalmoplegic migraine

	Diagnostic criteria
A	At least two attacks fulfilling criterion B
B	Migraine-like headache accompanied or followed within 4 days of its onset by paresis of one or more of the third, fourth and/or sixth cranial nerves
C	Parasellar, orbital fissure and posterior fossa lesions ruled out by appropriate investigations

ICHD-2, International Classification of Headache Disorders, 2nd edition.

In this issue of Cephalalgia, Akimoto et al. (4) report on a 54-year-old man, who experienced attacks of OM for more than 45 years. The MRI examination in the acute phase showed an enhanced nodular lesion in the root exit zone (REZ) of the left oculomotor nerve. Because the clinical symptoms were progressive, a biopsy was performed. Intriguingly, the biopsy did not show inflammatory cell infiltration or demyelination but neuromuscular hamartoma. This finding obviously does not support a prior belief that the MRI findings imply demyelination as the underlying cause for OM. Even though enhancement of the cisternal portion of the oculomotor nerve is the most common MRI finding for OM, it is not specific. Certain causes can present similar pictures, such as trauma, inflammation, demyelination, small vessel ischemia, tumor (schwannoma, lymphoma, hemangioma and carcinomatous meningitis), post-viral syndrome and systemic lupus erythematosus.

Is demyelination a requisite for OM?

The pathogenesis of OM remains obscure. Carlow (5) proposed a theory of sterile inflammation of the oculomotor nerve for OM. He suggested that trigeminovascular system activation during migraine attacks triggers the release of neuropeptides to the circle of Willis that induces a sterile inflammation. In this theory, the oculomotor enlargement results from repeated demyelination and remyelination. In this view, ophthalmoplegia and oculomotor enlargement were the ‘results’ of migraine-triggered neurogenic inflammation. In contrast, Lance and Zagami (6) proposed that headache associated with ophthalmoplegia was related to irritation of the sensory fibers of the ophthalmic division of the trigeminal nerve entering the oculomotor nerve. In their view, demyelination is the underlying cause of OM and headache is the ‘result’ of oculomotor nerve inflammation. These two hypotheses share one similar concept, i.e. oculomotor enlargement is a result of recurrent demyelination and remyelination.

The current case report shows that typical OM could be caused by neuromuscular hamartoma (4). In 2005, Murakami et al. (7) reported oculomotor nerve schwannoma in an 11-year-old girl presenting with OM. These two case reports suggest that residual oculomotor enlargement may indicate not only demyelination and remyelination, but also a tumor. Furthermore, spontaneous remission does not exclude the possibility of lesions other than demyelination.

Difference between childhood- and adult-onset OM

Recently, a growing number of reported cases have shown normal MRI findings in typical OM cases (8–11). What is the difference between OM patients with and without gadolinium enhancement? First, a positive MRI finding is usually reported in children or in adults with childhood-onset OM, just like the case demonstrated by Akimoto et al. (4). Except for a few cases (12, 13), most of the reported adult-onset OM patients showed normal MRI findings. Lal et al. (9) described 62 patients with OM (aged 15–68 years) (9); most of them had disease onset as adults. All of them had an uncontrolled migraine history. Many of them suffered from severe migraine attacks for 2 or more weeks followed by ophthalmoplegia. Their MRI findings were normal. Second, the oculomotor nerve is the most commonly involved cranial nerve in childhood-onset OM, in contrast to the abducens nerve (56.5%) in adult-onset OM followed by the oculomotor (33.9%) and trochlear (8.1%) nerves in the study by Lal et al. (9). Whether the disease nature or its underlying mechanism differ between childhood- and adult- onset OM is a question which needs to be explored more fully.

How does hamartoma cause OM?

Akimoto and colleagues suspected that oculomotor nerve tumors might be an important cause of OM (4) since most pediatric patients with OM did not receive surgical intervention. They proposed that trigeminovascular activation might induce dilatation of the vessels supplying the oculomotor nerve, which further caused muscle contraction of the neuromuscular hamartoma. The strangulation of the oculomotor nerve due to muscle contraction in turn causes ophthalmoplegia (4). This speculation needs to be proved in the future. In our opinion, we agree that patients with oculomotor or other cranial nerve enlargement on MRI should be carefully followed up due to the possibility of lesions other than demyelination. However, a progressive course as described in this new case report may suggest an aggressive treatment. On balance, however, the majority of OM patients experience no progressive disease course or any positive finding in repeated MRI examination.

The role of ‘cranial neuralgia’ or ‘migraine variant’

If cranial neuralgia is the cause of headache related to OM, it should be reasonable to find many patients with neuralgia-related cranial nerve palsy prior to headache attacks. However, most OM patients suffered from severe migraine-like attacks just before the onset of ophthalmoplegia. Therefore, severe headache or migraine might trigger ophthalmoplegia (4, 5). It is possible that any organic or inflammatory cranial nerve lesions, not limited to oculomotor nerve tumors, may decrease the threshold of ophthalmoplegia during migraine attacks, particularly in children (10).

In summary, the biopsy-proven case by Akimoto et al. (4) provides evidence that demyelination might not be the sole pathology for the typical MRI findings of OM. Follow-up MRI studies are necessary to exclude other possibilities, especially in those patients with a progressive course. More OM case collections and reports are needed to resolve the classification issue of migraine variant or cranial neuralgia.