Abstract
Ophthalmoplegic migraine (OM) typically occurs in a child or young adult with recurrent migraine-like headache, who develops ocular motor nerve palsy (usually the third) within 4 days of onset. The ophthalmoplegia lasts for days to weeks after cessation of the headache. On magnetic resonance imaging (MRI), the cisternal segment of the oculomotor nerve shows gadolinium uptake. This enhancement is followed by resolution, mostly over several weeks as symptoms resolve (1, 2). Prognosis is good, although signs may persist after repeated episodes. A permanent deficit after the initial attack is exceptional (3). Recent reports emphasize the possibility that OM would be caused by an (idiopathic) inflammatory neuritis (4). However, many questions remain to be resolved. We present four illustrative cases of presumed OM with heterogeneous or atypical presentation.
Case reports
Case 1
This 9-year-old boy had suffered from diplopia for the first time at the age of 7 years. Right exotropia and hypotropia was accompanied by ptosis of the right upper eyelid and light-reactive mydriasis. There had been no headache. Ophthalmoplegia resolved fully after 14 days. At the age of 9 years, the boy had had a similar episode without headache. Diplopia disappeared after 3 weeks, but ptosis and mydriasis remained for several months. Brain MRI taken during both episodes showed enhancement and thickening of the right oculomotor nerve where the nerve travels through the prepontine cistern (Figs 1 and 2). On the first occasion, enhancement of the oculomotor nerve was also seen in the right cavernous sinus (Fig. 3). During the second episode, MRI findings had still been present 5 weeks after the beginning of the third nerve palsy. Finally, all these findings had disappeared.
Coronal gadolinium-enhanced high-resolution T1-weighted spin-echo image through the mid-cisternal segment of the oculomotor nerve. There is clear enhancement of the right oculomotor nerve (white arrow). Compare with the normal, non-enhancing left third nerve (black arrow).
Coronal gadolinium-enhanced high-resolution T1-weighted spin-echo image through the interpeduncular cisternal segment of the oculomotor nerve. There is a clear enhancement of the right oculomotor nerve (white arrow). Compare with the normal, non-enhancing left third nerve (black arrow).
Coronal 512 × 512 matrix gadolinium-enhanced T1-weighted image: a cerebrospinal fluid-filled subarachnoid cyst (∗) is in contact with the oculomotor nerve which is enhancing on the right side (white arrow). Compare with the normal, low signal intensity oculomotor nerve on the left (black arrow).
Case 2
At the ages of 28, 30 and 41 years, this 41-year-old woman had experienced an episode of unilateral right temporal headache lasting for 2 days. She had not experienced nausea, vomiting, photophobia or phonophobia. The headache was followed by diplopia caused by a paresis of the right abducens nerve, without other neuro-ophthalmological or systemic illness. Brain MRI at the time of the first ophthalmoplegia had been normal, with, in particular, no detectable enhancement or thickening of the abducens nerve. Analysis of blood and cerebrospinal fluid, electro-encephalography, multimodal evoked potentials and cerebral four vessel angiography had all been negative. Symptoms had not improved after a 5-day course of intravenous corticosteroid treatment. MRI during the second episode had been repeatedly negative. The patient had finally recovered from both episodes spontaneously after 2 months. After the third episode, a right abduction deficit remained. This squint was treated with prisms.
Case 3
A 30-year-old man with a history of congenital nystagmus and convergent strabismus, for which he had had surgery at the age of 10 years, consulted the oto-neuro-ophthalmology unit. At the age of 15 years, he had first experienced diplopia when looking to the right. Diplopia was followed by pulsating headache at the vertex with retro-orbital pressure on the right. There had been no associated nausea, vomiting, photophobia or phonophobia. All complaints had disappeared after 1 day. Since theage of 30, similar episodes of diplopia and headache had occurred every month, never lasting more than 1 day. During a habitual attack, clinical examination could confirm right abducens palsy. Testing for myasthenia gravis was negative and brainstem reflexes were normal. Brain MRI showed a pituitary adenoma without any enhancement or thickening of the ocular motor nerves. Visually evoked potentials were disturbed on both eyes due to compressive optic neuropathy. Trans-sphenoidal resection of the tumour did not influence frequency or symptoms of the episodes of painful abducens palsy. Control MRI showed a status after pituitary resection without enhancement or thickening of the ocular motor nerves. The patient developed right convergent strabismus.
Case 4
This 48-year-old man had experienced five episodes of diplopia and ptosis on the left, accompanied by periocular pain and sometimes nausea since the age of 33 years. Diplopia lasted 4–10 weeks. At the first attack, oculomotor nerve palsy with pupillary involvement had been seen on the left. Angiography demonstrated aneurysms of the left anterior and the left medial cerebral artery. The anterior aneurysm was clipped, the medial aneurysm was bandaged. A perioperative infarction caused a right hemisyndrome with aphasia that partially recovered. The stroke was followed by lesional epilepsy. The vascular interventions did not influence clinical presentation or frequency of the periods of diplopia. MRI could not be performed due to the previous clipping. A computed tomographic scan confirmed an old medial cerebral artery infarction. Testing for myasthenia gravis was negative. One episode was treated with oral steroids: ptosis disappeared after 3 weeks, ophthalmoplegia improved but a paresis of adduction of the left eye remained, with a discrete deficit of depression and elevation. During another episode, verapamil seemed to be unsuccessful after 10 weeks.
Discussion
OM has been defined as recurrent attacks of migrainous headache associated with paresis of one or more ocular cranial nerves in the absence of any demonstrable lesion other than within the affected nerve. OM is a rare condition, possibly representing an inflammatory neuropathy (5). However, high frequency and short duration (as in case 3) create doubt as to the supposed pathogenesis. Although the diagnostic criteria are clearly defined, it is presumed that OM may present atypically, as illustrated in our series (Table 1).
Atypical findings in the present patients with presumed ophthalmoplegic migraine
OM has been reclassified by the Headache Classification Subcommittee of the International Headache Society into the category of neuralgias, although the diagnostic criteria include ‘migraine-like headache’ (5, 6). The pathophysiology of the headache may be a trigeminovascular epiphenomenon (7) subsequent to inflammation affecting the oculomotor nerve. However, the type of headache with which occasional episodes of OM are associated varies from case to case and no characteristic headache type has been identified. None of our patients suffered from typical migraine. Strictly, case 1 does not meet the criteria for OM because headache was absent. However, several authors have suggested that even painless recurrent oculomotor palsy in children belongs to the spectrum of OM (8, 9). Although ocular motor palsy may result from various neuromyogenic causes, recurrent palsy in childhood is suggestive for OM or myasthenia gravis.
While recurrent ocular motor nerve palsy is rarely observed in childhood, OM generally occurs in children. However, some adult cases have been reported (4, 10–13). Here, we add two cases with adult onset of presumed OM (cases 2 and 4).
Because of the characteristic headache and facial pain, Tolosa–Hunt syndrome is a common differential diagnosis of OM, especially in adults. The major differentiating feature depends on the finding in Tolosa–Hunt syndrome of granulomatous lesions in the cavernous sinus, by either imaging or pathological methods (14). In the present series, case 2 did not respond to steroids and case 3 had too many and too short-lasting attacks to be classified as Tolosa–Hunt syndrome (5). Moreover, no granuloma could be demonstrated. Diabetic ophthalmoparesis can produce a clinical condition similar to that of OM. However, none of our patients was diabetic and their blood biochemistry (including HbA1c or oral glucose tolerance test) was negative. Recurrent idiopathic sixth-nerve palsies have been described in adults. The palsies are unilateral. In contrast to patient 3, recurrent idiopathic unilateral sixth-nerve palsy lasts weeks to months and is typically painless (15).
Pupillary involvement (as in case 1) is a key finding to identify lesions of the third nerve in its peripheral course. A dilated pupil is also one of the commonly observed and generally clinical arguments for oculomotor OM (16). However, mydriasis may not necessarily be present in oculomotor OM for two reasons: first, isolated palsy of the superior division sparing the parasympathetic innervation to the pupils which runs in the inferior division, will not result in dilated pupils. Second, a dilated pupil usually occurs in the early stages of an episode and may later return to normal (4).
The clinical picture of OM may be secondary to intracranial lesions. Therefore, the importance of differential diagnosis is stressed. Life-threatening causes such as aneurysms, especially of the intracavernous portion of the internal carotid artery or of the posterior communicating cerebral artery, should be considered. However, cases 3 and 4 illustrate that even the presence of intracranial lesions is not necessarily the cause of OM. In case 3, there were no indications of abducens nerve compression by the pituitary adenoma, the ophthalmoplegic periods were frequent and short lasting and recurred after surgery. The aneurysms in case 4 did not have any anatomical contact with the oculomotor nerve, making a relation to her diplopia very unlikely.
In OM, abducens palsy appears to be 10-fold less frequent than oculomotor palsy, with an even rarer effect on the trochlear nerve. The reason for this differential affliction remains to be elucidated. Furthermore, as there is not the same enhancement of the abducens and trochlear nerve in OM as there is of the oculomotor nerve, this may mean that an abducens or trochlear nerve OM is not as convincingly a cranial neuropathy as oculomotor nerve OM. Thus, the aetiology of OM might be heterogeneous.
Characteristic neuroimaging findings have been noted during attacks, i.e. thickening and contrast enhancement of the oculomotor nerve as it exits the midbrain. Enhancement of the oculomotor nerve on MRI has suggested the classification of OM as a demyelinating cranial neuropathy (10). Enlargement and enhancement of the cisternal portion of the oculomotor nerve has been considered a diagnostic tool. However, thickening and contrast enhancement of the nerves as they exit the brainstem have been associated with several diseases besides OM (2). Differential diagnosis includes neoplasms (e.g. lymphoma, leukaemia), infections (such as AIDS), inflammatory processes (such as sarcoidosis and Tolosa–Hunt syndrome) and vascular anomalies. Enhancement may also been seen in schwannomas, and a unique patient with oculomotor nerve schwannoma presenting as OM has been reported (17). However, a schwannoma more frequently presents as a fusiform or nodular thickening in the course of the nerve and the lesion enhances even during symptom-free periods. In the case of OM, enhancement disappears during symptom-free periods and reappears when the ophthalmoplegia recurs. Contrast-enhanced T1-weighted MR images made during symptom-free periods can therefore differentiate between these two entities. In case 1, it should be noted that enhancement of the oculomotor nerve was seen not only at the cisternal segment, but also in the right cavernous sinus where the nerve seemed irritated by a subarachnoid cyst. Some rare cases of OM involving only the superior division of the third (3), the fourth (18) or the six nerves (11, 12, our cases 2 and 3) do not show enhancement. Thus, absence of enhancement does not rule out the diagnosis. Non-enhancement could be due to the small calibre of the trochlear nerve. However, the abducens nerve is larger and enhancement of intraparenchymal abducens nerve fibres has been observed in a unique case (13).
In conclusion, the presentation of OM seems to be heterogeneous and an inflammatory cause remains to be proven. After exclusion of diabetes and orbital or intracranial diseases such as Tolosa–Hunt syndrome and aneurysms, the diagnosis is still based on clinical grounds. Some cases of painful ophthalmoplegia without evident cause or with negative neuroimaging findings remain of uncertain classification. However, even painless recurrent oculomotor palsy in children and recurrent painful ophthalmoplegia in adults should raise the possibility of OM. Treatment is still unclear. Migraine preventive medications have been suggested and steroids have been used with mixed results.
Footnotes
Acknowledgements
The authors are grateful to Drs E. Fosselle, I. Aerts, J. Debruyne and M. D'Hooghe for referring some of the patients.