Ophthalmoplegic migraine: Migraine or oculomotor neuropathy?

Introduction

Ophthalmoplegic migraine (OM) is a rare disorder characterized by recurring headaches and palsy of the third, fourth or sixth cranial nerves, with the third cranial nerve most commonly affected.

Although the International Headache Classification in the first edition (IHCD-I) (1) had classified OM as a variant of migraine, in the second edition (ICHD-II) (2) it has been reclassified under the category of cranial neuralgias due to the fact that brain magnetic resonance imaging (MRI) frequently showed enhancement and thickening of the affected nerve. However, the etiopathology of OM remains unknown.

Recently, it was proposed that an uncontrolled migraine may be the primary cause of ophthalmoplegic migraine. In fact, most patients suffer from severe migraine attacks before the onset of ophthalmoplegic migraine (3,4).

We report on two patients affected by OM with normal MRI findings and a history of uncontrolled migraine before an attack of OM occurred. We will discuss the debate as to whether the disease should be considered as a migraine variant or an oculomotor neuropathy.

Case 1

A 7-year-old male was admitted to our Child Neuropsychiatry Unit because he manifested severe migraine associated with right ptosis and diplopia. There was a family history of migraine in both parents and multiple sclerosis in the father’s family. The subject was born following an uneventful pregnancy and delivery, and no perinatal complications were reported. Motor and neuro-linguistic developments were normal. School performance and socialization were normal. Since the age of 4, he had suffered from episodes of migraine with throbbing pain, of moderate intensity, in the frontal region associated with photophobia and vomiting, occurring approximately three to four times per year. Six months prior to our observation, the subject had his first episode of OM associated with ocular pain and ptosis in the right eyelid, lasting 24 hours. A week prior to this, the patient had gastrointestinal symptoms with diarrhea and abdominal pain, which disappeared within 24 hours. Immediately after this, the subject suffered from a moderate to severe intensity headache in the frontal and supra-orbital region on the right side, which was associated with photophobia and nausea. Paracetamol was administered with a transient remission of painful symptoms, which re-occurred again after a few hours. After 5 days of persistent migraine, an attack of OM took place. At this point, the subject was brought to our attention (Figure 1). Neurologic examination showed paresis of the third and sixth cranial nerves and general physical examination was normal. OPEN IN VIEWER

A laboratory investigation including blood cell count, glycemia, liver and renal functions, serum homocysteine, vitamin B12 and folic acid were all normal; in addition virological and organ-specific serum antibodies investigations excluded the presence of a viral infection and autoimmunity. Three days after the onset of ophthalmoplegia, the subject underwent a complete study of brain imaging with MRI brain and cervical spine with a contrast enhanced brain MRI and MR angio, all of which produced normal results (Figure 2). The awake/sleep electroencephalograph (EEG) showed brain bioelectrical activity in the normal range. OPEN IN VIEWER

The subject showed gradual and progressive improvement of headache symptoms in 3–4 days and regression of ophthalmologic migraine symptoms within 2 weeks. The patient was not treated with any pharmacological therapy except corticosteroids (prednisone 25 mg three times in 12 hours for a total dose of 75 mg) and antihistamines prior to performing the MRI due to an allergic diathesis.

At 1-year follow up, he reported two episodes of migraine-type headache of mild intensity and short duration; OM episodes were not referred.

Case 2

A 10-year-old male was admitted to our Child Neuropsychiatry Unit because of recurring migraine attacks, sometimes associated with eyelid ptosis. There was family history of tension headache and epilepsy in the mother’s family and migraine in the father.

The subject was born in the 38th week of pregnancy with threatened abortion in the first trimester. No perinatal complication was reported and motor development was normal. Neuro-linguistic development was delayed and learning problems were reported.

At age 2, he developed partial seizures, secondary symptoms of pharyngotracheitis. Anomalies were reported in awake and sleep EEG sporadic spikes in the left parietotemporal regions. From the age of 8, he presented episodes of mild to moderate headaches in the frontal region with photo/phonophobia, nausea and vomiting. Within a 6-month period, three to four episodes per month were associated with left eyelid ptosis, which dissipated within 24 hours. The patient was observed following an increase in the frequency of the headache attacks, which were both isolated and associated with ophthalmoplegic migraine. The neurologic examination during an ophthalmoplegic migraine attack showed paresis of the third cranial nerve. Neuropsychologic evaluation showed a learning disorder in reading and writing.

An investigation showed that blood cell count, glycemia, liver and renal functions, serum homocysteine, vitamin B12 and folic acid were all normal; in addition virological and organ-specific serum antibody investigations excluded the presence of infections and autoimmune deficiencies

One week after ophthalmoplegia onset and when the episode of OM was resolved, MRI brain and angio-MRI brain were performed and produced normal results. Awake EEG showed subcontinuous paroxysmal activity characterized by repetitive high-amplitude spikes and sharp waves in the right temporo-occipital regions, triggered by hyperventilation and accentuated by light stimulation (Figure 3). Sleep EEG showed sporadic atypical high-amplitude spikes-wave in the right temporal parieto-occipital regions. Sodium valproate therapy was introduced at a dose of 20 mg/kg/day. After a 6-month follow up, EEG recordings showed improvement with a marked reduction in paroxysmal activity limited to sporadic high-amplitude spikes and sharp waves. At the same time, a reduction in the frequency of migraines and one to two OM episodes per month were reported. OPEN IN VIEWER

Discussion

Ophthalmoplegic migraine, so named by Charcot in 1890, is a rare disorder characterized by recurring headache attacks and palsy of the third, fourth or sixth cranial nerves; the third cranial nerve being most commonly affected. The occurrence of OM is estimated to be around 0.7 per million. The first edition of the International Headache Classification (IHCD-I) classifies OM as a variant of migraine (1) while in the second edition (IHCD-II), the disorder has been reclassified under the category of cranial neuralgias (2). The IHCD-II defines ophthalmoplegic migraine as at least two attacks of a ‘migraine-like’ headache accompanied or followed within 4 days by paresis of the third, fourth or sixth cranial nerves; parasellar, orbital fissure and posterior lesions must be excluded by appropriate investigations.

The onset of OM is almost always in childhood, but growing evidence supports that it is not uncommon in adult onset (5,6). Male gender was thought to be most affected (7); however, recently, some authors report that it occurs equally in both the sexes (8). The majority of patients experience their initial attack in the first decade (7). In most cases, the headache occurs on the same side as the ophthalmoplegia and is mainly associated with ptosis and diplopia, and more rarely mydriasis. The family history of migraine and/or other type of headache is not constant. Magnetic resonance imaging with administration of gadolinium performed during an acute attack, reveals reversible contrast enhancement of the affected cranial nerve in almost all cases, with complete rehabilitation in about 7–8 weeks (6).

The role of neuroimaging is also important to exclude the presence of structural lesions and therefore possible forms of ophthalmoplegia. In fact, there are many conditions that may enter into the diagnosis of OM, for example intracranial infection, aneurysms, lipomas, schwannomas, Tolosa-Hunt syndrome and diabetic ophthalmoparesis (9,10). However, differences are not only evident in clinical presentation, but also the neurologic, laboratory and instrumental findings. The etiopathology of OM remains unknown. Lance and Zagami (11) suggested that OM may be caused by an inflammatory process that affects the oculomotor nerve in the intracisternal portion where sensory fibers from the ophthalmic division of the trigeminal nerve enter the oculomotor nerve (11). The inflammatory process could irritate the trigeminal sensory fibers, triggering headaches. Inflammation of the oculomotor nerve is the cause of ophthalmoplegia due to demyelinating neuropathy, which, in turn, is the reason for oculomotor enlargement. Carlow (12) suggested that OM may be a trigeminovascular migraine epiphenomenon that is dependent on the unique oculomotor nerve anatomy and porous blood–nerve barrier at the emergence of the oculomotor nerve from the brainstem (12). During migraine attacks, activation of the trigeminal-vascular system causes release of neuropeptides in the wall of the cerebral vessels resulting in sterile inflammation of the oculomotor nerve, therefore the contrast enhancement and thickening of the oculomotor nerve on MRI could be due to recurrent demyelination and remyelination of nerve. Demyelinating neuropathy is the common element for both pathogenic hypotheses of these authors. On this basis, OM has been removed from the group of migraines and reclassified in the category of cranial neuralgia in IHCD-II (2). Recently, a growing number of OM cases with normal MRI findings have reported other hypotheses therefore keeping open the discussion on the pathogenesis of the disorder and consequently on its appellation: ophthalmoplegic migraine or ophthalmologic oculomotor neuropathy.

Lal et al. (3) reported 62 patients between the ages of 15 and 68 years with OM, many of them adults, with ophthalmoplegia during a severe migraine attack. The majority of these patients reported an increase in the severity of the migraine headaches before the ophthalmoplegia. None of them had any nerve enhancement; cerebrospinal fluid (CSF) examination and biochemistry were normal; all patients recovered completely and use of oral steroids hastened the recovery (3).

On the basis of these data, in a subsequent article review, the author (5) has proposed that an uncontrolled migraine may be the primary cause of ophthalmoplegia, irrespective of the presence or absence of nerve enhancement. Others authors support this hypothesis (4).

In contrast, the idea that the OM may be a form of cranial neuropathy that triggers the headache was supported (6). The author came to this conclusion due to the fact that the head pain associated with ophthalmoplegia is not always the migraine type and it is not associated with migraine symptoms such as nausea or vomiting; the interval between headache onset and ophthalmoplegia extends up to 14 days and focal third nerve enhancement and thickening is frequently found. For these reasons, the author proposes the name Ophthalmologic Cranial Neuropathy for the condition. Chen and Wang (13) criticize this conclusion arguing that if the cranial neuropathy triggers headaches (13), it would be reasonable to expect patients to have ophthalmoplegia prior to the headache attacks; contrary to this, most patients suffer from severe migraine-like attacks just before the onset of ophthalmoplegia. Akimoto et al. (14) describes a 51-year-old male case of OM, who had suffered recurring headache attacks from the age of 6. The brain MRI scan revealed an enhanced nodular mass in the root exit zone of the oculomotor nerve. The biopsy excluded a demyelinating neuropathy and diagnosed a hamartoma (14). The author proposed that trigeminovascular activation may induce dilation of blood vessels that supply the oculomotor nerve causing a contraction of the neuromuscular hamartoma resulting in nerve strangulation and consequently ophthalmoplegia. The combination of these data sets suggests that the pathogenesis of the OM syndrome might be heterogeneous. Recently it was proposed that there is a possibility of two different OM variants for childhood and adulthood onset, referring mainly to the fact that a positive MRI finding is usually reported in children, whereas adult-onset OM patients, except for few cases, showed normal MRI findings (8–10).

The present study of two children aged 7 and 9 years, both males, reports a family history of migraine and a personal history of migraine before the development of ophthalmoplegia that was usually preceded or accompanied by an attack of severe migraine and showed little response to analgesic drugs. In both cases, the headache attack was ‘migraine-like’ and present on the same side of ptosis. In both cases thorough clinical observation, including laboratory tests, demonstrated the primary nature of ophthalmoplegia, excluding the secondary form. Magnetic resonance imaging was normal in both cases, but in only one case was performed during an acute attack of OM. Case 2, at age 2, had an isolated generalized seizure in the course of pharyngo-tracheitis and awake and sleep EEG showed sporadic spikes in the left parietotemporal regions; at the time of OM onset he performed an awake EEG recording revealing paroxysmal subcontinuous activity, without clinical correlation. In this patient, the introduction of therapy with sodium valproate resulted in an improvement of the EEG pattern and after 6 months a reduction in frequency of both migraine attacks and OM was reported. Because of the benign nature of the OM course, the improvement of the frequency OM is not still required in relation to the consumption of sodium valproate.

In our study, considering the personal history of migraine and the normal brain MRI, it is suggested that a migraine mechanism can play a central role in OM.

It is possible that different factors, inflammatory or structural, may represent a vulnerability of the nerve during a severe migraine attack causing ophthalmoplegia.

Beyond the year 2000, 121 cases of literature affected by ophthalmoplegic migraine were reported (Table 1).

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Table 1.

Analysis of 121 cases of ophthalmoplegic migraine with normal MRI findings.

References	Author	Years	Cases	Age	Gender	Migraine a	Nerve enhancement
36	Giraud et al.	2007	9	16–74 yr	3 male, 6 female	Yes	−
37	Miglio et al.	2010	1	8 yr	male	No	+
38	Borade et al.	2009	1	6 yr	female	Yes	−
15	Mucchiut et al.	2006	1	46 yr	female	Yes	−
39	Crevits et al.	2006	1	28 yr	female	Yes	−
			2	15 yr	male	Yes	−
40	Manzouri et al.	2007	1	28 yr	female	Yes	−
			2	ns	male	Yes	−
41	Bharucha et al.	2007	1	16 yr	female	Yes	+ / − c
16	Akaza et al.	2007	1	35 yr	female	Yes	−
17	Verhagen et al.	2003	1	44 yr	female	Yes	−
42	Stidham et al.	2000	1	8 yr	female	No	np
18	Fujita et al.	2003	1	15 yr	female	Yes
19	Weiss et al.	2004	1	7 yr	male	Yes	+
20	Vasconcelos et al.	2008	1	40 yr	female	Yes	−
21	Gulkilik et al.	2009	1	10 yr	female	No	−
6	Gelfand et al.	2011	1	19 yr	male	Yes	+/− c
			2	13 yr	male	Yes	−
			3	16 yr	female	Yes	−
			4	10 yr	male	Yes	+
43	Bek et al.	2009	1	21 yr	male	Yes	+
44	da Rocha et al.	2011	1	5 yr	male	Yes	+
22	Ogose et al.	2007	1	9 yr	male	Yes	+
23	Lee et al.	2002	1	42 yr	female	Yes	+/− b
14	Akimoto et al.	2012	1	51 yr	male	Yes	−
24	Pareja et al.	2010	1	36 yr	female	Yes	+/
			2	30 yr	female	Yes	+/
25	Lyerly et al.	2011	1	10 yr	female	Yes	+/
26	Arasho	2009	1	15 yr	male	Yes	−
8	Riadh et al.	2010	1	3 yr	female	No	−
7	Roy et al.	2011	1	11 yr	female	Yes	−
4	Lane et al.	2010	1	40 yr	female	Yes	+
			2	22 yr	male	Yes	−
3	Lal et al.	2009	62	15–68 yr	29 male, 33 female	Yes	−
			1	21 yr	male	No	+
27	Numao et al.	2012	1	56 yr	female	No	−
28	Simonetto et al.	2011	1	23 yr	female	Yes	−
29	McMillan et al.	2009	1	9 yr	female	Yes	+
			2	12 yr	male	Yes	+/− c
			3	16 yr	female	Yes	+
1	Lance et al.	2001	1	16 yr	female	No	+
			2	9 yr	male	Yes	np
			3	6 yr	male	Yes	−
			4	13 yr	male	Yes	−
			5	30 yr	female	Yes	−
30	Linn et al.	2008	1	51 yr	female	Yes	−
31	De Silva et al.	2005	1	28 yr	male	Yes	−
32	Peck	2006	1	1 yr	male	No	−
33	Çelebisoy et al.	2004	1	22 yr	female	Yes	−
			2	51 yr	female	Yes	−
34	O'Sullivan et al.	2006	1	35 yr	female	Yes	−
35	van der Dussen	2004	1	31 yr	male	Yes	+/– c

Gender showed a slight female predilection. The majority of these patients had a history of migraines before the final attack of ophthalmoplegic migraine (112 patients). Magnetic resonance imaging was normal in 99 patients; in 15 patients MRI showed enhancement of the involved nerve; four patients showed enhancement in acute MRI and normal MRI at follow up; two patients did not perform MRI; one patient showed initial normal MRI, with enhancement of the involved nerve at follow up. Almost all the cases reported by literature beyond the year 2000 showed similar characteristics to our patients. In summary, it is not uncommon to find patients with OM who have negative MRI and in which the migraine attacks preceded the OM onset. These results strengthen the hypothesis of a migraine mechanism in the etiology of OM. However, more cases and further research are needed to better understand the mechanisms underlying OM and consequently its classification.