SEARCH

SEARCH BY CITATION

Keywords:

  • ophthalmoplegia;
  • migraine;
  • adult;
  • abducens nerve

Abstract

  1. Top of page
  2. Abstract
  3. METHODS
  4. RESULTS
  5. ILLUSTRATIVE CASES
  6. DISCUSSION
  7. Acknowledgments
  8. REFERENCES

Objective.— Ophthalmoplegic migraine (OM) is a rare disorder characterized by recurrent oculomotor nerve palsy in children, following migraine headaches. We report 62 adults, seen consecutively, who developed acute ophthalmoplegia with severe attacks of migraine over a 10-year (1996-2005) period. An overwhelming majority of these patients had an antecedent worsening in severity of migraine headaches, before the ophthalmoplegic attack.

Methods.— Sixty-two patients, aged 15-68 years, with an acute attack of OM underwent detailed clinical, biochemical, and neuroradiological evaluation.

Results.— There were 62 patients with 86 attacks of OM. Whereas 48 patients had a single attack, 14 had 2 or more attacks, fulfilling the International Headache Society criteria for probable and definite OM, respectively. At presentation, isolated abducens, oculomotor, and trochlear nerve involvements were seen in 35 (56.5%), 21 (33.9%), and 5 (8.1%) patients, respectively. One patient had simultaneous involvement of 3rd and 6th nerves. Fifty-one (82.3%) patients exhibited an antecedent worsening in severity of migraine, before developing ophthalmoplegia during (59/95.2%) or within 24 hours (3/4.8%) of a severe migraine attack, respectively. Detailed biochemistry and cranial neuroimaging were normal. No case had any nerve enhancement. Use of steroids hastened recovery (P < .05).

Conclusion.— We conclude: (1) OM in adults is characterized by single attacks of ophthalmoplegia in a great majority of patients; and (2) 6th nerve involvement occurs commonly. Our results indicate that moving OM to the chapter on cranial neuralgias in the second edition of the International Headache Classification may be premature, since nerve palsy occurred during a severe migraine attack in all patients.

Ophthalmoplegic migraine (OM) is a rare disorder characterized by recurrent attacks of oculomotor nerve paresis in childhood, following severe migrainous headache.1-8 There are some case reports of adult-onset OM.9-15 Paresis of abducens nerve is rare.10-15 We describe our experience with adults who had ophthalmoplegia associated with migraine and were seen prospectively at our referral center during a 10-year period.

METHODS

  1. Top of page
  2. Abstract
  3. METHODS
  4. RESULTS
  5. ILLUSTRATIVE CASES
  6. DISCUSSION
  7. Acknowledgments
  8. REFERENCES

Approximately 7000 migraine patients presenting to the Department of Neurology, Postgraduate Institute of Medical Education and Research, Chandigarh, India, between 1996 and 2005, were evaluated. These patients were enriched for neuro-ophthalmological cases because the institute gets referrals from a large part of northern India. OM was diagnosed when all of the following criteria were met: (1) a history of headache consistent with the criteria of migraine of the International Headache Society (IHS), 1988 and 2004;1 (2) the onset of acute ophthalmoplegia during or within 24 hours of a migraine attack that likewise fulfilled the IHS criteria; and (3) no evidence of any parasellar or structural lesion on radiological imaging. Definite OM was diagnosed in patients with 2 or more attacks, whereas patients with a single attack fulfilling the above criteria were considered as “probable OM.” Patients with history of recent trauma, infections, malignancy, another known cause of ophthalmoplegia, and cardiac, renal, or hepatic insufficiency were excluded. The following data were recorded for all the patients: detailed demographic data; total duration, laterality, and location of migrainous headaches; duration and location of increased frequency and severity of headaches; time to ophthalmoplegia after onset of headache episode, side and type of ocular motor palsy and nature of previous ophthalmoplegic episodes, if any. A detailed clinical, ophthalmological, and neurological assessment was done.

All the patients underwent blood investigations including hemogram, erythrocyte sedimentation rate, coagulogram, glucose tolerance tests (GTT), lipidogram, collagen profile, antiphospholipid antibodies, serum electrophoresis, and serum Venereal Disease Research Laboratory (VDRL). Besides opening pressure, cerebrospinal fluid was examined for cells, protein, sugar, oligoclonal bands, VDRL, cytology, and was cultured for tuberculosis and fungi. Nasopharyngeal examination, testing for myasthenia, ultrasound of abdomen, echo, and carotid Doppler were also done in relevant cases. Contrast-enhanced computerized tomography (CECT) of head was done in all the patients. Magnetic resonance imaging (MRI) study of the brain using a 0.3 Tesla or 1.5 Tesla unit (SIEMENS, vision) was performed in almost all the patients, during an attack of OM. The orbits, cavernous sinuses, brain stem, and cranial nerves were studied in axial, coronal, and sagittal planes in a dedicated study using T-1 Spin Echo (TR – 450 millisecond, TE – 14 millisecond, FA – 60o, slice thickness – 3 mm), T-2 Fast Spin Echo (TR – 4500 millisecond, TE – 90 millisecond, FA – 180o, echo train length (ETL) – 8, slice thickness – 3 mm) and T-1 Gradient Echo (Flash – 3D, TR – 60 millisecond, TE – 7 millisecond, FA – 25o, effective slice thickness – 2 mm). [Correction added after online publication 6-Apr-2009: Megasecond updated to millisecond.] The T-1-weighted images were obtained both pre- and postcontrast and Gradient Echo sequence was used postcontrast (0.1 mmol/kg of gadolinium chelate IV). The field of view was kept in the range of 200-240 cm for maximal resolution. All the patients also underwent vascular imaging using MR angiography and/or conventional dye contrast catheter angiography. MR venography was also done to exclude venous sinus thrombosis.

All the patients were started on migraine prophylaxis using β-blockers or calcium channel blockers like flunarazine. Only patients who presented within a week of onset of ophthalmoplegia were given steroids in doses of 0.75-1 mg/kg/day for 4 weeks followed by tapering doses over the next 4 weeks. Twice-weekly follow-up was planned for all the patients till the time of complete recovery of ophthalmoplegia. However, many patients followed up irregularly, with review periods ranging from 2 weeks to up to a month. On every follow-up, one of the authors reviewed the patients and the recovery was documented.

Statistical Analysis.— The statistical analysis was performed using spss version 10.0 for Windows (SPSS Inc., Chicago, IL, USA). The descriptive values were expressed as mean and standard deviation, or frequencies and percentages. Univariate associations between categorical variables were evaluated using chi-square test and Fisher's exact test, while the independent sample t-test was applied for numerical variables, where appropriate. Analysis was done to evaluate the differences in clinical characteristics of patients as per ocular motor cranial involvement and the age of onset of ophthalmoplegia, as well as the type and frequency of ocular motor involvement before 35 years of age and later. To evaluate the response of ophthalmoplegia to treatment including the use of steroids, only the patients who had regular twice-weekly follow-up till complete recovery of ophthalmoplegia were included. A P value of <.05 was considered significant.

RESULTS

  1. Top of page
  2. Abstract
  3. METHODS
  4. RESULTS
  5. ILLUSTRATIVE CASES
  6. DISCUSSION
  7. Acknowledgments
  8. REFERENCES

Of approximately 7000 patients of migraine examined over the study period, OM was diagnosed in 62 (0.89%) patients. The clinical and demographic characteristics of these patients are summarized in Tables 1 and 2. Of these, 53.4% were female and the mean age was 36.4 years (range 15-68 years). A larger proportion of women (n = 20) as compared with men (n = 11) had onset of ophthalmoplegia before 35 years of age (P < .05).

Table 1.—. Clinical and Demographic Characteristics of Patients With Ophthalmoplegic Migraine (N = 62)
CharacteristicResult
  • Worsened headaches of a duration of 2 or more weeks prior to ophthalmoplegia were seen in 51 patients.

  • SD = standard deviation.

Age (years): mean ± SD (range)36.4 ± 12.8 (15-68)
Sex: male/female (%)29 (46.8)/33 (53.4)
Age of onset of migraine (years): mean ± SD (range)24.2 ± 9.7 (8-49)
Duration of migraine (years): mean ± SD (range)11.8 ± 8.1 (6 months to 30 years)
Duration of worsened headaches (weeks): mean ± SD (range)7.5 ± 6.3 (2-32)
Laterality of migraine/worsened headaches (%) 
 Unilateral27 (43.5)/39 (76.5)
 Bilateral33 (53.2)/11 (21.6)
 Unknown2 (3.2)/1 (2)
Distribution of migraine/worsened headaches (%) 
 Temporal23 (37.7)/28 (54.9)
 Frontal10 (16.4)/5 (9.8)
 Hemicranial5 (8.2)/3 (5.9)
 Global18 (29.5)/5 (9.8)
 Retro-orbital3 (4.9)/8 (15.7)
 Occipital2 (3.3)/2 (3.9)
Distribution of worsened headaches as per side of ophthalmoplegia (%) 
 Same side47 (75.8)
 Bilateral15 (24.2)
Family history of migraine (%) 
 Present26 (41.9)
 Absent36 (58.1)
Current ocular motor nerve involvement (%) [right and left] 
 Abducens nerve35 (56.5) [15 and 20]
 Oculomotor nerve21 (33.9) [7 and 14]
 Trochlear nerve5 (8.1) [3 and 2]
 Combined abducens and trochlear nerve1 (1.6) [right sided]
Table 2.—. Clinical Characteristics of Patients With Ophthalmoplegic Migraine as Per Current Cranial Nerve Involvement (N = 61)
CharacteristicCranial nerve involvementP value
AbducensOculomotorTrochlear
  • One patient had both oculomotor and abducens nerve palsy.

  • Significant P value, abducens nerve compared with oculomotor nerve palsy, independent t-test.

  • SD = standard deviation.

Number of patients35215 
Mean age (years) (±SD)35.8 (12.6)35.8 (13.7)43.8 (9.8).99
Mean duration of migraine (years) (±SD)10.6 (8.3)12.7 (7.3)16.6 (8.4).38
Mean duration of worsened headache (weeks) (±SD)4.6 (4.4)9.3 (7.9)5.6 (4.3).02, .67
Family history of migraine (%)    
 Absent21 (60.0)13 (61.9)1 (20.0).19
 Present14 (40.0)8 (38.1)4 (80.0) 
Gender (%)    
 Male19 (54.3)9 (42.9)1 (20.0).35
 Female17 (45.7)12 (57.1)4 (80.0) 
Laterality of worsened headache (%)    
 Unilateral24 (68.6)16 (76.2)4 (80.0).9
 Bilateral10 (28.8)5 (23.8)1 (20.0) 
 Unknown1 (2.9)00 

These patients had a total (present and past) of 86 attacks of OM, including 38 and 48 attacks in 29 men and 33 women, respectively. Forty-eight patients of probable OM (23 men, 25 women) had a single attack, whereas 38 attacks occurred in the remaining 14 patients of definite OM (6 men, 8 women). The average number of attacks was similar in men and women (P > .05).

Headache Characteristics of the Patients.— According to the IHS criteria,1 all patients suffered from migraine without aura; of these 2 patients also gave history suggestive of retinal migraine and 3 patients of visual aura in the past. The mean age of patients at onset of migraine was 24.2 years and the mean duration of migraine was 11.8 years (range: 6 months to 30 years). Family history of migraine was present in 42% patients. Prior to the development of ophthalmoplegia, an antecedent worsening in severity of migraine of 2 weeks or more duration was seen in 51 (82.3%) patients with a mean duration of 7.49 weeks (range 2-32 weeks). Fifty-nine patients (95.2%) developed ophthalmoplegia during an attack of severe migraine whereas the remaining 3 patients (4.8%) noticed diplopia on the next morning after the attack had subsided. The onset of ophthalmoplegia was followed by improvement of headaches for a variable period. The mean duration of worsened migraine headaches was significantly shorter in patients presenting with abducens nerve palsy, as compared with patients with oculomotor nerve palsy (P < .02). The rest of the migraine characteristics were comparable among patients suffering from different ocular motor palsies (Table 2).

Characteristics of Ophthalmoplegic Episodes.— At the time of presentation, isolated abducens, oculomotor, and trochlear nerve involvements were seen in 35 (56.5%), 21 (33.9%), and 5 (8.1%) of patients, respectively. One patient (1.6%) had combined right abducens and oculomotor palsy. Among patients with oculomotor nerve involvement (n = 21), isolated ptosis was observed in 4 (19%) and superior division palsy in 3 (14.3%) patients. Of the 14 patients with complete oculomotor palsy, pupillary sparing and involvement were seen in 10 (71.4%) and 4 (28.6%) patients, respectively. The proportion of oculomotor nerve involvement was significantly higher among patients with onset of ophthalmoplegia before 35 years of age as compared with those with onset later in life (42% vs 25.8%, P < .045), whereas trochlear nerve involvement was seen in 5 patients only at the age of 35 years or later.

Fourteen patients (22.6%) also reported past episodes of ophthalmoplegia. Table 3 summarizes the data of patients with 2 or more episodes of ophthalmoplegia. Over time and during different episodes, the involvement of a total of 2 and 3 different ocular motor nerves was seen in 4 (6.5%) and 1 (1.6%) of the patients, respectively. Overall, the abducens nerve was involved 42 times in 37 patients (Figs. 1 and 2), the oculomotor nerve 39 times in 23 patients (Fig. 3), and the trochlear nerve 6 times in 5 patients. All patients reported complete recovery from previous episodes.

Table 3.—. Summary of Data of Ophthalmoplegic Migraine Patients With More Than One Episode of Ophthalmoplegia
Age (years)/sexDuration of migraine (years)Duration of worsened headache (weeks)Current ocular motor palsyPrevious episodes of cranial palsyTotal attacksMRI P/CDSA/MRAFU (years)
  1. DSA = digital subtraction angiography; F = female; FU = follow-up; L = left; M = male; MRA = MR angiography; MRI P/C = magnetic resonance imaging – Plain/Contrast; N = normal; R = right; – = not done.

42/F2016R 3rd – ptosisR 3rd – ptosis – 6 months ago2N/ –N/N8
42/F34L 4thL 4th – 1 year ago2N/ –N/ –1.5
53/M253R 6thR 3rd – 20 years ago2N/NN/ –8
55/M208R 3rd – pupil sparingL 3rd – pupil sparing – 3 months ago2N/NN/ –1.5
44/MUnknown12L 3rd – pupil sparingL 6th – 3 months ago2N/NN/N4
24/M102L 3rd – pupil involvedL 3rd – 3 years ago2N/NN/N3
20/F52L 3rd – pupil sparingL 3rd – pupil sparing – 3 years ago2N/NN/ –5
26/F312R 3rd – ptosis onlyR 3rd – ptosis – 3 years ago2N/NN/ –2
52/M153L 6thR 6th – 4 years ago2N/NN/N7
34/F512L 3rd – ptosis onlyL 3rd – ptosis – 2 years ago L 3rd – ptosis – 6 months ago3N/NN/N1
26/F1012L 3rd – pupil sparingL 3rd – 9 months ago L 3rd – 2 months ago3N/NN/N5
28/F202L 6thL 3rd – 15 months ago R 3rd – 11 month ago back L 3rd – 5 months ago4N/NN/ –1
19/M51R 6thR 6th – 4 years ago R 6th – 3 years ago R 6th – 2 years ago R 6th – 1 year ago5N/NN/ –6
45/F108L 3rd – pupil sparingL 3rd – 3.5 years ago L 3rd – 2 years ago L 3rd – 1.5 years ago L 3rd – 7 months ago (All pupil sparing)5N/NN/ –3
image

Figure 1.—. (a) A 48-year-old man with isolated right 6th nerve palsy in ophthalmoplegic migraine (OM) (upper panel) that resolved without steroids in 4 weeks (lower panel). (b) The same patient, 4 years later, with isolated left 6th nerve palsy in OM (upper panel) that resolved without steroids in 10 weeks (lower panel).

Download figure to PowerPoint

image

Figure 2.—. A 32-year-old man with complete (L) 6th nerve palsy in ophthalmoplegic migraine (upper panel) that resolved in <3 weeks on oral steroids (lower panel).

Download figure to PowerPoint

imageimage

Figure 3.—. (a) Right pupil sparing 3rd nerve palsy in ophthalmoplegic migraine. (b) Complete resolution occurred in 10 weeks on antimigraine prophylaxis without steroids. (c) Gadolinium magnetic resonance imaging (Gd MRI) of 3rd nerve was normal.

Investigation Results.— Mildly elevated erythroctye sedimentation rate (ESR) levels were seen in 7 (11.9%) patients. Rheumatoid factor was positive in 2 of 61 patients (3.3%) in whom collagen profile was done. Lupus erythematosus (LE) cell, antinuclear antibody, and serum VDRL were negative in all these patients. Lumbar puncture was performed in 54 patients. Cerebrospinal fluid (CSF) opening pressure was normal in all of the patients. In 48 patients, CSF was acellular and disclosed normal sugar, and proteins. The remaining 6 patients showed nonspecific abnormalities. CSF VDRL was negative in all the patients.

Contrast-enhanced computerized tomography of head was normal in all the patients. Fifty-two patients had MRI scans, of which 45 were gadolinium-enhanced. Seven patients were scanned with 0.3 Tesla scanners whereas the remaining 45 were scanned using 1.5 Tesla MRI scanners. Thickening or contrast enhancement of the involved cranial nerves was not seen in any patient of OM. A single right parietal ring enhancing lesion without any mass effect suggestive of neurocysticercus that resolved 1 year later, and bilateral parieto-occipital infarcts were observed in one patient each. The latter was a 24-year-old chronic smoker since childhood, with normal lipids, blood sugar, echocardiogram, 4-vessel angiogram, and tested negative for antiphospholipid antibodies.

Conventional dye contrast catheter angiography and MR angiography were performed in 52 and 28 patients, respectively, and were normal in all except one (1.6%) who had evidence of narrowing of the proximal portion of the posterior cerebral artery (PCA) ipsilateral to ophthalmoplegia. Follow-up vascular imaging could not be done in this patient. Four patients developed attacks of migraine after angiography that resolved without sequelae.

Treatment and Follow-up.— The duration of follow-up was 4.1 ± 2.8 years (range 0.3-10 years). Thirty-eight patients were available for regular follow-up. Patients who received both steroids and migraine prophylaxis (n = 20) had significantly shorter recovery time as compared with patients who received migraine prophylaxis alone (n = 18) (4.1 ± 3.2 weeks vs 14.7 ± 8.9 weeks; P < .001). This finding must be interpreted with caution because of possible bias. However, it will be difficult to get better evidence in this rare disorder. All patients recovered completely. Two patients suffered from Bell's palsy 1 and 6 years after an ophthalmoplegic episode. No patient required a revision of diagnosis on follow-up.

Other Relevant Noninfective Causes of Painful Ophthalmoplegia and Enhancement of 3rd/4th/6th Nerves.— Between 1996 and 2005, we examined only 1 case of childhood-onset OM. This 21-year-old man had approximately 20 attacks of left-sided pupil involving 3rd nerve palsy since 4 years of age. There was aberrant regeneration of 3rd nerve and gadolinium enhanced magnetic resonance imaging (Gd MRI) disclosed nerve thickening and enhancement. Angiogram was normal.

Twenty-three cases of Tolosa-Hunt Syndrome (THS) were also seen during this period.1 These were characterized by: (1) painful ophthalmoplegia; (2) multiple cranial nerve involvement, often associated with 2nd/V1 neuropathy; and (3) universal presence of soft tissue in the cavernous sinus on MRI, with or without orbital extension (pseudotumor) or hypertrophic pachymeningitis. Six cases disclosed enhancement of the 3rd and/or 6th nerves. Biopsy confirmation was available in 5 cases. Follow-up was uneventful and MRI disclosed resolution of nerve enhancement and soft tissue.

Causes of Enhancement of 3rd/4th/6th Nerves.— Twelve cases of nerve enhancement included THS (6 cases), childhood OM (one case), neurosyphilis (one case), cranial tuberculosis (2 cases), and non-Hodgkin's lymphoma (2 cases). [Correction added after online publication 6-Apr-2009: Numbers of cases were previously listed as superscripts.]

ILLUSTRATIVE CASES

  1. Top of page
  2. Abstract
  3. METHODS
  4. RESULTS
  5. ILLUSTRATIVE CASES
  6. DISCUSSION
  7. Acknowledgments
  8. REFERENCES

Case 1.— This 48-year-old man presented in August 1998 with isolated right 6th nerve paresis following recurrent, daily, migrainous headaches of 6-week duration (Fig. 1a). The headaches were severe, occurring in the right temporal region, throbbing, and were associated with nausea, vomiting, and phonophotophobia. He noticed diplopia on looking toward the right side during a severe attack of migraine.

He had suffered from infrequent, tolerable, holocranial migrainous headaches for 15 years, which were relieved by going to sleep. These headaches would last between 4 and 6 hours and occurred once in 3 months. These headaches had markedly escalated in severity since 6 weeks. These were occurring almost daily and would last for 24 hours, forcing him to restrict his activities. He was never diagnosed or given prophylaxis for migraine. His elder brother and sister also had undiagnosed migraine headaches.

Relevant investigations including GTT, collagen profile, VDRL, and detailed CSF examination. Gd MRI of brainstem and cavernous sinus and conventional 4-vessel angiogram were all normal. A diagnosis of probable OM was made. He recovered completely in 4 weeks on propanolol prophylaxis alone, without steroids (Fig. 1a). He had 5-6 attacks of severe holocranial migraine headaches on prophylaxis, which was discontinued on medical advice after 1 year. He denied any significant migrainous headache on subsequent telephonic follow-up.

He again presented in February 2002 with left 6th nerve paresis, following recurrent, severe, migrainous headaches of a 3-week duration. This time, the headaches were predominantly left temporal, occurring almost daily, and were associated with irritability, nausea, vertigo, palpitations, phonophotophobia, and lack of sleep. He noticed diplopia on looking toward the left during a severe attack of migrainous headache. Questioning disclosed that an unforeseen severe financial stress had triggered his headaches. All relevant investigations including GTT, CSF, Gd MRI, and 4-vessel angiogram were again normal. This time, he developed severe holocranial migraine with profuse sweating following the angiogram. He recovered completely in 10 weeks, on migraine prophylaxis alone, without steroids (Fig. 1b).

To date, he has infrequent right or left temporal mild migraine headaches, which are relieved by taking nonsteroidal anti-inflammatory drugs (NSAIDs).

Case 2.— This 43-year-old man was admitted in May 2001 with complete, pupil sparing, right 3rd nerve palsy associated with migraine headaches of an 8-week duration (Fig. 3a). The headaches were unbearable, pulsatile, occurring daily in right temporal region, lasting between 12 and 24 hours, and associated with severe irritability, anger, vomiting, and phonophotophobia. He developed pupil sparing, right 3rd nerve palsy during a severe attack of migraine.

He had had predominantly left temporal migraine headaches for more than 15 years. These headaches were infrequent, tolerable, occurring once in 5-6 months, both throbbing and nonthrobbing triggered by stress and humidity. These headaches had increased during the past 6 months and were occurring once every week in right temporal region, were more severe and of longer duration, and would often be alleviated by sleeping or inducing vomiting. He had never been diagnosed or given prophylaxis for migraine. He denied any family history of similar headaches. He recovered completely in 8 weeks on antimigraine prophylaxis alone, without steroids (Fig. 3b).

The following investigations were negative or noncontributory: routine hemogram, blood sugar profile, collagen profile, serum VDRL, lipidogram, and detailed CSF examination. His 4-vessel angiogram, CECT, and Gd MRI of the 3rd nerve were normal (Fig. 3c). His headaches were controlled on propanolol prophylaxis, and there was no recurrence of ophthalmoplegia during a follow-up of 4 years.

DISCUSSION

  1. Top of page
  2. Abstract
  3. METHODS
  4. RESULTS
  5. ILLUSTRATIVE CASES
  6. DISCUSSION
  7. Acknowledgments
  8. REFERENCES

All our patients had a past history of uncontrolled migraine and developed ophthalmoplegia during or within 24 hours of a severe attack of migraine. This was preceded by a flurry of severe attacks in a great majority of cases. None of the patients had any clinical, biochemical, radiological, or CSF evidence of infection or any other ailment and all responded well to migraine prophylaxis, with or without steroids. Hence, all the patients fulfilled the IHS criteria for probable or definite OM.1

“Ophthalmoplegic migraine” is a rare complication of migraine that almost invariably begins in childhood and is characterized by recurrent attacks of 3rd nerve paresis, with a majority having pupillary involvement.5,6,16-26 Our patients differed from previously described series of patients with OM.27-37 All our patients were 15 years or older at the time of first attack of ophthalmoplegia. In contrast to recurrent oculomotor palsy in childhood type of OM, abducens palsy was the commonest (56.5%), followed by oculomotor (33.9%) and trochlear palsy (8.1%); most patients had single attacks of ophthalmoplegia (79%). Pupillary involvement was seen in only 28.6% of our patients with complete oculomotor nerve involvement. In childhood migraine there is a male preponderance,6 whereas we did not find any gender difference in our patients. Of the 5 patients with trochlear nerve involvement, 4 (80%) were female. There are some case reports of adult-onset OM.9-15 The present series is the largest series of adult-onset OM patients, to the best of our knowledge.

Diabetic ophthalmoparesis can simulate OM. However, all our patients had a normal blood sugar profile, on repeated testing. Unilateral headache and single or multiple ocular motor palsies seen in OM also has some resemblance to THS.26 There are, however, differences not only in clinical presentation, but also in the neurological examination. All our patients had characteristic uncontrolled migrainous headaches, developed cranial mononeuropathies without involvement of optic or V1 nerves, and cavernous sinus pathology was not seen on contrast-enhanced MRI in any of them.

If neuro-ophthalmological sequelae of migraine are not so uncommon, why were they missed before? The failure to recognize this complication of migraine can be summed in Charcot's profound words, “Disease is from old and nothing about it has changed.” It is we who change as we learn to recognize what was previously imperceptible.38 Idiopathic painful ophthalmoplegia has been documented before in India,39-42 Thailand,43 and Zambia.44 They were all adults with single or recurrent attacks of isolated 3rd and/or 6th nerve palsies, associated with severe unilateral or holocranial headache with or without nausea or vomiting. CSF showed nonspecific findings. Recovery was the rule. Thus, some of these cases closely resembled patients from our series.

The International Classification of Headache Disorders1 in its second edition has stated that OM is unlikely to be a variant of migraine and classifies it under cranial neuralgias. The finding of enhancement of the oculomotor nerves in patients with OM has led various authors to classify it as a demyelinating neuropathy of idiopathic or post-viral origin.8,11,16,18,27,28 Lance and Zagami have proposed that the migrainous pain in patients with OM is due to irritation of the trigeminal sensory fibers because of the post-viral inflammatory process affecting the oculomotor nerve. This activated the trigeminovascular system in those who are already migraineurs, thereby triggering the associated migraine headaches.8 This hypothesis depends on the finding that in primates and other species, sensory fibers from the ophthalmic division of the trigeminal nerve enter the oculomotor nerve, pass through it into the brainstem, and terminate in the spinal trigeminal nucleus.6-8 However, the universal absence of any antecedent or concomitant viral prodrome and a completely normal CSF examination in nearly all patients with OM with or without enhancement of nerves8-18,25,27-33 strongly militates against this hypothesis. This theory cannot explain the pain associated with involvement of abducens and trochlear cranial nerves and no evidence of infection, inflammation, or enhancement of involved cranial nerves was found in any of our patients.

The definite and pronounced increase in severity of migraine headaches prior to ophthalmoplegia, and occurrence of ophthalmoplegia during a severe attack of migraine strongly suggests that uncontrolled migraine is the primary cause of OM. Extensive blood and CSF studies were all normal. In light of our current understanding of an attack of migraine, the pathogenesis of OM may be as follows: Activation of the trigeminovascular system during an attack of migraine triggers the release of neuropeptides, by the ophthalmic division of the trigeminal nerve in the vessel wall. This causes sterile inflammation and edema of the vessel wall of both large and small intracranial vessels including vasa nervosa and capillaries.45 Both inflammation and edema cause reflex vasoconstriction and narrowing of blood vessels, leading to ischemia and nerve injury. Also, this sterile inflammation of vasa nervosa may open up the blood nerve barrier that is formed by tight closure of capillary endothelium.46 This may cause nerve edema, thickening, and enhancement in OM, whereas enhancement is absent in diabetic ischemic neuropathy6,8,27 (Fig. 4). For reasons not clear, nerve enhancement was absent in our series.

image

Figure 4.—. Schematic diagram explaining pathogenesis of ophthalmoplegic migraine. Release of neuropeptides in the vasa nervosa and other intracranial vessels produces edema and narrowing of blood vessels. This causes a breach in the blood nerve barrier causing edema and ischemic damage to the involved nerves.

Download figure to PowerPoint

The 3rd, 4th, and 6th nerves are supplied by branches arising from the cavernous portion of the carotid artery, and by perforating vessels arising from proximal PCA.47-49 This region has a high intracranial trigeminal receptor density,45 making the oculomotor nerves vulnerable, due to vessel wall edema and ischemia due to occlusion of ostia. Different studies have reported vasoconstriction in patients with OM22 and other forms of complicated migraine.50-56 Shin et al have convincingly documented reversible, ipsilateral ischemia in the territories of perforating branches of the PCA by brain SPECT, in patients of OM with 3rd nerve involvement.25 Absence of the enhancement of affected cranial nerves on contrast-enhanced MRI even in patients with recurrent episodes, normal CSF studies, demonstration of spasm of proximal PCA on the same side of abducens nerve palsy, and frequent occurrence of pupillary sparing favors ischemic etiology in our patients. A normal angiogram does not exclude ischemia because of microvascular constriction and narrowing.

All our patients recovered completely on migraine prophylaxis. The patients who received steroids additionally had a significantly faster recovery as compared with those who received only the migraine prophylaxis. Other authors have also reported benefits of prednisone.30

Hence, we hypothesize that there are 2 variants of OM – a well-described rare type that occurs in children who have recurrent oculomotor nerve palsies with abnormalities of the oculomotor nerve at its exit from the midbrain and may be painless. Adult-onset OM is usually preceded by recurrent severe migraine headaches; attacks are commonly single and involve the abducens nerve more often than the oculomotor nerve. Contrast-enhanced MRI brain and vascular imaging are normal in the great majority of these patients. Ophthalmoplegia invariably recovers completely. The use of corticosteroids along with migraine prophylaxis may hasten the recovery. OM should in future be classified under migraine.

Acknowledgments

  1. Top of page
  2. Abstract
  3. METHODS
  4. RESULTS
  5. ILLUSTRATIVE CASES
  6. DISCUSSION
  7. Acknowledgments
  8. REFERENCES

Acknowledgement: We are indebted to Professor Louis R. Caplan, for his valuable suggestions and critically reviewing and editing the manuscript.

REFERENCES

  1. Top of page
  2. Abstract
  3. METHODS
  4. RESULTS
  5. ILLUSTRATIVE CASES
  6. DISCUSSION
  7. Acknowledgments
  8. REFERENCES