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Abstract

Background

Recurrent painful ophthalmoplegic neuropathy (RPON) is an uncommon disorder characterized by recurrent unilateral headache attacks associated with ipsilateral ophthalmoplegia. We intend to study the clinical picture in our case series along with the published literature to discuss the pathogenesis and propose modified diagnostic criteria for recurrent painful ophthalmoplegic neuropathy.

Methods

We reported five cases diagnosed as ophthalmoplegic migraine/RPON in our medical centers and reviewed the published literature related to RPON from the Pubmed database between 2000 and 2020. In one of these cases, a multiplanar reformation was performed to look at the aberrant cranial nerve.

Results

The mean onset age for RPON was 22.1 years, and the oculomotor nerve was the most commonly involved cranial nerve (53.9%) in 165 reviewed patients. In most patients, ophthalmoplegia started within 1 week of the headache attack (95.7%, 67/70). Additionally, 27.6% (40/145) of patients presented enhancement of the involved nerve(s) from MRI tests. Finally, 78 patients received corticosteroids, out of which 96.2% benefited from them.

Conclusion

This is the first time multiplanar reformation has been performed to reveal the distortion of the oculomotor nerve. Modified diagnostic criteria are proposed. We hope to expand the current knowledge and increase the detection of recurrent painful ophthalmoplegic neuropathy in the future.

Keywords

Recurrent painful ophthalmoplegic neuropathy migraine ophthalmoplegia diagnostic criteria case reports

Introduction

Recurrent painful ophthalmoplegic neuropathy (RPON), previously known as ophthalmoplegic migraine (OM) and named by Charcot in 1890 (1,2), is an uncommon condition that is characterized by recurrent unilateral headache attacks associated with ipsilateral ocular cranial nerve paralysis. It is estimated that this disease is prevalent in the population at a rate of 0.7 per million people. While this disease mostly begins in childhood, growing evidence has also shown adult onset (3,4). Previous studies showed that the median age of onset of this condition was 8 years, ranging from 3 months to 50 years, and the maximum reported age of onset was 74 years (1,5 –7). The data on the sex ratio of this disease are not conclusive. While some researchers reported about two-thirds of the patients were females, others have shown that the ratio was more balanced or more skewed toward males (7 –9). Previous literature has shown that the commonly involved ocular nerves in this condition are the oculomotor, abducens, and trochlear nerve. Also, it was observed that paralysis of these nerves could go on for several days to weeks, but the symptoms of headache and muscular dysfunction usually completely recover with or without any special treatment (2,6,10). The neuroimaging tests, namely computed tomography (CT) and magnetic resonance imaging (MRI) of the brain and especially Gd-enhancement MRI scan, have found thickening and/or enhancement of these nerve (s) (11,12) in RPON. CT was usually negative, although rare abnormality of the involved nerve was also reported (12). Moreover, these imaging abnormalities were more commonly seen in children and recovery occurred within 12 weeks (13). In the latest classification of headache disorders, while this disease was classified into neuropathy, the debate on its pathogenesis, classification, and diagnostic criteria is still ongoing (1,14,15). Here, we report five cases diagnosed as OM or RPON in our centers, on the basis of the International Classification of Headache Disorders (ICHD) diagnostic criteria (16 –18), and also discuss reported cases identified in the literature review in order to have a better understanding of this disease.

Methods

This study contains two parts: The first part reports a case series from two headache clinics (Case 3 from the fourth medical center and the others from the first medical center), in which the patients were diagnosed with OM or RPON, and the second part entails a literature review. We searched PubMed database (http://www.ncbi.nlm.nih.gov/pubmed) concerning OM or RPON according to ICHD-2nd, 3 beta, and 3rd editions (16 –18). The keywords were “OM,” “RPON,” “recurrent painful ophthalmoplegic neuropathy,” “ophthalmoplegic migraine,” “migraine,” and “headache.” The literature from 2000 to 2020 was reviewed. The flow chart of the study process is shown in Figure 1.

Figure 1.

Flow chart of the exclusion process for references.

Statistical analyses

The statistical tests were performed using the Statistical Package for the Social Sciences software version 22.0 (SPSS Inc., Chicago, IL, USA). The chi-squared test was used to compare qualitative data. The p-value was two-tailed, and a p-value < 0.05 was considered to indicate statistical significance.

Results

Cases report

Case 1

A 33-year-old woman had a 20-year history of recurrent serious right orbital headache accompanied by nausea, vomiting, photophobia and phonophobia followed by right ptosis and diplopia. The headache happened one to two times in 1–2 months, and each time it could last up to 72 h. The right ptosis and diplopia occurred when the headache persisted longer than 10 hours or became severe (visual analog scale score increased from 5–6 to 8–9), and the ophthalmoplegia completely recovered within 72 h without any special treatment. The physical examination showed the negative direct and indirect pupillary reflexes of the right eye, and the pupil size was 4 mm/2 mm (right/left). The cerebrospinal fluid (CSF) examination, rheumatoid factors, erythrocyte sedimentation rate, antinuclear antibody, and the oral glucose tolerance test as well as other laboratory tests were normal. However, the MRI showed noticeable thickening and enhancement in the right oculomotor nerve (Figure 2). Furthermore, the multiplanar reformation (MPR) revealed a distorted right oculomotor nerve compared to the left side (Figure 3). Then, the patient was prescribed amitriptyline (25 mg daily) and sodium valproate (500 mg daily) as a preventive treatment and did not suffer from headache or ophthalmoplegia in the next 1-year follow-up.

Figure 2.

The enhanced MRI test of case 1. (a)–(c) T1-weighted post-gadolinium axial, coronal, and sagittal images show thickening and enhancement in the right oculomotor nerve (arrows); (d) normal sagittal images of the left oculomotor nerve.

Figure 3.

The MPR-MRI test of case 1. (a) Normal left oculomotor nerve in MPR-MRI (arrow); (b) distorted right oculomotor nerve in MPR-MRI (arrow).

Case 2

A 39-year-old male had right periorbital pain with ipsilateral limited eye movement for 20 years. The migraine-like headache occurred one to two times per month, and sometimes lasted for 10 days. Within 2 days after the onset of the headache, the patient suffered from partial paralysis of the third cranial nerve without pupil involvement. Neuroimaging findings including enhanced MRI were normal. The 5 mg dexamethasone alleviated symptoms within 1 hour. Sodium valproate (200 mg daily) and rizatriptan benzoate (5 mg as needed) were prescribed. However, the patient stopped taking them due to unsatisfactory effects 2 months later.

Case 3

A 14-year-old male suffered from paroxysmal bursting headache for 7 years. In the first three years, the severe migraine-like headache located on the left orbital and temporal regions took place one to two times per year and persisted for 1 day. At the age of 11, a similar headache attack lasted for a week followed by completely left-sided oculomotor nerve palsy, which had good response to corticosteroid treatment and completely recovered after 8 weeks. After another headache with ipsilateral third cranial nerve paralysis 1 year later, the frequency of headaches increased to six times per month, and the headache could last for several days. If the headache lasted longer than 3 days, the diplopia and ophthalmoplegia was noted. Thus, the patient was hospitalized to undergo corticosteroid treatment for about 2 months and did not have any headache attack during the treatment period. After he was discharged, the frequency of headaches decreased to one time per month without any ocular signs during a 1-year follow-up. He came to our clinic asymptomatically, and the related physical examination and laboratory tests were normal. Additionally, no abnormalities were found in the brain MRI enhancement scan or in the magnetic resonance angiography (MRA) test.

Case 4

A 39-year-old female with a maternal family history of migraine complained of 20-year recurrent left-sided throbbing headache accompanied by nausea, vomiting, phonophobia, and photophobia, which lasted for 3 days. Ipsilateral near-complete eyelid closure and limited left eye movement was noticed. The physical examination showed left eye ptosis and mild restriction of the medial rectus without mydriasis. The enhanced MRI did not indicate any abnormalities. The symptoms of ophthalmoparesis completely alleviated within several days after the headache disappeared. Flunarizine (5 mg daily) and rizatriptan benzoate (5 mg as needed) were prescribed during the 6-month follow-up and the headache occurred three times without obvious ocular symptoms, which were alleviated by rizatriptan.

Case 5

A 28-year-old female suffered from moderate to severe left-sided headache accompanied by nausea, photophobia, bilateral nasal congestion, runny nose (worse on the left side), and limited abduction of the ipsilateral eye with a frequency of twice per month for 8 years. Headache usually lasted 2 days, and ophthalmoplegia completely recovered within 1 week. MRI with enhancement and MRA scans were normal. Flunarizine (5 mg daily) and rizatriptan benzoate (5 mg as needed) were prescribed. For the following year, the headache occurred one to two times per month without ocular symptoms and was alleviated within 8 hours.

Literature review

Clinical features

As shown in Table 1, the demographic and medical characteristics of the cases in our clinic along with the reported cases from other studies that were diagnosed as OM or RPON from 2000 to 2020 were reviewed (4 –6,9 –15,19 –59). From the database, most reported cases were from the USA, India, Japan, and European countries (e.g. Italy and Spain). Only two cases were reported from Mainland China in 2005 and 2014 (15,53).

Table 1.

A summary of reported OM/RPON cases from 1 January 2000 to 1 January 2020.

Study/date of publication	Nation	Sex/age	Age at onset	Migraine	CN involvement	Pupil involvement	Enhancement finding in MRI	Corticosteroid treatment*	Prognosis
Ramelli et al. (11), 2000	Switzerland	F/8 yrs	20 mos	Y	III R	Y	Y	NA	Resolved within 2–4 weeks
Stidham et al. (19), 2000	USA	F/8 yrs	3 yrs	N	III R	N	N^a	N	Resolved within 6–10 weeks
O’Hara et al. (20), 2001	USA	F/7 yrs	4 yrs	Y	III R	NA	Y	N	Improved over 6 weeks
O’Hara et al. (20), 2001	USA	M/3 yrs	11 mos	Y	III L	Y	Y	Y	Rapidly resolved
Lee et al. (21), 2002	Korea	F/42 yrs	32 yrs	Y	VI R	N	Y	Y	Resolved within a few days
Shin et al. (22), 2002	Korea	M/8 yrs	8 yrs	Y	III L	NA	N^b	Y	Resolved after 15 days
		F/11 yrs	6 yrs	Y	III R	Y	N^b	Y	Resolved within 15–20 days
Doran et al. (23), 2004	UK	F/36 yrs	6 yrs	Y	III L	N	Y	Y	Resolved within 4 weeks
Dussen et al. (24), 2004	Netherlands	M/31 yrs	19 yrs	Y	III R, IV R	Y	Y^c	N	Spontaneously recovered within several weeks to 3 months
Weiss et al. (25), 2004	USA	M/7 yrs	2 yrs	Y	III L	Y	N	N	Resolved within 2 weeks
Çelebisoy et al. (51), 2005	Turkey	F/22 yrsF/51 yrs	22 yrs50 yrs	NY	VI RVI L	NN	NN	NANA	Resolved within 3 weeksResolved after 3 weeks
De et al. (52), 2005	Singapore	M/28 yrs	21 yrs	Y	III R	Y	N^a	N	Completely recovered within 8 weeks
Huang et al. (53), 2005	Taiwan	F/9 yrs	9 yrs	Y	III R	Y	Y	Y	Fully recovered after 50 days
Mucchiut et al. (56), 2006	Italy	F/46 yrs	41 yrs	Y	VI L	N	N	N	Resolved within 4 weeks
O’Sullivan et al. (57), 2006	Ireland	F/35 yrs	35 yrs	N	III R	Y	N	N	Resolved within 8 weeks
Manzouri et al. (55), 2007	UK	F/36 yrsM/44 yrs	28 yrs38 yrs	NY	VI LVI R	NN	N^a N^a	NN	Headache resolved within several weeksHeadache resolved within several days
Bharucha et al. (4), 2007	USA	F/16 yrs	1.5 yrs	Y	III R	Y	Y	Y	Completely recovered after 1 week
McMillan et al. (26), 2007	Canada	F/9 yrs	9 yrs	N	III R	N	Y	Y	Completely recovered within 2 months
		M/12 mos	12 mos	N	III L	N	Y	Y	Rapidly improved 2–3 days
		F/16 yrs	16 yrs	N	III R	Y	Y	N	Completely resolved within weeks
Arasho et al. (27), 2009	Italy	M/15 yrs	5 yrs	Y	III L	Y	N^a	NA	Resolved after 2 months
Lavin et al. (29), 2009	USA	F/45 yrs	33 yrs	Y	VI L	N	Y	Y	Partly improved after several weeks
Pareja et al. (30), 2009	Spain	F/36 yrsF/30 yrs	35 yrs28 yrs	NY	III LIII R	NY	YY	Y^fY^f	The nerve paresis subsided in 2 weeksResolved within 2 weeks
Ogose et al. (28), 2009	Japan	M/17 yrs	9 yrs	Y	III R	Y	Y	Y^f	Totally recovered within 8 weeks
Bek et al. (50), 2009	Turkey	M/21 yrs	8 yrs	Y	III R	Y	Y	Y	Resolved within 3 months
Miglio et al. (12), 2010	Italy	M/8yrs	8 yrs	Y	III R	N	Y	Y	Partly recovered after 2 weeks
Riadh et al. (58), 2010	Tunisia	F/3yrs	9 mos	Y	III L	Y	N	Y	Partly resolved within 1 week
Lane et al. (54), 2010	UK	F/40 yrsM/ 22 yrs	13 yrs12 yrs	YY	III LIII L, VI R	YY	YN	NAY	Resolved within several weeksCompletely resolved within 1 week
Tocco et al. (33), 2011	Italy	F/33 yrs	33 yrs	Y	III R	Y	N^d	NA	Totally recovered after 10 weeks
Lyerly et al. (31), 2011	UAS	F/10 yrs	3 yrs	Y	III R	Y	Y	Y	Partly resolved within 3 days
Patro et al. (32), 2011	India	M/43 yrs	14 yrs	Y	III L	Y	Y	Y	Without headache attack
Margari et al. (35), 2012	Italy	M/7 yrs	6 yrs	Y	III R, VI R	NA	N	Y	Recovered within 2 weeks
Margari et al. (35), 2012	Italy	M/10 yrs	9 yrs	Y	III L	NA	N^e	N	1–2 attacks per month
Rocha et al. (10), 2012	Brazil	M/10 yrs	5 yrs	NA	III R	NA	Y	NA	Fully recovered after 4 weeks
Maggioni et al. (34), 2012	Italy	F/23 yrs	8 yrs	Y	IV L	N	N^e	NA	Recovered from 2–20 days
Sobreira et al. (36), 2012	Portugal	F/15 yrs	9 yrs	Y	III R	Y	N	Y	Good clinical response
Sharma et al. (38), 2013	India	M/25 yrs	23 yrs	Y	III L, V1^# L	Y	N	Y	Recovered completely in 10 days
Pacheva et al. (37), 2013	Bulgaria	M/11 yrs	9 yrs	Y	III L	NA	N	NA	Resolved within 3–6 days
Shetty et al. (39), 2013	India	F/26 yrs	25 yrs	Y	III L	Y	N	N	Complete recovered in 2 weeks
Wang et al. (15), 2014	China	M/63 yrs	61 yrs	Y	III R	Y	N	N	Resolved after 7–10 days
Ghosh et al. (40), 2015	USA	M/5 yrs	18 mos	Y	III R	NA	Y	Y	Recovered within 3 weeks
Ramakrishnan et al. (41), 2015	India	F/30 yrs	25 yrs	Y	III R, L	Y	N	Y	Recovered within 1 month
Takizawa et al. (42), 2016	Japan	F/42 yrs	20 yrs	NA	III R	NA	Y	NA	Resolved within 2 months
Huang et al. (13), 2017	UK	F/26 yrs	19 yrs	Y	IV R, VI R	N	N	Y	Resolved fully in 6 weeks
Kobayashi et al. (14), 2017	Japan	F/48 yrs	32 yrs	Y	III R	Y	Y	Y	Partly improved within 5 days
Okura et al. (43), 2017	Japan	M/12 yrs	9 yrs	Y	III R	Y	Y	Y	Partly resolved within 8 weeks
Tripathi et al. (45), 2017	USA	F/36 yrs	33 yrs	Y	VI L	N	Y	N	Recovered after 2 months
Qureshi et al. (44), 2017	USA	F/53 yrs	53 yrs	Y	III R	N	Y	N	NA
Hurd et al. (46), 2018	USA	M/12 yrs	4 yrs	Y	III L	Y	Y	Y	The episodes occur but are less severe.
Zamproni et al. (47), 2019	Brazil	F/21 yrs	21 yrs	N	VI R	N	N	Y	Completely recovered within 1 week
Sharifi et al. (59), 2019	USA	M/15 yrsM/11 yrs	15 yrs11 yrs	NY	III RIII L	NANA	YY	YN	Resolved within several weeksLast for 1 week and gradually resolved
Liu et al. (current cases), 2020	China	F/33 yrsM/39 yrs F/14 yrsF/39 yrsF/28 yrs	13 yrs9 yrs11 yrs19 yrs20 yrs	YYYY	III RIII RIII LIII LVI L	YNNNN	YNNNN	YYYNN	Completely recovered after 3 daysRecovered within 1 hourCompletely recovered within 8 weeksRecovered within several daysRecovered within 1 week
Lance et al. (5), 2001	Australia	Five patients (two females), age of onset varied from 3 months to 30 years old. All had third cranial involved and one of them also had possibly sixth cranial involved. One patient showed enhancement of the third nerve, two had normal unenhanced MRI results and two did not show this detailed data. One patient took prednisone and acetazolamide. The prognosis was good.
Carlow (48), 2002	USA	Six patients (five girls), age of onset varied from 16 months to nine years, with a mean of 3.7 years. Headache preceded the onset of a third nerve paralysis by up to 11 days. The pupil was dilated in five. Permanent oculomotor paresis or paralysis was present in four of the six children after multiple episodes, and two developed aberrant regeneration. MRI brain signal abnormalities were present in all cases.
Giraud et al. (6), 2007	France	Nine patients (six females), average age 36 (16–74) years old. All patients suffered from migraine. Four patients had third nerve affected and two of them had sixth affected. One of them had third or sixth affected during different attacks. Unenhanced MRIs were normal in eight patients and one patient did not mention the prognosis. Three used oxetorone and two used NSAIDs; the cranial palsy and headache were always reversible in a few weeks.
Lal et al. (9), 2009Gelfand et al. (7), 2012	IndiaUSA	Sixty two patients (33 females), average age 36 (15–68) years old. Isolated abducens, oculomotor, and trochlear nerve involvements were seen in 35, 21, and five patients, respectively. One patient had simultaneous involvement of third and sixth nerves. No case had any nerve enhancement. Use of steroids hastened recovery. Four children (one girl), age of onset varied from 3–9 years. All patients had third nerve affected and two had enhancement from MRI test. Three patients suffered migraine-like headache and two got benefit from steroids.
Chakravarty et al. (49), 2012	India	Eighteen patients (13 females), mean 37 years old (range from 27–51 years old). Fourteen had sixth nerve palsies and four had third cranial nerve palsies; all had normal contrast-enhanced MRI results and they were all treated with prednisolone. The pain subsided in all in 4–7 (mean 5.8) days, but ophthalmoplegia took 9–16 (mean 11) days to recover fully.

F: female; M: male; yrs: years old; mos: months; Y: Yes; N: No; NA: not available; III: oculomotor nerve; IV: trochlear nerve; VI: abducens nerve; R: right side; L: left side.

*Use tapered over several weeks.

^#Sensory loss over V1 distribution of trigeminal nerve.

^aUnenhanced MRIs were normal.

^bThe Single Photon Emission Computed Tomography revealed significantly decreased rCBF in the left thalamus.

^cOnly fourth enhancement was found without third enhancement.

^dCTA showed a fetal-type posterior cerebral artery.

^eElectroencephalogram showed the anomalies.

^fSteroids were not so effective.

In total, 165 patients were analyzed, including five patients from our centers; 57.6% (95/165) of these patients were female. Thus, the sex ratio was 1.4:1 (female 95: male 70). The average onset age was 22.1 years and ranging from 3 months to 74 years. In patients who reported the age of onset accurately, in 50 out of 76 (65.8%), the age of onset was under 18 years. We found that the most common type of headache was migraine-like (87.9%, 145/165), which was always accompanied by nausea and/or vomiting, photophobia, and/or phonophobia. About 10 patients (6.1%, 10/165) did not suffer from migraines, and the other 10 patients (6.1%, 10/165) did not provide this information. A total of 60 patients reported an accurate headache location, while 62 patients in one of the studies did not report the location (9). While the location of the headache differed, in all cases it was on the same side as the ophthalmoplegia. The results showed that 29 patients (48.3%, 29/60) had orbital-related pain (nine orbital pain, seven periorbital pain, five supraorbital pain, four retro-orbital pain, and four mixed areas), 20 patients (33.3%, 20/60) had hemicrania, and seven patients (11.6%, 7/60) had frontal headache. Besides, there were two patients who suffered from temporal pain, one patient had an occipital headache, and another had line-shaped pain. Although in two other articles (n = 27 patients) (6,49) the exact regions affected in each patient were not described, they did note that the headache was ipsilateral to the palsy, involving the orbital, periorbital, frontal, and temporal areas. We also found that 57 (34.5%, 57/165) of these patients had a family history of migraine, whereas another 52 (31.5%, 52/165) patients did not. Finally, the frequency of headaches ranged from one time in several years to several times in a month, and the headache duration varied depending on different treatments.

The other important characteristic among these patients was the interval between the headache attack and the onset of ophthalmoplegia. A total of 70 patients reported this interval (Figure 4). Only two of them initially had ophthalmoplegia followed by the headache in a very short time (39,46). The other 67 patients got ophthalmoplegia concurrently or within 1 week after the headache attack (concurrently: Five cases; within one day: 20 cases; 1–4 days: 20 cases; 4–7 days: 22 cases). In one patient, there was a 15-day interval between the headache and the ophthalmoplegia (47). Sixty-one patients reported that they developed ophthalmoplegia during a headache attack (6,9). Two studies showed the interval between headache onset and ophthalmoplegia ranged from immediate to up to 11 or 14 days (7,48). Taken together, we found that the symptoms of ophthalmoplegia could develop immediately after the headache attack to up to 15 days after it; the most common time was within 1 week (96.7%, 67/70).

Figure 4.

The distribution of intervals between headache and ophthalmoplegia attack. (a) The different intervals among 70 patients; the majority had less than 1 week interval between the two events; (b) the detailed information from 15 cases to show the exact onset time and duration of headache and ophthalmoplegia.

As in all the cases, the oculomotor nerve was most commonly involved (third: 53.9%, 89/165; fourth: 3.6%, 6/165; sixth: 37.0%, 61/165; two nerves combined: 4.2%, 7/165). Considering the different onset ages, we found that among childhood-onset patients (<18 years old), the third nerve involvement was observed in 47 patients (94.0%, 47/50), followed by two nerves combined (4.0%, 2/50) and fourth nerve (2.0%, 1/50). In the remaining 26 adult-onset patients, the third nerve was still the most commonly involved nerve (53.8%, 14/26), followed by the sixth nerve (38.5%, 10/26) and two nerves combined (7.7%, 2/26). There were two patients who only reported diplopia without detailed information (6). In a previous study, the estimated mobility of abducens nerve paresis was about 10% (8), while from our pooled data, we found it to be much higher (37.0%), and the paresis of the abducens nerve also occurred in one of our five cases (20.0%). Unlike the third and sixth cranial nerves, the isolated trochlear nerve palsy was rarer as shown above. Apart from the single nerve disorder, there were few cases (4.2%, 7/165) of combined two nerve palsies (1,24). We did not observe any clear side predominance from the 135 patients who provided detailed information (right side: 48.2%, 67/139; left side: 50.3%, 70/139; in two patients, both sides were involved). The involvement of the pupil was only observed in one of the cases from our centers, although previously reported cases have shown that mydriasis could be a common symptom (48). Out of 78 patients (47.3%, 78/165) who reported about the pupil examination, 55.1% (43/78) had mydriasis. Apart from the third, sixth, and fourth cranial nerves, a case reported from India (38) showed that a RPON patient with third nerve palsy also had sensory loss over the V1 distribution of the trigeminal nerve, which indicated that trigeminal nerve might also be involved.

Neuroimaging features

The neuroimaging tests, especially the enhanced MRI scan, were very important for differential diagnosis. One of five patients in our centers showed enhancement of the third cranial nerve in the MRI test. When we combined all the reported cases, we found that out of 145 patients who received enhanced MRI tests, 27.6% (40/145) had thickening and/or enhancement, as observed in the MRI, of the involved cranial nerve(s). Furthermore, we found that among childhood-onset patients who underwent enhanced MRI tests, 31 out of 49 (63.3%) revealed abnormalities of at least one involved cranial nerve under MRI. In adult-onset patients, this proportion was 34.6% (9/26), which indicated significant differences between these two groups (p = 0.028). However, there were 105 patients who did not show any significant abnormality based on enhanced MRI tests. Also, 18 patients did not receive the enhanced tests, and their regular MRI tests were normal. In some cases, electroencephalogram (EEG) and CT digital cerebral angiography (CTA) have also been used for detecting the pathogenesis (9,14). The MPR revealed a distorted oculomotor nerve in one of our cases.

Treatment

We found that in our pooled data, there were 78 patients (47.3%, 78/165) who received the corticosteroids alone (36/78) or in combination with antimigraine treatment (42/78), and 75 of them (96.2%, 75/78) benefited from the therapy. In three of them, the treatment failed to have a satisfying effect, and the symptoms even got worse with corticosteroids (28,30). Additionally, 34 patients (69.4%) only accepted antimigraine treatment, which included beta-blockers (like propranolol) or calcium channel blockers (like flunarizine) as part of the commonly used prophylactic therapy. Compared with patients who only used antimigraine medicine, the combined use of steroids hastened recovery (9). It is worth noting that, in total, six patients benefited from NSAIDs like indomethacin (6,30). For the acute treatment of headache, triptans were always prescribed (1).

Prognosis

All five patients from our centers completely recovered spontaneously or benefited from the corticosteroid and prevention therapy within several hours to 2 months, which is consistent with the previous reporting. However, it is important to be aware that patients suffering from OM or RPON who have a tendency to recurrent episodes would have more severe and persistent nerve involvement. In fact, about 30% of patients could have permanent neurological sequelae after recurrent attacks (2,26,27). The analyzed data from these 165 patients are shown in Table 2.

Table 2.

Analyzed characteristics of patients with OM/RPON between 1 January 2000 and 1 January 2020 (n = 165).

Characteristics	Results
Gender (n, %)
Female	95 (57.6%)
Male	70 (42.4%)

Age of onset (years)	Mean 22.1 (range 0.25–74)
Exact onset age (n = 76) (n, %)
<18 yrs*	50 (65.8%, 50/76)
≥18 yrs	26 (34.2%, 26/76)
Migraine-like headache (n, %)
Yes	145 (87.9%)
No	10 (6.1%)
NA	10 (6.1 %)
Family history of migraine (n, %)
Yes	57 (34.5%)
No	52 (31.5%)
NA	56 (33.9%)
The regions of headache (n = 60) (n, %)
Orbital-related	29 (48.3%)
Hemicrania	20 (33.3%)
Frontal	7 (11.6%)
Temporal	2 (1.2%)
Occipital	1 (1.6%)
Line-shaped	1 (1.6%)
The interval between headache and ophthalmoplegia attack (n, %)
Exact interval (n = 70, 42.4%)
Paresis first	2 (2.9%, 2/70
≤1 week	67 (95.7%, 67/70)
>7 d	1 (1.4%, 1/70)
During**	61 (37.0%)
NA	34 (20.6%)
Involved cranial nerve (n, %)
CN III	89 (53.9%)
CN IV	6 (3.6%)
CN VI	61 (37.0%)
Combined two of above	7 (4.2%)
NA (only diplopia)	2 (1.2%)
Mydriasis (n, %)
Yes	43 (26.1%)
No	35 (21.2%)
NA	87 (52.7%)
Received enhanced MRI tests (n, %)
Yes (n = 145, 87.9%)
Abnormal	40 (27.6%, 40/145)
	<18 yrs 31 (63.3%, 31/49)^#
	≥18 yrs 9 (34.6%, 9/26)
Normal	105 (72.4%, 105/145)
No (normal in regular MRI)	18 (10.9%)
NA	2 (1.2%)
Received corticosteroids treatment (n, %)
Yes (n = 78, 47.3%)
Effective	75 (96.2%, 75/78)
Non-effective	3 (3.8%, 3/78)
No (n = 49, 29.7%)
Nothing	15 (30.6%, 15/49)
Antimigraine	34 (69.4%, 34/49)
NA	38 (23.0%, 38/165)

NA: Not available; III: oculomotor nerve; IV: trochlear nerve; VI: abducens nerve.

*yrs: years old.

**The ophthalmoplegia occurred during the initial headache attack without detailed information about the exact interval.

^#Among the patients whose onset age was under 18 years old, one did not mention the MRI results; there is a significant difference between these two groups (p = 0.028).

Discussion

In the present study, we report five cases from our centers and review a total of 165 patients with RPON from the published literature within the past two decades. The sex ratio was 1.4:1 (female 95: male 70) and mean onset age was 22.1 years. In all, 27.6% of patients presented enhancement of the involved nerve (s) from MRI tests. An enhanced and distorted oculomotor nerve was found in the MRI test of one patient in our case series. The oculomotor nerve was the most commonly involved cranial nerve, followed by the abducens nerve and the trochlear nerve. In most patients, ophthalmoplegia started within 1 week of the headache attack. Also, 78 patients received corticosteroids, out of which 96.2% benefited from them.

RPON, which was named OM previously, was thought to be a variant of the migraine type as it shares some common characteristics with migraine (17). Our current study found 87.9% of reported cases of RPON had a migraine-like headache. Some of these patients might have frequent migraine attacks over a long period, and then the onset of ophthalmoplegia was noted (our case 3). Besides, some patients eventually developed ophthalmoplegia as the intensity or duration of the migraine-like headache attacks increased (our case 1 and case 3). These clinical manifestations seem to support the etiology of migraine for RPON. Additionally, CTA revealed a fetal-type right posterior cerebral artery (PCA) in an OM patient, validating the compressive or ischemic hypothesis (33). The hypothesis states that edema of the wall of the internal carotid artery or PCA could compress the cranial nerves in the carotid sinus, and the swelling could lead to occlusion of the arterial supply for these nerves (1,9,35). Based on this view, the OM/RPON appears to be classified as a variant of migraine.

However, the mechanisms underlying migraine cannot completely explain the ophthalmoplegia during the migraine attacks and there are only a few documented cases of vascular abnormalities. Also, only a few of the RPON patients have certain pupil involvement during ophthalmoplegia, seeming not to support the mechanism of compression, which would easily affect the parasympathetic nerve. Unlike previous reports that females are three times more likely to have migraines than males (60,61), the sex ratio was found to be 1.4:1 (female: male) among patients with OM/RPON based on our pooled data. Most importantly, no aura symptoms or chronic migraine attacks, which indicate brain dysfunction related to migraine pathophysiology (62), were found among OM/RPON cases.

Peripheral neuropathy related to an infection or inflammation, which likely releases neuropeptides such as calcitonin gene-related peptide in the trigeminovascular system, has recently been proposed as a possible mechanism for RPON (1,7,26). Therefore, OM was modified to RPON in the recent edition of ICHD (16,18). A recurrent RPON case was found to be related to a rise of cytomegalovirus-specific IgG antibody (28). Another case illustrated oculomotor paresis after injections of a vaccine (5). These cases support that the mechanism of RPON is related to the inflammatory nature of cranial neuropathy. It was speculated that an inflammatory process affects the involved cranial nerve(s) and irritates the trigeminal sensory fibers, then triggers a headache. Our summarized data demonstrate that 27.6% of patients have certain oculomotor nerve enhancement and thickening in the MRI. In the case from our centers, an MPR was firstly performed, which showed a distorted oculomotor nerve. These neuroimaging findings also support the possibility of recurrent inflammation-related etiology. Although an abnormality in the nerve was not found in all reported patients in an MRI test, we noticed that in some cases the abnormality could not be observed during the interictal periods or in an MRI test conducted for the first time, and could only be found after attacks had happened several times (4). Thus, negative results should be taken into thorough consideration. Furthermore, it was found that there was a high response rate (96.2%) among patients who received corticosteroid therapy, and some reports showed that administration of steroid therapy at the time of attack might minimize the permanent sequelae of ophthalmoplegia, such as residual weakness of the cranial nerve and pupillary dysfunction (4,8,13,63). The permanent oculomotor paresis could be present after multiple episodes in some cases (48).

In summary, these mentioned findings indicated that the underlying mechanisms of migraines and RPON might be correlated. RPON are more likely to be an intermediate status that might involve mechanisms associated with both migraines and ophthalmoplegia, but the peripheral inflammatory mechanisms could play a more important role. At the same time, this phenomenon is not uncommon in some types of headache disorders. For example, cranial autonomic symptoms are distinguishing features of trigeminal autonomic cephalalgias, of which cluster headache is the most common, but they can also occur in patients with migraines (64). Migraineurs may also similarly experience frequent headaches during a finite period (several weeks to months), recurring during the same season and rarely at other times, like cluster headache patients (65). Thus, we believe that different types of headaches may share overlaps, including RPONs and migraines.

Given the above information, we believe that the current diagnostic criteria of RPON (16) (Table 3, left) are not clear enough and need further clarification. First, we hold the view that apart from the clinical signs of ophthalmoplegia, the MRI observations including the enhancement, thickening, or distortion of the involved motor nerve(s) should be added into diagnostic criteria but not as a sine qua non. This would draw more attention among clinicians to the importance of enhanced MRI in the diagnostic progression. Besides, the MRI results can help differentiate the diagnosis of RPON from other diseases, such as Tolosa-Hunt syndrome, in which there are neuroimaging abnormalities of the cavernous sinus. Second, we suggest adding the interval between headache and ophthalmoplegia attack into the diagnostic criteria, similar to the criteria for Tolosa-Hunt syndrome (16). This is as the headache develops in temporal relation with the motor nerve palsy; we found that the headache could precede ophthalmoplegia anytime within 15 days, or develop approximately at the same time. Third, we think the current item C should be removed from the diagnostic criteria due to its meaning being similar to item D. Lastly, we referenced the diagnostic criteria for 13.7 Headache attributed to ischaemic ocular motor nerve palsy and 13.8 Tolosa–Hunt syndrome in ICHD-3 in order to maintain consistency in wording and phrasing. The modified diagnostic criteria for RPON are shown in Table 3 (right). Hence, the revised diagnostic criteria are more rigorous and could expand knowledge about RPON as well as increase the detection of this disease in the future.

Table 3.

Current and modified diagnostic criteria for RPON.

Current diagnostic criteria for RPON		Modified diagnostic criteria for RPON
A.	At least two attacks fulfilling criterion B	A.	At least two unilateral headache attacks fulfilling criterion C
B.	Both of the following: 1. unilateral headache2. ipsilateral paresis of one, two or all three ocular motor nerves	B.	The clinical signs of paresis of one or more of the third, fourth and/or sixth cranial nerves and/or the enhancement, thickening or distorted of involved motor nerve(s) demonstrated by MRI
C.	Orbital, parasellar or posterior fossa lesion has been excluded by appropriate investigationD. Not better accounted for by another ICHD-3 diagnosis.	C.	1. Headache is ipsilateral to the ophthalmoplegia2. Headache has preceded ophthalmoplegia by ≤15 days, or developed approximately at the same timeD. Not better accounted for by another ICHD-3 diagnosis.

Limitation

Our study is limited by its observational nature and it being mixed with retrospective characteristics for some reported cases. Although we summarize the data from the last 2 decades with a total of 165 cases of OM/RPON, we should keep in mind that there may be some bias in the overall reporting as we did not have detailed information from each patient in some reports (6,7,9,48), such as the interval between headache and ophthalmoplegia attack. Despite these limitations, our pooled data are detailed and accurate, and thus we propose modified diagnostic criteria for RPON.

Conclusion

This is the first time all the recently published cases of OM/RPON have been summarized with their detailed clinical picture. We found that the oculomotor nerve is most commonly involved in RPON. MPR is, for the first time, performed to reveal a distortion of the oculomotor nerve, which strengthens the evidence for the abnormality of this cranial nerve in RPON. Steroid therapy showed a satisfactory beneficial effect in RPON. Based on our summarized data, we support the possibility that recurrent inflammation-induced etiology could play a more important role than a migraine-related pathology as the underlying mechanisms of RPON. Finally, we suggest revised diagnostic criteria for RPON, and we hope that will increase the knowledge and detection of this disease. We believe a longer follow-up period and detailed medical education are important for patients suffering from RPON.

Clinical implications

Among patients with RPON, the oculomotor nerve is the most common involved cranial nerve, followed by the abducens nerve and the trochlear nerve.

Most patients benefit from corticosteroid therapy.

RPON are more likely to be an intermediate status that might involve mechanisms associated with both migraines and ophthalmoplegia, but the peripheral inflammatory mechanisms could play a more important role.

The neuroimaging results, as well as the interval between headaches and ophthalmoplegia attack, are important in the diagnostic process and should be added into diagnostic criteria.

Footnotes

Declaration of conflicting interests

The authors declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Funding

The authors disclosed receipt of the following financial support for the research, authorship, and/or publication of this article: This work was supported by the National Science Foundation of China (grants 81671077, 81600952, 81771180, 81771200, 81901134 and 81901145), and Beijing Natural Science Foundation Essential Research Project Z170002.

Informed consent

Informed consents were obtained from our five cases in this study.

ORCID iD

Shengyuan Yu

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Proposed modified diagnostic criteria for recurrent painful ophthalmoplegic neuropathy: Five case reports and literature review

Abstract

Background

Methods

Results

Conclusion

Keywords

Introduction

Methods

Statistical analyses

Results

Cases report

Case 1

Case 2

Case 3

Case 4

Case 5

Literature review

Clinical features

Neuroimaging features

Treatment

Prognosis

Discussion

Limitation

Conclusion

Clinical implications

Footnotes

Declaration of conflicting interests

Funding

Informed consent

ORCID iD

References