Could recurrent painful ophthalmoplegic neuropathy be caused by a neurovascular conflict?: A case report

Abstract

Objective:

Describe and discuss a typical case with recurrent painful ophthalmoplegic neuropathy (RPON), and demonstrate a likely extrinsic compression of the sixth cranial nerve by a vascular loop.

Background:

RPON is a rare, but well-known entity, characterized by attacks of ophthalmoplegia associated with ipsilateral headache. The etiology is unknown, but a neurovascular conflict (NVC) has been suggested as a cause.

Method:

A 62-year-old woman presented in the emergency department with a horizontal diplopia that developed a few hours after the onset of a left temporal headache. In the past she had presented to the clinic with the same problem several times. She had been thoroughly examined, but no cause had been found. The symptoms had resolved by themselves. In addition to a classic finding in RPON, gadolinium enhancement and thickening of a cranial nerve, the new MRI scanning detected an NVC. Herein we discuss the relevance of this finding.

Conclusion:

A neurovascular conflict causing inflammatory demyelination of a single cranial nerve and relapsing remitting painful ophthalmoplegic neuropathy is an alluring idea. However, it is hard to conceive theoretically, and more reported cases with compelling data are needed to give credibility to such an idea.

Background

Recurrent (at least two attacks) idiopathic migraine-like headache associated with paresis of one or more of the third, fourth, and/or sixth cranial nerves was previously considered a rare variant of migraine, denoted ophtalmoplegic migraine. ¹ The demonstration of thickening and enhancement of affected cranial nerve on magnetic resonance imaging (MRI) scanning in some cases ultimately led to rejection of the old term, and the condition is now considered a recurrent painful ophtalmoplegic neuropathy, abbreviated RPON. The latest diagnostic International Headache Society classification criteria (ICHD-3) ² are listed in Table 1. Based on five own cases and a review of 165 cases from the literature, Liu et al recently suggested modified criteria ³ which also are listed in Table 1. RPON is an idiopathic and rare condition, often with onset in childhood. ³ Here we present an adult case potentially caused by a neurovascular conflict (NVC).

Table 1.

Recurrent painful ophthalmoplegic neuropathy.

ICHD-3 criteria 2 Diagnostic criteria: At least two attacks fulfilling criterion B Both of the following: ipsilateral paresis of one, two or all three ocular motor nerves Orbital, parasellar or posterior fossa lesion has been excluded by appropriate investigation Not better accounted for by another ICHD-3 diagnosis Modified criteria after Liu et al. 3 Suggested new criteria: At least two attacks fulfilling criterion C 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 Both of the following: Not better accounted for by another ICHD-3 diagnosis

Case presentation

A 62-year-old woman presented in the emergency room with a horizontal diplopia. She had developed a moderate dull aching pain in the left temple in the afternoon 6 days earlier, and the following morning she had woken up with the double vision. No migrainous features (such as aura, throbbing, nausea and hypersensitivity) were present. Upon physical examination, the headache had subsided. She had normal vital signs, except a blood pressure of 209/103 mmHg, which normalized within few hours. She had no history of hypertension. A neurological examination revealed an isolated partial palsy of the left abducens nerve. Routine blood tests, including erythrocyte sedimentation rate and C-reactive protein, were all normal. Standard CSF-analyses and polymerase chain reaction tests to identify common viral and bacterial agents were also negative. A contrast enhanced MRI scan of the head was performed on day 2 (including axial T2-weighted (T2W) isometric 3-D acquisition with 0.5 mm slice thickness through the posterior fossa and both pre- and post-contrast sagittal T1-weighted (T1W) isometric 3-D acquisition with 1 mm slice thickness). A marked thickening (Figure 1(b)) and gadolinium enhancement (Figure 1(a)) of the left sixth cranial nerve (abducens) was seen, and a contact between the nerve and a vessel was strongly suggested (Figure 1(b and c)).

Figure 1.

Head magnetic resonance imaging (MRI). (a) MRI post-contrast T1W axial slice showing gadolinium enhancement of an evenly thickened left abducens nerve (arrow) from the root exit zone (REZ) to the entrance of Dorello’s canal. (b) MRI T2W axial slice showing a thickened left abducens nerve (arrow) compressed by, or at least in perpendicular contact with, the anterior inferior cerebellar artery (AICA) at the REZ (arrow head). (c) MRI T2W sagittal slice showing the close relationship between the thickened left abducens nerve (arrow) and AICA (arrow head).

The patient’s symptoms resolved without any treatment on day 7 after onset, and she was discharged. On a follow-up 5 months later she felt fine, had a normal examination, and she had not experienced any symptoms after the discharge. A new MRI still showed thickening and slight gadolinium enhancement of the nerve.

Scrutinizing the patient’s medical history, it revealed no migraine, nor in her family. She had a left Bell’s palsy at the age of 28, diagnosed by her GP, and she had been treated at our eye clinic for uveitis on her right eye twice in her late 50s, otherwise she was healthy using no drugs. However, she had experienced several episodes of diplopia associated with headache in the past. Her first attack of moderate left temporal pain of pressing quality followed by an ipsilateral sixth nerve palsy happened at the age of 40 (1999) She was thoroughly examined by an ophthalmologist less than 2 days after onset and by a neurologist after 2 weeks. The episode was almost identic to the present, lasting 4 days at that time. In between these attacks she had experienced five equivalent episodes, with double vision occurring a few hours after headache onset, and lasting from 24 hours to 2 months. The headache had never been severe, always unilateral, but otherwise featureless, and resolved within a few days. MRI scans had been performed during the acute phase in 2004 and 2013, but no pathology had been detected in any of them. Notably, no time-of-flight (TOF) magnetic resonance angiography (MRA) had been performed, and the post-contrast T1W sequence from 2004 with 5 mm slice thickness and 2 mm gap between the slices was not able to demonstrate the abducens nerve. A re-examination in 2022, however, showed marked thickening of the abducens nerve on the images from 2013.

Discussion and conclusions

The present patient has a typical history of RPON, fulfilling criteria (2) drawn from the past and present history with the recurrent course of a painful ophtalmoplegia in a relapsing-remitting pattern. In RPON, the cranial nerve palsy begins at onset of the headache or within a week in the vast majority. ^3,4 The headache, described as migraine-like in most patients, ³ usually resolves within a week and long before the ophtalmoplegia resolves. Most often there is complete resolution of the ophtalmoplegia within 3 months. ^3,4 Contrast enhancement of the affected nerve on MRI (typically in the cisternal exit zone), seen in 27.6% of 145 cases from the literature, ³ and thickening of the cranial nerve may resolve as the patient’s diplopia subsides, ⁵ completely from 7 weeks to 4 years. Recurrence of attacks may occur from days to years later.

The mechanisms underlying RPON are not known. Ischemia, compression of the affected nerve, and an inflammatory demyelinating process have been proposed. ⁵ One mechanism, however, does not exclude another one. Pooled data from the last two decades shows that in 96% of the patients with RPON only one cranial nerve was involved, ³ most often cranial nerve (CN) III (54%) followed by CN VI (37%). The recurrent course, nerve enhancement, and reported high response rate to corticosteroid therapy ³ support an inflammatory demyelinating process in many cases.

A vascular compression of the affected nerve in RPON was postulated already in 1960, ⁶ but pupillary sparing seen in many patients with oculomotor nerve affection has been used as a major argument against a compressive mechanisms (—the parasympathetic fibers reside in the periphery of the nerve and are vulnerable to external compression). There has, however, been an increasing acceptance of neurovascular compression syndromes (NVCs) of the cranial nerves since the first description by Dany in 1934, and these now include trigeminal neuralgia, hemifacial spasm, vestibular paroxysmia and glossopharyngeal neuralgia. ⁷ Linn et al suggested NVC in an adult female with recurrent palsy of the abducens nerve in 2008, ⁸ and recently it was suggested as a cause of RPON in two male children. ⁹ Could the same be true in our patient?

First of all, a plausible NVC requires evidence of vascular contact with the cranial nerve. This could be obtained by applying high-resolution MRI 3-D T2-weighted steady-state free precision sequences showing precise contact of a vessel (artery or vein) and the offended cranial nerve within the root exit zone (REZ) and with or without displacement of the nerve. Notably, a neurovascular contact is often found (around 20–30%) in asymptomatic individuals. ⁷ Secondly, is it plausible that the NVC has caused demyelination and contrast enhancement of the affected nerve? Contrast enhancement is an unspecific finding that can reflect a tumor (schwannoma for instance), vascular damage and inflammation. But, repeated pulsations at the vulnerable transitional zone of the nerve (where central glial myelin transitions into peripheral Schwann cell myelin) could lead to both focal demyelination and axonal ischemia. ¹⁰ A demyelinating-remyelinating process, which is alluring from a time perspective, ¹¹ could potentially explain the relapsing remitting course of RPON. Over the years however, this could also cause increasing episodes of neuritis, ephaptic neurotransmission (with spasms of the innervated muscles), atrophy of the affected nerve and permanent loss of function, which are not typical for RPON. In light of our patients’ history of uveitis, autoimmune mechanisms must be considered. The time span with episodes over more than 20 years, always affecting the same cranial nerve, makes it less likely. However, mechanical disruption (by the vascular compression) could contribute to exposure of self-antigens in the particular nerve and a secondary immune attack. Such mechanism has been suggested in the rare stretch-induced recurrent condition of Wartenberg’s migrant sensory neuritis. ¹¹ Focal thickening of the nerve (perineurum) with lymphocytic infiltration and immunoglobulin deposition support the suggestion of an autoimmune etiology in that disorder. Another crucial question is why mechanical irritation of a single pure peripheral motor nerve such as CN VI should cause trigeminal pain. Isolated recurrent pain-free ophthalmoplegic neuropathy (“RON”), affecting either CN IV ¹² or CN VI, ¹³ has previously been attributed to a NVC. In RPON the pain has been attributed to the inflammatory nature of cranial neuropathies (somehow triggering trigeminal sensory neurons, releasing mediators such as calcitonin gene-related peptide), but hemifacial spasm caused by a NVC for instance does not usually cause headache. In optic neuritis (ON), the inflamed optic nerve sheath is the plausible cause of the pain, ¹⁴ and the more severe the inflammation is, the higher the possibility that the patient will suffer from headache. ¹⁵ Pain in ON usually subsides in about a week, and the visual acuity improves slowly over a few weeks. In contrast to ON, the recurrence of attacks in RPON does not normally result in cranial nerve atrophy and residual functional impairment.

In conclusion, the cause of RPON remains an enigma. The wide ICHD-3 criteria probably encompass heterogeneous conditions. Based on the present case, some factors might suggest a vascular compression syndrome, but theoretically, it is not fully conceivable. More reported cases could perhaps shed more light on this.

Clinical implications

• Recurrent painful ophthalmoplegic neuropathy (RPON) is a rare condition with unknown etiology.

• A neurovascular conflict as cause of RPON is an alluring idea, but hard to conceive.