A Case of Recurrent Painful Ophthalmoplegic Neuropathy with Frequent Relapses and Prophylaxis with High-Dose Vitamin B2 Supplementation

ABSTRACT

Recurrent painful ophthalmoplegic neuropathy (RPON) is characterized by recurrent unilateral headache associated with ipsilateral ophthalmoplegia due to palsy of one or more ocular cranial nerves, including the oculomotor, trochlear, and abducens nerves. Herein, we report a case of RPON with frequent recurrence over a short period, wherein further recurrence was prevented using high-dose riboflavin. The patient was a 6-year-old boy who presented with a 3-day history of headache, right eye pain, vomiting, and right oculomotor nerve palsy. He had a similar episode 3 years earlier, which resolved spontaneously after 1 month. Initial treatment with intravenous methylprednisolone alleviated eye pain, ocular motility disorder, and ptosis, but not the dilated pupil. Despite steroid treatment, the patient experienced frequent relapses triggered by infectious diseases, resulting in side effects such as moon face and weight gain. High-dose riboflavin (200 mg/day) was initiated as prophylaxis after other treatments, including lower doses of riboflavin and sodium valproate, failed to prevent relapses. The patient remained relapse-free for 9 months after increasing the riboflavin dose. Although it remains unclear whether high-dose riboflavin alone or in combination with valproic acid was effective, this case suggests that high-dose riboflavin might be an effective prophylactic treatment for RPON.

Introduction

Recurrent painful ophthalmoplegic neuropathy (RPON), formerly known as ophthalmoplegic migraine, is a recurrent unilateral headache associated with ipsilateral ophthalmoplegia due to palsy of one or more ocular cranial nerves, including the oculomotor, trochlear, and abducens nerves.¹ Most cases of ophthalmoplegia are caused by oculomotor nerve palsy.² The pathophysiology of RPON is not well understood, and several etiologic mechanisms, including migraine pathogenesis, neuropathy pathogenesis, or tumor pathogenesis, are thought to be involved.³ Although RPON is considered to have a good prognosis and self-resolving nature, some cases are difficult to treat with permanent deficits after multiple attacks.⁴ We report a case of RPON with frequent recurrence over a short period, which was successfully treated with high-dose riboflavin.

Case report

A 6-year-old boy presented with a 3-day history of headache, right eye pain, and vomiting. On initial examination, ptosis of the right eye was noted (Figure 1a). The pupil diameters were 5 mm and 3 mm in the right and left eyes, respectively, and the light reflex of the right eye was sluggish. The movement of the right eye was impaired, with an inability to adduct, infraduct, or supraduct (Figure 1b). Neurological examination revealed no abnormalities in the other cranial nerves or muscle weakness. The patellar and Achilles reflexes were normal, and the Babinski reflex was negative. Laboratory tests showed elevated C-reactive protein levels (0.05 mg/dL, <0.14 mg/dL; normal). Anti-acetylcholine receptor antibody, anti-GQ1b antibody, angiotensin-converting enzyme, lysozyme, and thyroid function tests were all within normal limits. The test for herpes simplex virus antibodies was negative. The IgG index was within the normal range, and oligoclonal bands were negative in the cerebrospinal fluid. The tensilon test result was negative. Gadolinium-enhanced magnetic resonance imaging and magnetic resonance angiography of the head and orbit revealed swelling of the nasal mucosa in the right maxillary sinus, consistent with right sinusitis. No other abnormalities were observed in the head, including the midbrain, subarachnoid space, cavernous sinus, and superior orbital fissure, or orbit (Figure 1c). These findings ruled out tumors, posterior commissural aneurysms, Tolosa-Hunt syndrome, cavernous sinus syndrome, cavernous sinus thrombosis, and carotid-cavernous fistulas as potential causes of oculomotor nerve palsy.

Figure 1.

Ocular findings and magnetic resonance imaging at initial presentation.

External photographs showing right upper eyelid ptosis (a) and limited supraduction, adduction, and infraduction of the right eye (b). (c) Magnetic resonance imaging of the orbit.

The patient also had a history of right oculomotor nerve palsy at 3 years of age, including ptosis, adduction disturbance, and a dilated pupil of the right eye 2 days after fever and vomiting, which spontaneously resolved after a month. Based on two recurrent episodes of unilateral headache and ipsilateral oculomotor nerve palsy, the absence of orbital and intracranial lesions, and the exclusion of other causes, his condition was diagnosed as RPON according to the ICHD-3 diagnostic criteria.¹ Intravenous methylprednisolone therapy (IVMP; 500 mg/day for three consecutive days) was initiated on the same day. The headache and eye pain disappeared on the first day after IVMP. As the symptoms of oculomotor nerve palsy did not improve, three courses of IVMP were administered. Subsequently, the ocular motility disorder and ptosis gradually improved, but the dilated pupil did not.

One month after the initial visit, the patient developed a headache and ocular pain. As there was no ocular motility disorder or ptosis, IVMP was not performed, and oral prednisolone (1 mg/kg/day) was initiated. After the initiation of oral steroids, the patient’s headache and ocular pain improved, and prednisolone was tapered. Thereafter, headaches and ocular pain with symptoms of oculomotor nerve palsy, such as ptosis, occurred frequently (Figure 2). Relapse was triggered by infectious diseases such as the common cold, COVID-19, or gastroenteritis. Symptoms improved with systemic steroid administration each time they occurred. However, moon face and weight gain developed owing to the use of steroids. Therefore, 8 months after the initial presentation, 20 mg/day of oral vitamin B2 (riboflavin) was administered as prophylaxis.⁵ Three months after riboflavin treatment, RPON with oculomotor nerve palsy was observed, and two courses of IVMP were administered. The patient was started on oral sodium valproate (200 mg/day), which is reported to be effective for migraine⁵ and RPON^6,7 prophylaxis. Despite a gradual increase in the oral dose of valproate to the maximum dose (750 mg/day), RPON recurred. One year and 5 months after the initial visit, the riboflavin dose was increased to 200 mg/day, and no recurrence of RPON was observed for the next 9 months. Although yellowing of the urine, frequent urination, and diarrhea are known side effects of riboflavin,⁸ none were observed in this case. Additionally, there were no complaints of gastrointestinal discomfort or elevated liver enzymes on blood tests.

Figure 2.

Clinical course and treatment.

Discussion

In this report, we describe a rare case of RPON with nine episodes in 1 year and 5 months, in which no relapse occurred after starting high-dose vitamin B2 supplementation. RPON is a rare, heterogeneous disease with various clinical manifestations. There may be multiple underlying mechanisms, including migraine, neuropathy, and tumor pathogenesis, but there is no consensus on its etiology.^3,9 Although RPON is considered to have a good prognosis with spontaneous resolution, permanent deficits, such as persistent mydriasis in this case, have been reported in patients with RPON with multiple attacks. In a meta-analysis, Gelfand et al. reported permanent deficits, including tropias, ptosis, and persistent mydriasis, in 54% of patients with RPON.⁴ Therefore, in addition to treatment during acute attacks, prophylactic treatment is important for preventing frequent recurrences. No randomized controlled trials of therapeutic agents for RPON have been conducted; therefore, no standard treatment has been established. Migraine prophylactics, such as calcium channel blockers and β blockers may prevent attacks,¹⁰ but this remains controversial. In the present case, valproic acid and vitamin B2 supplementation, recommended for the treatment of migraine,^5,11 was administered to prevent RPON attacks. Due to concerns about potential adverse effects such as bradycardia and blood pressure changes, calcium channel blockers and β blockers were not used. Although low-dose vitamin B2 supplementation and valproic acid did not suppress the attacks, high-dose vitamin B2 supplementation did. However, it is not clear whether high-dose vitamin B2 alone or in combination with valproic acid is effective. To our knowledge, this is the first report describing the effects of high-dose vitamin B2 supplementation in a patient with RPON.

Although the mechanism of action of riboflavin in preventing RPON has not been clearly elucidated, several potential actions may be involved. Previous studies have demonstrated the role of mitochondrial dysfunction in the pathophysiology of migraine,¹² and riboflavin plays a crucial role in the production of adenosine triphosphate, a coenzyme precursor required for the redox reactions during mitochondrial energy production.¹³ Riboflavin also reportedly exerts neuroprotective effects against oxidative stress, neuroinflammation, and glutamine excitotoxicity through various mechanisms.^12,14

The pupil is regulated by parasympathetic fibers in the outer layer of the oculomotor nerve. Therefore, mydriasis in patients with RPON suggests that the inflammation affects not only the motor innervations within the oculomotor nerve but also the parasympathetic fibers outside it. To our knowledge, the etiology and mechanism of residual mydriasis after RPON have not been fully clarified, and further studies are needed to elucidate this mechanism. Various inflammatory mediators, such as calcitonin gene-related peptide, serotonin, histamine, and nitric oxide, are secreted during migraine.¹⁵ It is possible that these mediators cause nerve damage, leading to symptoms, although the damage may become irreversible if vulnerable parts of the nerve are affected.

In conclusion, high-dose vitamin B2 May hold promise as a prophylactic agent against recurrent RPON attacks. However, this report cannot establish a cause-and-effect relationship, and further research and clinical trials with longer observation are needed to determine its sustained efficacy in larger cohorts.

Funding Statement

No funding was acquired for this study.

Disclosure statement

No potential conflict of interest was reported by the author(s).

Ethical approval

Written informed consent was obtained from the patient’s parents for the publication of this report. The IRB review and approval was waivered according to the Ethical Guideline for Clinical Research issued by the Ministry of Health, Welfare and Labour, Japan.