A Case of Recurrent Painful Ophthalmoplegic Neuropathy Successfully Treated with Beta-blocker Eye Drop Instillation

ABSTRACT

Recurrent painful ophthalmoplegic neuropathy (RPON) is a rare disorder, which typically occurs in children, and causes headaches and unilateral oculomotor palsy. Early high-dose corticosteroid therapy is recommended to rapidly resolve acute episodes. However, the pathophysiology and therapeutic options for this disorder remain to be fully elucidated. We report a case with typical clinical features of RPON successfully treated with beta-blocker eye drop instillation after the effects of high-dose corticosteroid and other therapies were not sufficient. We propose that beta-blocker eye drop instillation should be considered for patients with corticosteroid-resistant RPON.

Introduction

Recurrent painful ophthalmoplegic neuropathy (RPON) is rare disorder, previously known as ophthalmoplegic migraine, with an incidence of approximately 0.7 per million.¹ This disorder typically occurs in children and has a female predominance.² RPON causes unilateral oculomotor palsy preceded by headache. Its symptoms tend to remit spontaneously, but recurrent attack episodes may result in permanent neurological sequelae.^3–5 Mydriasis commonly develops.² T1-weighted magnetic resonance imaging (MRI) with gadolinium contrast uniquely shows thickening and enhancement of the cisternal part of the oculomotor nerve in patients with RPON.^6,7 Early high-dose corticosteroid therapy is recommended to rapidly resolve acute episodes^8;−10 however, not all patients respond to this therapy.^11–13 Other orally administered drug therapies (non-steroidal anti-inflammatory drugs, paracetamol [acetaminophen], ergotamine, gabapentin, sodium valproate, triptans, pregabalin, or antihistaminic drug) are sometimes used empirically.^13–15 However, it is difficult to verify their effects adequately because of RPON rarity.

Here, we present a case of RPON with typical clinical features in a patient successfully treated with beta-blocker eye drop instillation after the effects of high-dose corticosteroid and other therapies were not sufficient. The present understanding of RPON aetiology is that it is due to a relapsing-remitting inflammatory or demyelinating process. However, the link to migraine remains controversial.¹⁶ We believe that the present case will help to clarifying the pathophysiology of RPON.

Case report

A 14-year-old Japanese girl had left frontal headaches and vomiting, followed by drooping of her left eyelid and double vision. She had previously experienced a similar episode triggered by tympanitis at the age of 2 years. Her history included migraine and her mother also suffered from long-standing migraine. On our clinical examination, her vital signs and physical findings were normal (except for the ptosis and ocular motility disorder). Visual acuity was normal in both of her eyes. She had an oculomotor nerve palsy with ptosis of the left eye. Her external ocular movement findings are shown in Figure 1. Her pupil sizes were 3.5 mm on the right and 4.5 mm on the left. The left eye had weak direct and indirect pupillary reflexes. An edrophonium chloride test was negative.

Figure 1.

Nine diagnostic positions of gaze before the first visit. There was an extraocular movement disorder that resulted from oculomotor nerve palsy with ptosis of the left eye

Laboratory analyses including thyroid hormone levels were generally non-specific. Her angiotensin-converting enzyme (ACE) was at a normal level and varicella zoster virus antibody (IgG) was positive (its IgM was negative). Her antinuclear antibody titre was 80 times normal. Her anti-acetylcholine receptor antibody titre was negative. A cerebrospinal test revealed three mononuclear cells/µL, a protein level of 38 mg/dL, and a glucose level of 59 mg/dL.

T2-weighted MRI revealed focal thickening of the left oculomotor nerve at its exit from the brainstem. T1-weighted contrast-enhanced MRI with gadolinium revealed enhancement of this portion of the nerve. These MRI findings are shown in Figure 2. No other abnormal MRI findings were observed and the magnetic resonance angiography findings were normal.

Figure 2.

T2-weighted axial magnetic resonance imaging showing a 3 mm diameter focal thickening of the left oculomotor nerve at its exit from the brainstem (white arrow, a), which was prominently enhanced on contrast-enhanced T1-weighted images (white arrow, b), with normal magnetic resonance angiography (c)

The patient was diagnosed with recurrent painful ophthalmoplegic neuropathy (RPON) and was treated with 13.2 mg dexamethasone (Decadron) intravenously for 12 days. Administration of oral paracetamol and rizatriptan benzoate was also started. Her headache and ptosis improved somewhat, and then her therapy was tapered to oral dexamethasone and indometacin. However, over 1 month later she was still suffering from moderate ptosis and double vision due to an untreated paralytic exotropia. She also had corticosteroid-induced ocular hypertension (interocular pressures of both eyes were 22 mmHg), so she was treated with 0.5% timolol maleate extended release eye drop instillation once daily to both eyes with the expectation for improvement of her ocular hypertension. Just a few days later, she realised her double vision was significantly improved, and her ptosis and ocular motility disorder had resolved completely on examination. This finding is shown in Figure 3. Her pupil size became 3.5 mm on the right and 4.0 mm on the left. Follow-up MRI with gadolinium 6 months later showed resolution of the enhancement. No recurrence was observed in over 12 months of follow up.

Figure 3.

Nine diagnostic positions of gaze after timolol eye drop treatment. Extraocular movements have become normal

Discussion

Generally, beta-blocker eye drops are used to treat ocular hypertension or glaucoma. Ishikawa et al. reported a 4-year-old girl with ophthalmoplegic migraine with recurrent oculomotor nerve palsy.¹⁷ Her migrainous attack frequency and severity were remarkably reduced by using topical administration of 0.25% timolol maleate twice daily to both eyes. They considered that the plasma timolol concentration rise resulted in central serotonin receptor block and cerebral artery spasm suppression as with oral administration of beta-blockers as a migraine medication. In our presented corticosteroid-resistant case, the symptom also significantly improved soon after topical administration of a beta-blocker.

Notta reported the first clinical description of ophthalmoplegic migraine in 1854.¹⁸ Walsh and Hoyt suggested that it was caused by a nerve root problem according to symptomatological reasoning in 1969.¹⁹ Its specific MRI findings were reported subsequently.^6,7 Hypotheses of microvascular ischaemia, vascular compression, or tumour have been proposed as its cause. However, these cannot fully explain the recurrences of oculomotor nerve palsy preceded by headaches. Currently, an inflammatory or demyelinating neuropathy is generally accepted as the causative mechanism. Lance and Zagami advocated an inflammatory process where the oculomotor nerve inflammation irritates the ophthalmic division of the trigeminal sensory fibres and activates the trigeminovascular system, resulting in migrainous headache.²⁰ By contrast, Carlow proposed that the ophthalmic division of the trigeminal nerve is triggered to release a neuropeptide cascade in intracranial sites at the onset of migraine.²¹ This creates a sterile inflammatory vascular response in the circle of Willis and other adjacent arteries. The blood–brain barrier is relatively porous at the nerve root junction.²² Therefore, neuropeptides may stimulate the oculomotor nerve. Repeated demyelination and remyelination causes a unique onion bulb proliferation of Schwann cells. According to this theory, migraine is regarded as the primary aetiology of RPON. Although oral beta-blockers, including timolol, are already approved as a migraine preventive,²³ beta-blockers taken orally are not necessarily effective in treating acute migraine attacks. Recently, the benefits of topical application of timolol eyedrops in patients suffering acute migraine were reported.^24,25 Timolol eyedrops may provide a rapid route of delivery, with the maximum plasma concentration achieved within 15 min of administration.^26,27 Therefore, to treat acute migraine, topical administration of timolol eyedrops might have a pharmacokinetic advantage over oral administration. In our patient with RPON, topical administration of the beta-blocker was effective against not only headache but also oculomotor palsy, although generally a beta-blocker does not have a direct anti-inflammatory effect. Therefore, we adopt Carlow’s hypothesis, and deduce that a local plasma timolol concentration increase induced by tropical timolol administration may effect a neuropeptide-mediated suppression of the trigeminovascular system estimated primary lesion.

In summary, we report a case with typical clinical features of RPON successfully treated with beta-blocker eye drop instillation after effects of high-dose corticosteroid and other general therapy were insufficient. We propose that beta-blocker eye drop instillation should be considered for patients with RPON resistant to corticosteroids.

Patient consent

The patient described in this case report and her guardian consented in written form to publication of all data and images related to the case.

Declaration of interest statement

The authors declare that there are no conflicts of interest.