Migraine is a type of vascular headache, a paroxysmal headache disorder caused by dilation of branches of the external carotid artery. It is characterized by recurrent throbbing headaches, broadly divided into those with and without aura. Scintillating scotoma is a typical visual aura preceding migraine, classically described as zigzag patterns of light caused by vasospasm leading to transient ischemia of the visual cortex in the occipital lobe. Currently, cortical spreading depression (CSD) is understood as the main mechanism (see §6).
It lasts 4 to 72 hours, accompanied by nausea, photophobia, phonophobia, and visual aura. It is classified as episodic (less than 15 days per month) and chronic (15 or more days per month for more than 3 months).
The subtypes of migraine according to the International Classification of Headache Disorders, 3rd edition (ICHD-3) are shown below.
Recurrent Painful Ophthalmoplegic Neuropathy (RPON), formerly known as “ophthalmoplegic migraine,” was renamed in ICHD-3. The reason for the renaming is that it is more characteristic of a demyelinating inflammatory neuropathy than migraine.
It is a rare disorder characterized by recurrent attacks of headache and ipsilateral ophthalmoplegia, with an incidence of 0.7 per million people. It primarily occurs in children under 10 years of age, with a median age of onset reported as 8 years. Adult onset is also recognized; in a pooled analysis of 165 cases, the mean age of onset was 22.1 years, and 34.2% of cases occurred at age 18 or older 6). The oculomotor nerve (III) is most commonly affected, followed by the abducens nerve (VI) and trochlear nerve (IV).
Cortical spreading depression (CSD) and involvement of the trigeminovascular system are the main causes. CSD is a wave of neuronal depolarization that begins in the visual cortex of the occipital lobe, causing scintillating scotoma. Additionally, activation of the trigeminovascular system releases inflammatory substances such as CGRP and substance P, leading to vasodilation and neurogenic inflammation, which cause photophobia and headache.
The main differences are in the nature of the visual symptoms, laterality, and duration. Scintillating scotoma is a positive symptom (zigzag lights) that is binocular and lasts 20–30 minutes (up to 60 minutes). Transient monocular blindness is a negative symptom (darkening or graying) that is monocular and resolves quickly within 1–5 minutes (up to 10 minutes). Transient monocular blindness may be caused by embolism of the carotid or ophthalmic artery and should not be overlooked.
Clinical findings by subtype presenting with ocular signs are shown below.
Retinal Migraine
Monocular vision loss: Reversible monocular visual impairment or loss.
Scotoma: C-shaped, colored, scintillating, expanding scotoma. Diagnosis requires at least 2 episodes.
Exclude TMVL: Always differentiate from serious causes (arteritis, embolism).
Hemiplegic Migraine
Motor weakness: Unilateral reversible motor paralysis occurs as an aura.
Various auras: Accompanied by visual, sensory, and language symptoms. Each symptom lasts 5 to 60 minutes.
ICHD-3 criteria: Develops over ≥5 minutes, with headache occurring with the aura or within 60 minutes2).
RPON (Ophthalmoplegic Neuropathy)
Third cranial nerve palsy: Oculomotor nerve most commonly affected (in children). Ptosis, eye movement disorder, mydriasis.
MRI findings: Localized contrast enhancement and thickening of the oculomotor nerve in the acute phase. A literature review of 52 cases reported MRI third nerve enhancement in 75% and nerve swelling in 76%6).
Recurrence: Two or more attacks are required for a definitive diagnosis. In some cases, recovery becomes incomplete with repeated attacks9).
Basilar-type migraine
Brainstem symptoms: accompanied by dizziness, dysarthria, ataxia, tinnitus, and hearing loss.
Diplopia: may be accompanied by bilateral sensory abnormalities or altered consciousness as a typical aura.
Syncope: transient loss of consciousness may occur in severe cases.
There is a time lag from headache onset to the appearance of ophthalmoplegia, ranging from immediately to up to 14 days. Ophthalmoplegia usually resolves spontaneously within 2 weeks to 3 months, but incomplete recovery may occur after recurrent attacks. In cases with long-term recurrence, 54% develop persistent ocular motor palsy 9).
Oculomotor Nerve (III)
Ptosis: Drooping due to paralysis of the levator palpebrae superioris muscle.
Restricted eye movement: Limitation of adduction, elevation, and depression.
Mydriasis and decreased light reflex: Pupillary fibers are often involved. However, in a review of 39 cases by McMillan et al., the pupil was spared in 23%.
Abducens Nerve (VI)
Abducens palsy: Esotropia due to limited abduction.
In adults, this is the cranial nerve most commonly affected in RPON.
Trochlear Nerve (IV)
Limitation of depression and intorsion: Vertical diplopia is the main complaint.
Compensatory head tilt to the opposite side is observed. Relatively rare involvement.
In typical migraine, ophthalmic examinations (including visual field tests) are usually normal. During a migraine attack, OCTA (optical coherence tomography angiography) may show a marked decrease in choroidal vascular density and enlargement of the foveal avascular zone (FAZ).
It usually resolves spontaneously within 2 weeks to 3 months, but in some cases recovery becomes incomplete after repeated attacks. In long-standing recurrent cases, persistent ocular motor palsy has been reported in 54% of patients 9). Although it improves spontaneously after onset, the duration may lengthen with each attack and become permanent in some cases.
Food triggers include red wine, beer, chocolate, aged cheese, MSG (monosodium glutamate), and aspartame. Medications that may trigger or worsen migraines include oral contraceptives, estrogen therapy, nasal decongestants, opioids, and SSRIs. Since triggers vary greatly among individuals, self-monitoring with a headache diary is important.
Migraine diagnosis is based on medical history, physical examination, and ICHD-3 criteria. Imaging is not necessary for typical symptoms. Diagnostic tools include ID-Migraine, VARS, MIDAS questionnaire, and MSQ 2.11).
If migraine is suspected, first exclude organic diseases such as cerebrovascular disorders or neoplastic conditions using CT or MRI. Next, prescribe a drug that suppresses vasospasm and confirm the diagnosis by checking whether the attack can be aborted with this medication.
Indications for imaging (brain MRI/CT) are limited to the following cases:
Perform a complete ophthalmic examination (visual acuity, visual field, eye movement, pupillary light reflex, fundus examination, slit-lamp examination). In RPON, MRI shows characteristic findings of localized thickening and contrast enhancement of the cranial nerves 3).
Differentiation can be made by comparing the following three points.
| Item | Scintillating Scotoma | Transient Monocular Vision Loss |
|---|---|---|
| Nature of visual symptoms | Positive (zigzag lights) | Negative (darkening/graying) |
| Unilaterality of eye | Binocular, homonymous | Mostly monocular |
| Duration | 20–30 minutes (within 60 minutes) | 1–5 minutes (within 10 minutes) |
The diagnostic criteria for RPON according to the International Classification of Headache Disorders, 3rd edition (ICHD-III) are as follows.
MRI is the most important diagnostic test. Characteristic findings include local contrast enhancement and thickening of the cisternal segment of the oculomotor nerve. In a literature review of 52 cases, MRI showed third nerve enhancement in 75% and nerve swelling in 76% 10). However, MRI may be normal in 25–81% of acute cases. Contrast enhancement usually resolves within 7–9 weeks but may persist for 2–4 years in some cases.
A complete MRI evaluation including TOF-MRA is recommended from the first attack 5). In oculomotor palsy involving pupillary function, MRA is particularly important to exclude posterior cerebral artery (PCA) aneurysm.
It is important to differentiate RPON from diseases with similar symptoms.
| Disease | Key points for differentiation |
|---|---|
| Tolosa-Hunt syndrome (THS) | MRI shows cavernous sinus wall thickening. Dramatic response to steroids. |
| Oculomotor nerve schwannoma | Contrast enhancement persists for 12 weeks or longer (resolves within 12 weeks in RPON) 11) |
| Myasthenia gravis | Diurnal variation and fatigability. Ice pack test and anti-AChR antibodies |
| Posterior communicating artery aneurysm | Oculomotor nerve palsy with mydriasis. Urgent evaluation with MRA/CTA |
| Migraine with aura | Ophthalmoplegia resolves within 72 hours (RPON lasts ≥2 weeks) |
Clinical tests include cerebrospinal fluid analysis (usually normal; to differentiate from malignancy and MS) 5), and blood tests to rule out diabetes, infection, inflammation, and autoimmune diseases.
Yes. In 25–81% of acute cases, MRI findings may be normal 5). In RPON with normal MRI, a strategy of observation with NSAIDs and assessment of response has been reported. However, in recurrent or persistent cases, repeat MRI is essential to exclude other organic lesions.
Treatment for migraine includes preventive medications, drugs used during the aura phase, and medications for acute attacks, which are used appropriately.
For mild attacks, NSAIDs, dihydroergotamine mesylate, and oral triptans are effective. For severe attacks, oral triptans are used.
When aura occurs, dihydroergotamine mesylate should be used early. Since administration in the early stage of a migraine attack enhances efficacy, prompt administration upon sensing aura is important.
Hemiplegic migraine 2):
No standardized treatment guidelines exist. For acute attacks, NSAIDs and non-narcotic analgesics are used. For prevention, beta-blockers, calcium channel blockers, tricyclic antidepressants, and antiepileptic drugs are used. For frequent attacks, long-acting verapamil or lamotrigine may be used.
Although symptoms improve spontaneously after onset, some attacks become prolonged and permanent, so aggressive anti-inflammatory therapy is recommended.
Corticosteroids are the most common acute treatment. Pooled analysis showed rapid improvement in 96.2% of 76 patients treated with steroids 6). For inflammatory lesions of oculomotor nerve palsy, prednisolone 50–60 mg/day is given for the first 3 days, then tapered carefully to avoid relapse.
The main steroid regimens are shown below.
| Regimen | Dosage and administration | Report |
|---|---|---|
| Methylprednisolone (pediatric) | 25–30 mg/kg/day (max 1 g/day) × 5 days | Frattini 20235), Nandana 20219) |
| Methylprednisolone (adults) | 250 mg 4 times/day for 3 days → prednisone 60 mg tapering | Koo 20246) |
| Dexamethasone (intravenous) | 13.2 mg for 12 days | Takemoto 20218) |
Response to steroids is often not as dramatic as in Tolosa-Hunt syndrome.
For RPON with normal MRI, one option is to observe with NSAIDs (ibuprofen 10 mg/kg/dose, 3 times/day). There are reports of complete recovery within 48 hours with ibuprofen 5).
If frequent recurrences occur, consider the following preventive medications.
Topiramate is widely used as a migraine preventive, but it can cause acute angle closure (TiAAC) around 2 weeks after starting treatment. Ciliochoroidal effusion causes forward movement of the lens-iris diaphragm, leading to a rapid increase in intraocular pressure. If eye pain, vision loss, or blurred vision occur, promptly consult an ophthalmologist and contact the prescribing physician4).
Calcium channel blockers such as flunarizine and verapamil, beta-blockers such as propranolol, and antiepileptic drugs such as valproic acid, gabapentin, and topiramate are used as preventive medications. Since there is a 30% risk of permanent sequelae, it is important to consider active preventive therapy in cases of frequent recurrence 6).
The basic mechanism of migraine is stimulation of the meninges, blood vessels, and trigeminal nerve territory, triggered by dilation of branches of the external carotid artery 1).
Triggers such as stress, food, and hormones → dysregulation of brainstem vascular control → peripheral vasodilation → stretch signals to trigeminal neurons → production of inflammatory and vasoactive substances such as CGRP and interleukins → further dilation and increased vascular permeability → tissue edema forms a cascade 1).
The neurotransmitters involved are substance P, nitric oxide, and CGRP. The periaqueductal gray (PAG), locus coeruleus (LC), and raphe nuclei (DRN) are brain regions implicated in the pathophysiology of migraine.
Classically, it was explained that cerebral vasospasm leads to transient ischemia in the occipital visual cortex, causing scintillating scotoma. Currently, cortical spreading depression (CSD) is widely supported as the main mechanism of visual aura 2).
A wave of neuronal depolarization originating in the occipital region propagates forward. Depolarization increases potassium concentration, and the release of excitatory amino acids further enhances spreading. CSD causing temporary dysfunction of the occipital visual cortex corresponds to the occurrence of scintillating scotoma.
Several hypotheses have been proposed regarding the pathogenesis of RPON, and debate continues.
Demyelination/Inflammation Theory (Mainstream)
Lance & Zagami: Recurrent demyelinating neuropathy/neuritis theory. MRI oculomotor nerve enhancement is cited as evidence.
Carlow hypothesis: A neuropeptide cascade from the ophthalmic branch of the trigeminal nerve induces aseptic inflammatory vascular reaction in the circle of Willis. Repeated demyelination and remyelination lead to onion bulb proliferation of Schwann cells8).
Ischemia Theory
Ambrosetto et al.: Vasospasm of vasa nervorum during migraine → reversible ischemic disruption of the blood-nerve barrier → vasogenic edema (explains MRI enhancement and thickening).
Vijayan et al.: ICA wall edema → occlusion of small vessel openings → watershed infarction-type injury. Shin et al.’s SPECT study confirmed reversible ipsilateral ischemia in the PCA perforator territory.
Neurovascular compression theory
Bui et al. reported a case of a 13-year-old boy in whom MRA confirmed compression of the oculomotor nerve exit zone by a sharp loop of the left posterior cerebral artery (PCA)10).
Arguments against the compression theory: (1) pupillary sparing in 23% of cases, (2) no vascular stenosis demonstrated on carotid angiography during attacks, and (3) recovery from RPON is slower than after decompression.
Among these hypotheses, the demyelination/inflammation theory is currently mainstream. Similarities to the relapsing-remitting patterns of CIDP, MS, and MOGAD have been noted, but CSF studies are usually normal, and direct evidence of viral infection or immune-mediated neuropathy has not been obtained.
During spontaneous migraine attacks, OCTA shows a marked decrease in choroidal vascular density and enlargement of the FAZ. These findings suggest that choroidal circulation is more vulnerable than retinal circulation during attacks.
Three genes are known to be associated with familial hemiplegic migraine: CACNA1A (calcium channel), ATP1A2 (Na/K pump), and SCN1A (sodium channel)2). Mutations in the TREK gene (two-pore potassium channel) are involved in impaired regulation of resting membrane potential and neuronal hyperexcitability1).
Fremanezumab, erenumab, and galcanezumab are FDA-approved preventive medications for chronic migraine 1).
A meta-analysis of anti-CGRP mAbs showed a significant improvement in the 50% responder rate, with reductions in monthly migraine days and acute medication use. There is broad agreement that their benefit-risk profile is superior to propranolol and topiramate 1).
Galcanezumab, with a regimen of a 240 mg subcutaneous loading dose followed by 120 mg monthly for 5 months, improved headache severity, frequency, and duration. Injection site itching and rash have been reported as main side effects 1).
Ubrogepant was FDA-approved in 2019 as an oral acute treatment. It can be used with or without aura 1). Atogepant is being developed as an oral preventive medication.
Tonabersat is a novel benzopyran molecule that inhibits glial-neuronal gap junction communication and suppresses CSD. A 39-patient RCT (Goadsby et al. 2009) showed efficacy in preventing migraine with aura, but it is currently not FDA-approved 1).
Mutations in two-pore potassium channels (TREK) cause impaired regulation of resting membrane potential, leading to neuronal hyperexcitability. Therapeutic research targeting TREK activation/inhibition is ongoing 1).
Takemoto et al. (2021) reported a 14-year-old girl with steroid-induced intraocular pressure elevation whose diplopia markedly improved within days and ptosis and ocular movement disorder completely resolved after administration of 0.5% timolol maleate eye drops 8). It is speculated that topical timolol may have exerted an effect on RPON through neuropeptide-mediated inhibition of the trigeminal vascular system. Beta-blocker eye drops may be effective even without elevated intraocular pressure, and further exploratory studies are expected.
Koo et al. (2024) proposed revised diagnostic criteria based on Liu et al.’s pooled analysis: “at least two unilateral headache attacks (almost simultaneous with or up to 15 days before ophthalmoplegia)” plus “clinical findings of cranial nerve palsy or MRI enhancement” 6). Discussions continue to include adult-onset and atypical cases.
Castillo-Guerrero et al. (2024) reported a case of internal ophthalmoplegic migraine during pregnancy (bilateral mydriasis without external ophthalmoplegia) 7). Spontaneous remission on the fifth postpartum day was confirmed, suggesting that hormonal and physiological changes may be involved in the onset.
An association with anti-GQ1b antibody syndrome has been reported, and in recurrent cases that respond rapidly to steroids, testing for atypical anti-GQ1b antibody syndrome is recommended 5). Additionally, evaluation of neurovascular compression using high-resolution MRA is becoming increasingly important in the diagnosis of pediatric RPON, and compression of the oculomotor nerve exit by the PCA has been confirmed in some cases 10).
