The blood-brain barrier breakdown results in vasogenic edema, which promotes the development of RPON. Neuropeptides-induced
Alternatively, it is proposed that migraine-related release of neuropeptides from trigeminal nerve fibers terminating on the circle of Willis might be the cause. Some of the neuropeptides released are potentially toxic, and may induce blood-brain barrier breakdown that accounts for ophthalmoplegia. Neuropathic mechanism
Additional models have been proposed to explain the cause of RPON. The thickened and enhanced symptomatic nerve, as shown in recent MRI findings, might be indicative of the existence of structural nerve damage in RPON. Therefore, neuropathy is suggested as the primary cause of RPON, either induced by recurrent viral infections or immune-mediated inflammation. However, cerebrospinal fluid (CSF) analyses are normal in the vast majority of RPON cases, which is inconsistent with the findings of autoimmune or inflammatory-mediated pathomechanism. Nevertheless, several neuropathic mechanisms have been proposed. Benign viral infection
The enhancement and thickening of the oculomotor nerve can occur in a variety of infectious inflammatory conditions. However, spontaneous resolution is unlikely to occur in viral infection, except for benign viral infection that usually causes mild or no symptoms in humans. Therefore, benign viral infection could be an explanation for the development of RPON. Immune-mediated inflammation
Recent MRI findings have led to the current understanding of RPON as an inflammation-induced neuropathy. Recurrent demyelinating neuropathy is proposed as a pathophysiological pathway because similar MRI findings have been observed in both RPON and chronic inflammatory demyelinating neuropathy.
Inflammatory demyelination of the ocular cranial nerves would likely lead to the release of neuropeptides, such as calcitonin gene-related peptide, to the trigeminovascular system. This would irritate the trigeminal sensory fibers, and consequently, a headache as manifested in RPON is triggered. Diagnosis
Diagnostic criteria
To be diagnosed with RPON, a person must have a minimum of 2 unilateral headache attacks with ipsilateral ocular cranial nerve paralysis that cannot be explained by other causes of headache in ICHD-3 after investigation. Diagnostic tests
RPON is a diagnosis of exclusion, meaning that other conditions with similar clinical presentation, such as vascular, inflammatory, neoplastic, and infectious causes, must be ruled out before the confirmation of RPON diagnosis. Physical examination, neuroimaging, and laboratory tests are routinely conducted in clinical practice to evaluate this disease. Physical examination
After obtaining the medical history of people with suspected RPON, thorough eye examination and neurological examination are usually performed to assess the extent of neurological impairment, localize the brain regions being affected, and rule out other possible causes for the symptoms. These involve the assessments of visual acuity, eye movements and alignment, pupillary responses, and mental status. Neuroimaging
Contrast-enhanced magnetic resonance imaging (MRI) is a diagnostic tool that can facilitate the differentiation of RPON from other diseases. The transient, reversible enhancement or thickening of the ocular motor nerve(s), which can be observed in the MRI scans of a small proportion of affected individuals during acute attacks, is a distinguishing feature of RPON.