A diagnosis of RPON is always challeging, especially under 24 months of age. In fact, children are not able to describe headache and the first symptom is often irritability. Our case is highly suggestive of RPON but a definite diagnosis was not possible at the first attack(9).
Third nerve thickening and post-contrast enhancement are suggestive of oculomotor nerve schwannoma, carcinomatosis, granulomatosis, inflammatory or infectious neuritis(10). The case presented was from the beginning highly suggestive for RPON but MRI findings still have no relevance in the diagnostic criteria. Our case reported represents a diagnostic controversial: all symptoms and neuroradiological lesions were highly suggestive but no diagnostic possibilities were admitted during the first attack. In 1997 Wong and Wong(11) suggested to include these MRI findings associated to a single reversible episode of ophthalmoplegia as a supportive diagnostic criteria of RPON. Notwithstanding, neuroradiological imaging during the first episode have only suggested a probable and not a definitive diagnosis so far. It is important to highlight that in our case CT was positive, unlikely Ambrosetto et al.(2) reviewed, showing that CT is normally negative. We systemically reviewed in Pubmed all cases of RPON occurred within 24 months of age and we compared it with our patient. PubMed was searched for all cases of RPON using the search terms “ophthalmoplegic migraine OR recurrent painful ophthalmoplegic neuropathy”. Only articles in English or Spanish have been filtered. We performed the PRISMA (Preferred Reporting Items for Systematic Reviews and Meta-Analyses) statement (figure 5). Inclusion criteria were age (up to 24 months), presence of MRI findings and diagnosis of RPON, for these reasons, we excluded 208 records from database searching. Two reviewers independently agreed on selection of eligible studies and achieved consensus on which studies to include. The methodological quality of this systematic review has been assessed using the AMSTAR 2(12) tool as a “low quality review”, since no randomized controlled trials (RCTs) are available to date on the scientific literature.
We abstracted the following information: age at onset and current age; sex; cranial nerve (CN) involved (side); headache (side); associated symptoms: photophobia, phonophobia, nausea, vomiting, irritability, other findings; ocular findings: ocular symptoms/signs, diplopia, ophthalmoplegia, palpebral ptosis, pupillary dilation; MRI findings in the acute phase: nerve thickening, post-contrast enhancement; altered cerebrospinal fluid (CSF) if lumbar puncture performed; headache duration; ophthalmoplegia duration; interval between headache onset and ophthalmoplegia; time to resolution of symptoms/signs; therapy in the acute phase; follow-up; prophylactic therapy; control MRI, number of acute episodes; interval between episodes; comorbidity; family history of migraine. The median age at the first attack was 14,3 months. 69,2% of patients were females and 30,8% males. The cranial nerve involved was always the third one, except for two patients where it was not mentioned(13). headache was the most frequent symptom, followed by nausea and vomiting. One third of patients presented associated symptoms such as photophobia, phonophobia and irritability. Ocular symptoms/signs were always present: ophthalmoplegia and palpebral ptosis were the most frequent ones, followed by diplopia. Unlikely reported by Huang(3), we found some patient who presented pupillary dilation. It is interesting to highlight the MRI findings: it had been showed a nerve thickening in 61,5% of cases and a post-contrast enhancement in 53,8% of patients. In cases where MRI was negative, it is important to understand whether the imaging was really negative or the timing was wrong. In fact, in some patients there is no evidence of MRI abnormalities neither during the interictal phase nor during the first attack and it could only be found after attacks(14). Therapy in acute phase had been administered in 70% of patients using corticosteroids. In 50% of cases, at follow-up examination was noted a periodic recurrence of migraine with or without ophthalmoplegia. A limited number of patients (20%) had permanent neurological damage. Control MRI had been performed in 50% of cases. It showed in a limited number of patients (20%) normal findings and in the majority of them (80%) a persistent enlargement but to a lesser degree. Notably that family history of migraine was positive in 46,1% of patients and in most cases was on the mother side. We compared the characteristics of our patient with the ones of the review (MRI findings in the acute phase, symptoms and its duration and response to therapy). For the aforementioned reasons, we strongly supported from the first attack that this case was highly suggestive of RPON. We highlight that the first diagnostic hypothesis were aneurysm and schwannoma. Our work let us to extend the knowledge about RPON, suggesting to think at this diagnosis at its very first attack, even in presence of initial MRI findings referable to vascular anomaly or tumors as schwannoma. A relationship between RPON and schwannoma has been often discussed. In 2019 Petruzzelli et al.(15) reported a patient affected by RPON who developed, after years, a schwannoma of the third cranial nerve. They proposed two explanations of the aforementioned correlation. According to the first one, tumor could intermittently release chemical substances which stimulate trigeminal nerve receptors, leading to the headache. In this case, schwannoma would mimics RPON and it would be an initial manifestation of the tumor, which would be too small to be found in MRI. The second hypothesis, instead, considers RPON as an inflammatory cranial neuralgia and not a migraine. In this case, episodes of inflammation lead to demyelination and remyelination. Schwann cells proliferation could lead to the transformation into schwannoma. As a result, isolated oculomotor schwannoma could be considered as a long-term complication of RPON. Both hypothesis suggest the importance of serial brain MRIs in the long-term follow-up of RPON. In conclusion, our case, compared to the reviewed literature, a diagnosis of RPON was highly suggestive even at the first attack. Our work highlights the importance to consider RPON in presence of MRI findings and clinical symptoms referable to aneurysm or schwannoma. This review defines the characteristics of MRI findings at the first RPON attack occurred under 2 years of age. Although two attacks are necessary, it strongly suggests to consider RPON even at the first attack, in presence of described characteristics. Thus, as mentioned by Wong(11) and Yinglu(14), we suggest to add into the diagnostic criteria the MRI findings, including enhancement and thickening of the nerve involved. We analyzed the relationship between RPON and schwannoma. As proposed by Petruzzelli et al.(15), we are performing a long-term follow-up at our institute in order to prevent any complications.