THS and RPON in children are rare causes of painful ophthalmoplegia. At onset, a correct diagnosis is challenging since the differential diagnosis include neoplasm (e.g. schwannomas), aneurysm, carotid dissection, temporal arteritis, sarcoidosis, and infectious etiologies.

As confirmed by a recent review, 12 cases of THS were reported in the past 10 years [5, 7], while RPON seems to be more common in the paediatric age, even if this diagnosis should be confirmed after an adequate follow-up period [8]. We compared our patients’ characteristics with previously described patients, with respect to MRI findings in the acute phase, response to therapy, symptoms and duration.

In clinical practice, brain MRI with or without intravenous administration of paramagnetic fluid is routinely performed in the acute phase, but sometimes there is a time delay from the onset and TOF angiography is not included [5]. In both our patients, brain MRI was performed within 72 h from the onset and the presence of abnormal blood vessel thickening of the cavernous sinus led to prompt THS diagnosis.

In paediatric patients with THS, the main site of involvement is the cavernous sinus [9]. Granulomatous inflammation, even affecting the superior orbital fissure or the orbit could be detected only by angiographic methods or biopsy. On the other hand, in almost 60% of RPON cases in patients younger than18 years of age, brain MRI reveals asymmetric thickening or gadolinium enhancement of the cisternal segment of the affected cranial nerve [9, 10].

In RPON a second attack with unilateral headache and ipsilateral paresis is needed to confirm the diagnosis, but negative brain MRI with TOF angiography easily excludes orbital, parasellar or posterior fossa lesions, avoiding inadequate therapy. In our cases, we considered RPON since the beginning due to spontaneous resolution and negative brain MRI, even if the diagnosis was confirmed thanks to the recurrence of additional attacks during follow-up. Moreover, follow-up can be required not only to confirm a diagnosis of RPON, but even in the case of misdiagnosed nerve schwannomas [11].

According to ICHD criteria, in cases with negative brain MRI or cranial nerve thickening and gadolinium enhancement, the diagnosis of RPON could only be suspected and not confirmed before a second episode, whereas a diagnosis of THS could be made since the first attack.

Some controversies arise regarding which cases should be eligible for steroid therapy, and when [5].

Steroid therapy, although effective and recognized as the first-line therapy in THS, should be introduced after extensive investigations confirming granulomatous inflammation or cranial nerve swelling. It was successful in all reported paediatric cases of THS, except for one with ophthalmoplegia and granulomatous inflammation of the cavernous sinus, but without pain and spontaneous resolution [6, 12]. Conversely, more than half of the cases (both adults and younger) with RPON completely recovered within 72 h without specific treatment [9].

In case of negative brain MRI with good response to NSAID therapy, it would be preferable to adopt a waiting conduct, with a timeline depending on clinical features and a cut-off of 72 h from the onset [8]. On the other hand, corticosteroids could be useful in the acute case of RPON when nerve inflammation is documented [5, 9]. As performed in our patients, lumbar puncture with cytological CSF examination is mandatory even in case of a negative brain MRI, in order to exclude hematologic neoplastic diseases primarily affecting the central nervous system. A lumbar puncture should be possibly performed within 48 h from symptoms onset and before steroid treatment.

In relapsing cases with prompt resolution after steroids therapy, an inflammatory mechanism with cranial nerve neuritis should be always investigated, with particular attention to atypical presentation of anti-GQ1b antibody syndrome [13, 14]. In cases of confirmed THS or suspected RPON, without spontaneous resolution, we propose the treatment strategy previously adopted in our units for neuroimmune disorders: 25 mg/kg/day (or 1 g/day, for patients over 40 kg) iv methyl-prednisolone for 5 days, followed by oral deflazacort 0.9 mg/kg/day for 1–3 months depending on the clinical and neuroradiological evolution [15]. Our diagnostic and therapeutic algorithm (Fig. 2) can support clinical diagnosis and correct treatment of unilateral periorbital headache associated with third-fourth or sixth cranial nerve paresis in children.

Diagnostic and therapeutic algorithm. MRI: Magnetic Resonance Imaging; CT: Computer Tomography; CSF: cerebrospinal fluid; NSAID: non-steroidal anti-inflammatory drugs; RPON: recurrent painful ophthalmoplegic neuropathy