Anatomically, after the fascicular portion of the oculomotor nerve travels ventrally from the nucleus origin in the dorsal midbrain tegmentum, it can be divided into the cisternal, cavernous and intraorbital segments, which branch into superior and inferior branches within the superior orbital fissure (8, 9). In total, extra-axial lesions should account for the ONP observed in our study. However, ONP in diabetic patients does not always indicate diabetes-related microvascular ischemic ONP, and further evidence, such as imaging procedures, is indispensable for obtaining an etiological diagnosis.
In our study, the most common imaging findings were thickening and enhancement of the cavernous segment and the inferior division of the intraorbital segment of the ipsilateral oculomotor nerve. Oculomotor nerve enhancement was previously confirmed to be an indication of a variety of underlying etiologies, such as Tolosa-Hunt syndrome (THS), recurrent painful ophthalmoplegic neuropathy and oculomotor nerve tumors (6, 10–13), each of which could be eliminated as a differential diagnosis in our patients. However, immediate pain relief was not achieved within 72 hours of treatment with glucocorticosteroids, and no study of THS has reported a case in which the oculomotor nerve is solely thickened and enhanced without enlargement of the cavernous sinus in THS (11). Several patients with recurrent painful ophthalmoplegic neuropathy have also revealed unilateral thickening and enhancement of the oculomotor nerve, but an association between recurrent headache and ONP must be emphasized, with most affected patients having pupillary involvement (14–17). Solid tumors frequently demonstrated nodular enhancement of the cisternal segment, and some show either extension of a mass lesion into the cavernous sinus or increased tissue in the sinus that may extend into the superior orbital fissure; however, spontaneous resolution of both presentations of ONP and imaging abnormalities has never been reported under these circumstances. Isolated unilateral cranial nerve palsy without systemic manifestations is relatively rare in nonsolid tumors, and thus far, only Joana Meireles has reported one such patient, a 69-year-old woman in whom the first presentation of Hodgkin’s lymphoma was left oculomotor nerve enhancement with no brain parenchymal or meningeal abnormalities or cavernous sinus involvement (18); importantly, pancytopenia emerged three months after ONP in this patient. In addition, pupillary involvement and spontaneous recovery within 6 months are not classical manifestations of lymphoma and should thus be excluded in diabetic ONP patients.
Our study first demonstrates that enhancement of the ipsilateral oculomotor nerve was observed in 64.41% of the included patients, which may therefore be added as a supportive diagnostic criterion for diabetic ONP with main involvement of the cavernous segment and inferior division of the intraorbital segment. The pain incidence was higher in patients without enhancement of the oculomotor nerve than in those with enhancement, although this difference may have been caused by recall bias and differences in pain tolerance among the patients. Similar to previous reports, more than three months was required for our patients to achieve complete recovery even when treated with glucocorticosteroids in the early stage, which may indicate that glucocorticosteroids use does not shorten the disease course of diabetic ONP. Therefore, oculomotor nerve enhancement should not be habitually interpreted as inflammation and glucocorticosteroids should not be directly administered to these patients. Refraining from glucocorticosteroids in diabetic ONP may reduce the risk of poorer glycemic control, infection and other vascular events.
Thickening and enhancement of the oculomotor nerve have never previously been reported in diabetic ONP. Although scholars have not reached a consensus on immediate neuroimaging for patients up to 50 years of age with isolated ONP (19–21), MRI is routinely performed in our clinic regardless of the onset age to evaluate the entire course of the oculomotor nerve and surrounding structures to avoid missing any rare causative factors, especially in deeply embedded structures, given the intense medical environment in our country.
In our study, the occurrence of nerve enhancement was not always positively correlated with blood sugar control. Other factors such as elevated levels of inflammatory biomarkers may accompany nerve enhancement in a hyperglycemia-independent manner (22, 23). These insults can also break down the blood-nerve barrier, an initial key step in the development of diabetic neuropathy (24–26) that allows the leakage and accumulation of contrast material with resultant nerve enhancement as observed in our study. Differences in the kinds and concentrations of these metabolic and inflammatory elements, which were unaffected by the level of blood sugar and the timing of imaging, may be the underlying explanation for the observed nerve enhancement.
In 1970, Asbury AK et al reported an autopsy case of a diabetic ONP patient who had experienced right ONP three years prior to and a second ophthalmoplegia event on the left side just one month prior to death (27). A striking focal demyelinating lesion of the intracavernous portion and enlargement and septation of the left oculomotor nerve by connective tissue bands in the anterior half of the cavernous sinus were found, which may have been the underlying pathologies for the thickening and enhancement of the intracavernous portion of the oculomotor nerve observed in our patients. However, pathological changes in the intraorbital segment were not explored. Asbury AK et al also found no evidence of previous damage to axons or myelin sheaths in the right oculomotor nerve. However, the enhancement of the oculomotor nerve observed in our patients did not disappear until follow-up. This discrepancy may be due to the relatively short follow-up period of our study. Partial restoration of the appearance of the EOMs may suggest gradual functional recovery prior to the disappearance of nerve enhancement. The follow-up should be continued to determine whether the appearance of the EOMs will be restored, the time required for this process, and when the nerve enhancement will finally disappear.
Our study has several limitations. First, its retrospective nature did not allow us to evaluate the detailed time of recovery from ONP, and further analyzing differences in recovery times between patients with and without nerve enhancement was difficult. Second, follow-up imaging data were lacking for the vast majority of the patients, and these data should be obtained after complete recovery from ONP to track changes in the trends of oculomotor nerve enhancement and determine whether this kind of enhancement will finally disappear. Third, our study did not enroll patients with ischemic ONP with other atherosclerotic risk factors apart from diabetes; therefore, the incidence of unilateral oculomotor enhancement among all patients with ischemic ONP remains unclear. Extensive investigation is needed to resolve these issues in future studies.