The current study has several findings. Benign THS and ocular diabetic neuropathy accounted for the majority of cases of painful ophthalmoplegia with normal cranial imaging (91.4%). Clinical presentations were similar between the groups, except for the age of onset, response to glucocorticoids, and duration of disease course. Nearly all patients with benign THS and OM had an immediate improvement in ocular motor function after initiation of glucocorticoid treatment, whereas only partial patients with diabetic ophthalmoplegia did so. Patients with OM recovered more rapidly than the other groups did. Overall, most patients recovered completely during the follow-up period.
Patients with ocular diabetic neuropathy were significantly older than patients with benign THS and OM. This result is in accordance with previous reports; the mean reported age of diabetic ophthalmoplegias ranges from 50.2 to 68 years [6, 17–19], which is more than that of benign THS (48.6 years) and adult OM (36.4 years) [8, 9]. Diabetic neuropathy is predominantly a disease of older adults , whereas OM predominantly affects children and younger adults [7, 8], and THS may present at any age [1, 9].
Glucocorticoid administration is of therapeutic and partial diagnostic utility. The response of diplopia resolving was of higher diagnostic value than that of pain relieving. Orbital pain was dramatically relieved after glucocorticoid treatment in almost all patients. Regarding diplopia resolving, only THS and OM respond exquisitely to glucocorticoid therapy [1, 7] The immediate improvement of ocular motor nerve dysfunction might reflect the inflammatory pathogenesis of these diseases [7, 12, 21, 22]. In contrast, ischemic pathogenesis associated with ocular diabetic neuropathy [5, 23, 24] decreases the response to glucocorticoids, even though glucocorticoids can partially relieve pain caused by ischemic injury.
Patients with OM recovered faster than patients with THS and ocular diabetic neuropathy, consistent with previously reported results [7, 10, 18, 19, 25, 26]. The average recovery time of OM is approximately 3 weeks, whereas that of THS is approximately 2 months and ocular diabetic neuropathy is 3–4 months [7, 9, 10, 18, 19]. Although the disease course varied among groups, the outcomes were generally good. In our experience, most patients recovered completely within 3 months. Physicians should be more vigilant if a patient fails to improve within 3 months, and further aggressive investigation may be indicated.
Pupil sparing was not only common in patients with ocular diabetic neuropathy, but was also common in patients with THS and OM. It is widely accepted that pupillary dysfunction is suggestive of aneurysmal or neoplastic compressive lesions [27, 28], and it is not common in diabetic ophthalmoplegia [25, 26, 29]. Only 14–18% of patients with diabetic ophthalmoplegia develop pupillary dysfunction . In addition, the pupil is occasionally affected in THS . Although a majority of child patients with OM have pupillary involvement , adult patients with OMs tend to spare pupillary response . Pupil sparing can be used as a potential marker for differentiating these ophthalmoplegias from those caused by structural compressive lesions.
Occasional reports have documented an elevated ESR in the acute stage of THS . However, there is no convincing evidence for a correlation between connective tissue disease and THS. In our study, the ESR results were grossly normal in patients with benign THS. Therefore, ESR is of no diagnostic value in differentiating THS from other causes.
In the past, the absence of radiographic evidence of inflammation in patients with THS was confusing to clinicians, and a diagnosis of “idiopathic painful ophthalmoplegia” was applied to these patients [30–32]. The eponym of “benign THS” was first introduced by La Mantia et al. in 2006 to describe these patients . According to the review by La Mantia et al., half of the THS patients manifest as benign condition. Given the nosography of benign THS has been proposed for less than a decade, it is probable that such cases will continue to be diagnosed. The exact proportion of benign and inflammatory cases remains to be determined. A strong similarity between benign and inflammatory THS was recently identified, and inflammation may contribute to the pathogenesis of both conditions . An official definition and elaboration of benign THS is essential for clinical practice.
Painful ophthalmoplegia usually mandates an extensive systemic workup for an underlying neoplastic, inflammatory, infective or autoimmune disease. Because of the limitations of a retrospective study, an exhaustive checkup for screening was not possible. However, all recruited patients had ancillary laboratory workup, cranial MR imaging, and cerebral vascular investigation. In addition, none of the patients had newly diagnosed malignancies, autoimmune disease, or CNS infection during the follow-up period. Furthermore, the results were generally favorable during the follow-up period and all patients completely recovered or experienced minor sequelae. Therefore, after the follow-up, we could conclude that other causes of painful ophthalmoplegia were less likely and further confirmed the suitability of our diagnoses.
In this study, the classification was based on the ICHD-2 criteria and clinical specificity of each disease. Patients with definite diabetes (fasting plasma glucose ≥ 126 mg/dL or HbA1c ≥ 6.5%) were designated as ocular diabetic neuropathy . In fact, it is difficult to differentiate ocular diabetic neuropathy from benign THS comorbid with diabetes or impaired glucose tolerance at this present technological stage. The limitation of the diagnostic criteria might lead to selection bias in the classification.
Diabetic neuropathy may manifest before the diagnosis of DM . It is possible that patients manifesting ophthalmoplegia with undiagnosed DM could be mistaken as those with THS. However, diabetic cranial neuropathies mainly occur in older individuals with a long duration of diabetes (mean = 8.5 ~ 16 years) [6, 17, 19]; an occult diagnosis of diabetes is very less likely at this stage. In addition, none of the THS or OM patients in this study had a diagnosis of diabetes mellitus (fasting plasma glucose ≥ 126 mg/dL or HbA1c ≥ 6.5%) or impaired fasting glucose (fasting plasma glucose ≥ 100 mg/dL) . Due to the limitation of a retrospective study, the data of impaired glucose tolerance (IGT), tested by oral glucose tolerance test, were incomplete in THS patients. Further prospective studies are warranted to clarify the relationship of benign THS and glucose intolerance.
Our study also had other limitations. First, the sample size of each group, especially the OM group, might be too small for adequate comparisons. Second, the conclusion that steroid is of partial diagnostic utility might result from the selection bias caused by the diagnostic criteria. Third, the retrospective analysis limited our ability to collect detailed information, forcing a reliance on documented findings of examinations. Fourth, histological examinations for pathological diagnoses lacked. Nevertheless, this study provides useful information about the clinical features of painful ophthalmoplegia and may warrant large-scale prospective studies to assess the optimal treatment approach.