TED usually involves both orbits, although clinical signs tend to manifest asymmetrically. When TED presents with unilateral proptosis, clinical signs and symptoms such as inflammation, impairment of eye motility and eyelid retraction , may be present in the fellow eye, and contralateral proptosis may become clear during the course of the disease [9, 12]. Literature on actual unilateral TED is relatively scarce and heterogeneous and there are no conclusive data and explanations for this event. The number of patients having pure unilateral TED reported to range from 9% to 15% [9, 10, 23]. In our study, we found 13% of patients presenting unilateral TED with the appearance of unilateral proptosis. Bartley reported unilateral proptosis at the onset in 8,5% of patients in a cohort of cases with TED . Kendler and Rootman reported unilateral exophthalmos in 13% of patients from a series of 557 consecutive cases . This variation could be explained by the fact that in previous studies, the evaluation of proptosis was based solely on Hertel exophthalmometry, hence the different percentages reported might be explained by an unavoidable inter-observer variation when using this method [25, 26]. Our study includes a review of CT imaging to more accurately define the proptosis as being asymmetric, because some reports suggest that clinically unilateral disease is bilateral from the onset [9, 12]. It is also known that a CT scan can demonstrate contralateral eye muscle involvement in 50–90% of patients with clinical unilateral eye involvement [18, 23]. Given the systemic nature of the disease, it seems far more likely that both orbits were involved but to a very different extent. This is supported by the fact that CT imaging picked up some sign of contralateral involvement in this study patients despite no clinical signs. Eventually, it is possible that Hertel and CT imaging measurements, though within the normal range, may be increased for an individual patient. More accurate testing, such as MR imaging, would likely show a higher number of uninvolved orbits having subtle changes, but we were unable to collect data on MRI exam on all patients.
Published data concerning delayed development of proptosis in the contralateral eye are very few. Kalmann and Mourits have described one case of late recurrence of unilateral TED on the contralateral side after 7 years of follow-up .
We observed 13 patients who developed a subsequent increase in exophthalmometry measurements in the non-proptotic eye within a period ranging from 6 months to 7 years. We believe that such a variable range of time for this occurrence suggests the presence of different pathological mechanisms. For those presenting with proptosis within 36 months, unilateral TED probably represents an early stage of the disease-initially limited to only one eye, and the contralateral proptosis is due to a prolonged manifestation of the disease, concealing its activity due to the use of corticosteroids and radiotherapy . A high percentage of patients in both groups in our study had been treated with a corticosteroid before presentation, and it remains a challenge to explain factors leading to a less rapid progression of TED in one eye rather than the fellow eye. Considering that the 78% patients in group 2 needed corticosteroid versus the 53% of patients of group 1, it could be argued that patients who progressed onto bilateral proptosis have worse disease in general, and this could be suggested by a trend even in the absence of statistically significant p value.
When proptosis occurred within a period between 3 and 5 years, which describes 40% of patients in our study, it may be considered to be a result of subclinical, slow progressing, chronic inflammation and (or) fibrosis. We did not observe an actual increase of the CAS (4.41±1.3) before the proptosis occurred.
We observed 3 patients who had contralateral proptosis after >5 years, perhaps as a consequence of a late reactivation of TED (CAS: 5±0.786). Late reactivation of TED was also reported in 5% of patients having, with an increase in "Hertel" exophthalmometry readings after 5 years of follow-up . The authors suspected that this was not due to a slow subclinical progression of disease activity or to fibrosis prior to representation, but rather due to a significant increase in activity at the time of recurrence . We observed an increase of CAS during the 6 months prior to the presentation of proptosis; this observation is consistent with this proposed mechanism.
The clinical course of TED is independent of thyroid status and a temporal relation to thyroid disease is not consistent , but TED tends to be more severe in patients with poorly controlled hyperthyroidism and those rendered hypothyroid . TED may occur under euthyroid conditions with no obvious precipitants and it often presents as a reactivation of myopathy . In our cases, there was no significant difference in the initial thyroid status when comparing the 2 groups of patients. We considered only the thyroid status during the previous 6 months prior to development of the contralateral proptosis, and hence we are unable to offer statistics concerning the influence of different treatments used for thyroid disorders and TED, which may in some way affect the evolution of proptosis.
It is thought that individuals >50 years of age tend to have worse ophthalmopathy than younger individuals [23, 28]. In our investigation, the risk for developing contralateral proptosis was higher in younger patients (average age of group 1 was 8.5 years less than age of group 2).This finding correlates well with the results reported by Rootman, who found that TED in young patients tends to be more asymmetric .
It is possible that the difference in average age between the groups could be accounted for by younger patients who tend to have a prolonged active phase (which would be more likely to progress on either side), while older patients came to our clinic in the post-inflammatory phase.
It is well known that smoking also contributes significantly to the severity and recurrence of TED [29, 30]. In our study smoking history was found to be related to the development of contralateral proptosis, thus, it is important for patients with Graves’ disease to refrain from smoking.
Comparing the different therapies previously administrated (corticosteroids, radiotherapy, and surgical decompression), only surgical decompression was associated with a statistically significant occurrence of contralateral exopthalmos. We believe that this result could be related to the fact that TED is an autoimmune disease, and the releasing and spreading of an immunogenic orbital inducer during surgical decompression can serve as a trigger agent in developing contralateral proptosis. Wai et al. described a severe reactivation of TED, which occurred 3 weeks after cataract surgery in a patient who had inactive ophthalmopathy for 24 years. The authors hypothesized that trauma and pressure in the retrobulbar space induced by retrobulbar anesthsia triggered local inflammatory and immune responses, which in turn caused progression of TED [31, 32]. Recently a similiar mechanism was reported to explain 3 cases of homolateral reactivation of the disease after orbital decompression . Wenz et al. described 3 patients who had orbital decompression for compressive optic neuropathy and then subsequently relapsed due to progressive extraocular muscle enlargement .
Even if no significant difference was found for corticosteroids therapy, the low levels of p-value and power of the statistic test (0.14, power <70%) could suggest a trend of a worse disease in general for those patients who developed contralateral proptosis, since they needed corticosteroid in higher percentage.