Dysthyroid Optic Neuropathy
Dysthyroid Optic Neuropathy
Dysthyroid optic neuropathy (DON) is an optic nerve dysfunction that is one of the most severe complications of thyroid eye disease (TED). Either of compressive(CON), ischemic, optic nerve stretch or mixed etiology, it may result in long-lasting visual loss.   Because of its potential reversibility with prompt intervention medically, surgically or in combination, accurate and prompt diagnosis and appropriate management are important.
TED, also termed Graves Orbitopathy(GO), is an autoimmune disease initiated by several antibodies against thyrotropin (TSH) receptors and adjacent IGF1-receptors on the surface of orbital pluripotential fibrocytes. Binding of these receptors leads to adipogenesis, activation of T-lymphocytes with release of cytokines and initiation of inflammation, and deposition of glycosaminoglycans in orbital fat and muscle. Two main types of TED could be categorized. About 2/3 of TED patients have primarily fat expansion and levator muscle scarring (“adipogenic” phenotype) which rarely leads to DON in cases of nerve stretching from severe proptosis. The other third have a “myopathic” phenotype with enlargement of EOMs and may develop secondary congestive soft tissue signs, ocular motility disruption, and compression of the optic nerve.8 In reality, most patients have variable combinations of the above two processes.
TED affects women more frequently than men with a female to male ratio of 4:1. However, DON is seen more frequently in men with older age, diabetes mellitus and smoking being risk factors.  Compressive mechanism of DON occurs mainly in the myopathic subtype. The most common risk factors for this type of optic neuropathy (ON) include smoking  immune response stimulators (such as intermittent infections, local surgery, and other trigger factors), and comorbidities such as diabetes mellitus. Treatment of hyperthyroidism with radioactive iodine not only increases the risk of progression of TED up to 40% but also the risk of DON.
DON occurs in 5–8% of all cases of TED. According to the demographic findings of several previous studies, similar to myopathic TED, DON is associated with older age and a higher male-to-female ratio.   
Several mechanisms have been proposed for the pathogenesis of DON. The most accepted mechanism is compression of optic nerve (CON) by enlarged EOMs at the orbital apex which disturbs axoplasmic flow. The second is from optic nerve stretch from severe proptosis with disruption of the axonal function and blood flow of the optic nerve. This occurs much less frequently than the compressive mechanism.  The third mechanism is inflammation which causes optic neuritis. This is supported by the benefit of anti-inflammatories such as corticosteroids for many cases of DON.  Occasionally significant weight gain with Type I disease resulting in increased orbital pressure may also predispose to optic neuropathy. In reality, patients may have variable combinations of the above mechanisms.
In general, diagnosis of DON is made when decreased visual function is related to compromised optic nerve function secondary to TED . DON is thus diagnosed based on clinical findings, optic nerve dysfunction studies on automated perimetry, and confirmed by imaging such as CT scans or MRI demonstrating apical optic nerve compression or ON stretch. In some cases, visual-evoked potentials (VEP) may be helpful to provide additional data to support diagnosis. However it is not considered among the first line workup, nor are abnormal results an early finding in DON.
History and Clinical Features
Patients often present with a history of underlying hyperthyroidism under medical treatment, not always under poor control. Patients often also confirm a recent precipitating event – deterioration in general health, personal stress, etc.
The most common presenting symptoms include blurring of central vision and desaturation of colors.   A relative afferent pupil defect (RAPD) may be noticed in asymmetric cases. Absent RAPD could happen when both eyes have similar vision loss. Optic disc changes such as edema or hyperemia may be detected.  In myopathic phenotype, most patients with DON complain about diplopia due to restricted motility. Congestive soft tissue signs are also evident.  
Clinical features of DON include reduced visual acuity (80%), decreased color vision (77%), visual field defect (71%), typically inferior to begin with, often associated with reduced ocular motility (70%) and rarely optic disc swelling (20%).
76% of cases of DON are bilateral.50% to 70% of cases of confirmed DON have best corrected visual acuity of 20/40 or better. These patients may have a greater rise of IOP in upgaze (> 9 mmHg), congestive orbitopathy, tight orbital septum, resistance to retropulsion, and an aching discomfort in the orbit.
Proptosis is not a remarkable finding in compressive DON and some authors believe that tight eyelids may limit anterior movement of the globe and lead to diffuse elevation of orbital tension.  Conversely, it has been shown that proptosis is not correlated with occurrence of DON.
Other clinical features include a greater rise of IOP in up gaze (> 9 mmHg), congestive orbitopathy from tight orbital septum, resistance to retropulsion with an aching discomfort in the orbit. In the myopathic phenotype, patients have associated diplopia due to restricted motility. Congestive soft tissue signs are also evident.     
These above clinical findings are supported by variable degrees of TED and orbital apex crowding on orbital CT scan. Severe apical crowding is a good predictor of DON, with a sensitivity of 62% and specificity of 91%.
Amongst various ancillary tests, perimetry is the most available and commonly performed.
Central and paracentral scotomas occur in most patients with DON. Inferior partial or complete arcuate and altitudinal defects, generalized constriction and enlarged blind spot are detected in 70%.
Color desaturation- Red
In patients with previously normal color vision, asymmetric optic nerve neuropathy may present as color desaturation in the worse eye. If symmetric and delayed onset, however, the desaturation may not be obvious.
Relative Afferent Pupillary Defect (RAPD)
This is a simple but very useful finding detecting optic neuropathy, however, if there is symmetrical optic nerve dysfunction , an RAPD would be absent
Visual evoked potentials
Increased latency and decreased amplitude of VEP waves are recorded in ¾ of DON cases.VEP can be useful when clinical exams and visual field results are equivocal. This may however represent a late stage of the disease, not universally available and often technique dependent.
Optical coherence tomography (OCT)
Thinning of the retinal nerve fiber layer and macular ganglion cell complex could be seen by means of OCT and this finding correlates with patients' visual function. This finding is an objective way to measure atrophy or thinning prior to any fundus abnormality.
Computerized tomographic (CT) and magnetic resonance imaging (MRI)
CT and MRI are both useful techniques for diagnosing DON. Both CT scan and MRI can show apical crowding, muscle enlargement, intracranial fat prolapse, bony orbital angles that are correlated with occurrence of DON (Fig 1).
CT scans are chosen for surgical planning as it is readily accessible, fast to perform, less expensive and define bone better than MRI. Apical effacement of the optic nerve by more than 50% is both sensitive (80%) and specific (70.6%) in diagnosis of DON. CT scans can also demonstrate changes to the angle of the inferomedial orbital strut (AIOS) and reduction of the angle of the medial wall (AMW),orbital volume and size of globe. However, the role of orbital geometry, size of globe and orbital volume of bony orbit especially among different types of orbital geometry and races have not been clearly elucidated. The DICOM data can also be used to plan surgery and for intraoperative guidance and navigational surgery. Steep bony orbital angles and intracranial orbital fat prolapse, seen in about 20% of cases, although non-specific, may be correlated with DON.
MRI can provide additional findings regarding activity of the disease especially with STIR sequences. An enlarged medial rectus or superior rectus/levator muscle complex increases the incidence of DON, apparently because of their proximity to the optic nerve as it passes between the annulus of Zinn. 
Fat prolapse through the superior orbital fissure can be seen in 20% of patients although not limited to patients with DON.
Figure 1. CT scan. orbital apex crowding. prominent enlargement of the four recti muscles complex on both sides in a 61 year old woman. Visual acuity 2 mCF and 20/200 in right and left eye, respectively.
This technique may show decreased or reversed flow of the superior orbital vein in compressive cases. Steep bony orbital angles and intracranial orbital fat prolapse are highly correlated with DON.
In one study it was found that 96% of patients with recent DON have high titers of thyroid-stimulating immunoglobulins (TSI). Serum TSI levels may help to identify patients with DON of recent onset.TSI has positive correlation with disease activity in patients with TED. Further studies are needed to evaluate the possible role of serology tests to discriminate patients with DON among those with active without DON.
Intravenous corticosteroids (CS) are the first therapy in active TED and for cases of progressive compressive DON.Intravenous methylprednisolone (IVMP) pulse therapy has greater efficacy and less adverse events compare to oral prednisolone. More severe complications are associated with doses exceeding 8 g per cycle and when administered daily. EUGOGO suggested IVMP as the first line treatment in DON.A variety of protocols have been suggested by different authors. One widely used regimen is the original EUGOGO protocol which suggested 500 mg IVMP every week for 6 weeks followed by 250 mg IVMP weekly for another 6 weeks. This protocol was proposed to improve the safety of IVMP administration as apposed to large daily disease of medication. Another regimen is 500mg-1000mg IVMP daily for 3 successive days to be repeated in one week if incomplete response occurs. The EUGOGO 2021 protocol advocates higher doses of unto 1gm daily for 3 days and repeated as necessary weekly if improvement is noticed, not exceeding 8gm. Early orbital decompression should be considered if insufficient or no improvement in optic nerve function is achieved within a few weeks following medical treatment. Complete visual recovery may occur in about 40% of patients with DON after treatment but far more so with surgical decompression.
Immunosuppressive and Immunomodulatory agents
A variety of immunosuppressive and immunomodulating agents have been studied in patients with active TED and DON. These include Rituximab (an anti-CD20 monoclonal antibody) , Tocilizumab (an anti-IL-6 monoclonal antibody)and more recently Teprotumumab (an anti-IGF-1R monoclonal antibody).  
Both rituximab and tocilizumab may be considered in patients with refractive active inflammatory orbitopathy but with some proven benefit in DON   Teprotumumab has proven effective in active inflammatory TEDin reducing proptosis, and is now promising on treating chronic TED.
External beam radiotherapy (EBRT)
EBRT as adjunct to systemic corticosteroid is considered an alternate treatment of DON. It decreases inflammation by targeting lymphocytes and fibrocytes and may help in early progressive TED.Radiotherapy takes longer to reduce inflammation in active TED compared to CS but has a synergistic affect with CS. In a retrospective study, a large cohort of patients with active TED who received either CS alone or CS combined with EBRT were assessed for subsequent onset of DON: no patient with combined CS/EBRT developed DON compared with 17% of those in the CS group.
Surgical expansion of the orbital apex can provide prompt improvement of DON and remains the gold standard in severe and refractory cases. The goal is to achieve apical orbital volume expansion – both along the medial wall, the orbital floor including the palatine process and possibly the deep lateral wall. Urgent orbital decompression is considered if there is no improvement of optic nerve function within 2 weeks following medical treatment. In contrast to elective surgery in other non-sight threatening conditions, surgery is often offered during the progressive phase.  Several studies have shown that different methods of decompression including medial wall, the inferior wall, deep lateral wall, and the orbital fat, can all be effective in patients with DON. Bilateral orbital decompression may be performed concurrently or sequentially. Approaches to the orbit may include transcutaneous approach (the upper eyelid crease approach to the deep lateral wall), medial and inferior transconjunctival approaches (to the medial wall and floor including the posterior strut) and trans nasal endoscopic approaches have also been found to be effective. Preoperative treatment planning and intraoperative navigation is often helpful to minimize under decompression , avoid complications including CSF leaks. Sometime, postoperative immunosuppression for persistent active inflammatory disease may have to be continued until quiescence.
Even if vision loss has been chronic and severe, orbital decompression can save vision in some patients. In a cases series by Devoto et al, a 43yo patient with progressive vision loss of CF right and NLP left eyes and after decompression via medial wall(transcaruncular) and posterior medial floor, the vision recovered to 20/20 bilateral, while another 68yo patient with 3month vision loss to CF right and NLP left eye recovered to 20/400 and 20/50 respectively after decompression. <
A Word of Caution
Radioactive iodine (RAI) is a well known treatment for persistent or refractory hyperthyroidism. However, in some patients with TED, the ocular symptoms may worsen after radiation-RAI, and vision can worsen,  even to the point of compressing the optic nerve further. It is hypothesized that RAI releases thyroid antigens that are then directed toward the orbit.
In few case reports If the patients were treated with prednisone prior to radiation, the progression of ophthalmopathy was not seen. Therefore, as a general recommendation, the patients with TED who are scheduled to receive RAI, are placed on peri-RAI steroids. This is particularly important in patients that have pre-existing TED with enlarged EOM that are very close to the optic nerve.
In summary, DON is an infrequent yet devastating consequence of Thyroid Eye Disease. Prompt recognition, confirmation with appropriate investigations, institution of medical followed by surgical treatment with postoperative rehabilitation help restore vision and and patient satisfaction.
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