Continuing Education Activity

Dysthyroid optic neuropathy (DON) is a sight-threatening complication of thyroid eye disease (TED), characterized by thyroid-related impairment of visual function, leading to permanent sight loss. To avoid blindness, prompt diagnosis and timely intervention are required. This activity reviews the evaluation and treatment of DON and highlights the role of the interprofessional team in managing patients with this condition.

Objectives:

• Outline the etiology of dysthyroid optic neuropathy.
• Describe the pathophysiology of dysthyroid optic neuropathy.
• Review the typical clinical features of dysthyroid optic neuropathy.

Introduction

Dysthyroid optic neuropathy (DON) represents the most dreaded manifestation of Thyroid Eye Disease (TED), one of the most common autoimmune diseases of the orbit.[1] DON, previously termed as the crowded orbital apex syndrome, is characterized by thyroid-related impairment of optic nerve function that may lead to a profound loss of vision. The European Group on Grave’s Orbitopathy (EUGOGO) classifies the severity of TED as mild, moderate-severe, or sight-threatening. Sight threatening TED, characterized by DON and/or keratopathy, warrants the need for urgent intervention.[2] 

DON is a multifactorial entity, the diagnosis of which is extremely challenging, owing to its early subclinical stage, presence of confounding factors, and alternative causes of sight loss in TED. A thorough evaluation of DON and subsequent timely management is crucial to avoid permanent blindness in TED.

Etiology

Several etiological factors have been implicated in the progression of TED, which may also be linked to dysthyroid optic neuropathy. Thyroid status impairment is one of the most important associations. The majority of cases of DON are associated with hyperthyroidism. This can be attributed to the fact that hyperthyroidism is the most common form of thyroid dysfunction in TED.[3] 

It is worth noting that hypothyroidism, autoimmune thyroiditis, or even a euthyroid status may be found in relation to DON. Radio-active Iodine (RAI) therapy, a well-known risk factor for TED progression, may increase the incidence of DON, although any meaningful evidence is lacking.[4] Studies have demonstrated smoking as an independent modifiable risk factor for the development of the DON.[5][6] A recent study has discovered a correlation between early-onset DON and thyroid-stimulating immunoglobulin positivity.[7]  

It has also been shown that in patients with diabetic vasculopathy, especially those on injectable insulin, hypoxia of the optic nerve occurs, leading to subsequent nerve damage.[8] Such patients of TED with superimposed comorbidities must closely be monitored for the development of optic neuropathy. Numerous genes have been linked to the pathogenetic mechanism of TED in previous studies; however, none of these are specific for DON.[9]

Epidemiology

Approximately every 5 in 100 patients with TED progress to sight-threatening optic neuropathy.[10] Younger patients are less likely to develop DON as compared to older age groups. It is found that for every 10-year increment in the onset of ophthalmopathy, the risk of developing optic neuropathy increases by approximately 60%.[11] Increased age at presentation of DON is associated with poorer long-term outcomes.[12]  

Although the White-race population demonstrates female preponderance in TED, DON is more common in males. Hence, an old male is far more likely to develop DON than a young female.[13][14][15]

Pathophysiology

There are several hypothesized pathophysiological mechanisms. Currently, the most widely accepted theory is the direct mechanical compression of the optic nerve by the edematous Extra-Ocular Muscles (EOMs) and intra-orbital fat, leading to the deceleration of the axonal flow and the resultant ischemia.[16][17] The subsequent crowding at the orbital apex also often results in increased orbital pressure. Substantial evidence to support the above theory can be derived from the fact that the visual acuity, as well as the retrobulbar pressure significantly, improves after orbital decompression, a surgery that relieves the crowding and the congestion in orbit.[18][19] 

The traditional hypothesis of optic nerve inflammation as the implicated mechanism is obsolete due to a lack of strong evidence of inflammatory cells in the histopathological specimen of the optic nerve in patients with suspected or clinically diagnosed DON.[20] Stretching of the optic nerve is yet another postulated mechanism of optic neuropathy in TED. As opposed to the peripheral nerves, the optic nerve has a regular and uniform organization of nerve fibers. This anatomical difference presumably makes it more vulnerable to damage through circumferential straining.[21][22] Impaired venous drainage and hypoperfusion of the apical portion of the optic nerve may also contribute to further optic nerve injury.

History and Physical

Besides the clinical features of TED, the most common presenting symptoms specific to DON include blurring of vision and impaired perception of color sense.[23][24][25] In subclinical forms, the patients may even be asymptomatic. A comprehensive clinical examination is required that may reveal a decrease in best-corrected visual acuity, relative afferent pupillary defect (RAPD, in unilateral and asymmetric cases), optic disc edema and hyperemia (acute form), optic atrophy (chronic form), which may or may not be accompanied by features of ‘activity,’ that is, a Clinical Activity Score (CAS) of more than 2 out of 7 (EUGOGO 2016 guidelines), restricted extra-ocular movements, proptosis, strabismus, and even ptosis.[26][16]

Evaluation

DON is a controversial disease entity whose diagnostic criteria are yet to be established. Color vision and contrast sensitivity tests may help detect an early onset DON. Characteristic visual defects include a central or a paracentral scotoma. Other patterns consist of an enlarged blind spot, arcuate or altitudinal scotomas, inferior defects being more common than superior.[27] Retinal never fiber layer (RNFL) along with macular ganglion cell analysis using Optical Coherence Tomography (OCT) is gaining popularity, owing to the test's property of being non-invasive, non-contact, and highly reproducible.[28] 

Electrophysiological assessment to test the integrity of the optic nerve using pattern Visual Evoked Potential (pVEP) signals must be considered by the clinician, which may reveal a decreased amplitude and increased latency of the P-wave.[29] Radiological evaluation using Computed Tomography (CT) and Magnetic Resonance Imaging (MRI) play a very important role in DON. Imaging may reveal one or more of the various predictors, which include apical crowding, prolapse of the orbital fat through the superior orbital fissure, increased extra-ocular muscle volume (specifically the medial rectus volume that lies close to the optic nerve), and increased superior ophthalmic vein diameter.

Several measurements, such as Barrett’s Muscle Index (MI), Extra-ocular Muscle Volume/ Orbital Volume (MV/OV), Crowding index (CI), have been implicated as reliable indicators of the disease in the literature. MV/OV > 20% has potentially come up as a more predictable index of acuity as well as field loss as compared to MI (MI > 60% is indicative of DON).[30][31][32][33][34] 

Color Doppler ultrasonography has detected orbital blood flow changes such as reduced resistivity index and flow velocities of Central Retinal Artery (CRA) in early-onset DON.[35] However, none of the above parameters is solely diagnostic of DON. In 2007, a useful diagnostic algorithm was proposed by Dayan and Dayan.[36] The initial step is to look for the clinical features suggestive of TED and the presence of damaged visual function, which is indicated by any one of the following: impairment of color vision, diminished visual acuity, disc edema/atrophy, presence of RAPD, specific field defects or electrophysiological abnormalities. If none of these features are present, DON is “unlikely.” If present, rule out an alternative etiology of visual loss in TED.

If none could be found in the presence of supporting radiological evidence of compression, DON is “likely” to be present. If no radiological evidence is present or if an alternative cause is found but with radiological compression, DON is still “possible.” In the presence of a different etiology of visual impairment without any compressive features on imaging, DON is again “unlikely.” The key message from the hypothesized flowchart is that DON can never be completely ruled out, and a high index of suspicion must always be maintained, especially in cases with subclinical stage, euthyroid presentation, and bilaterally symmetric DON where most of the ancillary tests may give confusing results.

Treatment / Management

TED complicated with DON requires aggressive management. The treatment options include medical decompression using corticosteroids, radiotherapy, surgical decompression. There is no single best treatment option, and sometimes, even a combination of the above choices is recommended.[37] Corticosteroid therapy is the proposed first-line treatment in DON. EUGOGO recommends intravenous methylprednisolone (IVMP) as the immunosuppressant of choice in DON. The regimen states the use of 500-1000 mg IVMP daily for 3 consecutive days, followed by a repeat dose after 1 week (if needed). If improvement in visual parameters is observed at 2 weeks, the dosage can be tapered or alternate forms such as oral steroids may be used. This is referred to as “medical decompression”. Complete visual recovery has been shown to occur in 43% of cases with this regimen.[38][39][40] It has been shown that almost half of the patients may avoid surgery if treated with IVMP.[41] At no point in time, should the cumulative dose of IVMP exceed 8g, otherwise, fatal systemic adverse effects may occur such as acute heart failure, liver dysfunction, and even sudden death.[42][43] 

The clinician must perform a thorough clinical assessment and get all the baseline investigations, such as blood sugar, liver function tests, serum electrolytes, chest x-ray, electrocardiography, and blood pressure done prior to administering steroids. Inadequate response to IVMP is defined as persistent activity and disc edema even after 2 weeks of treatment.[44] In this scenario, urgent surgical decompression of the orbit is recommended. In general, orbital decompression is advised only after achieving at least 6 months of euthyroid status in inactive TED. DON is probably the only indication of doing an urgent orbital decompression in the active stage of the disease.[26] Surgical decompression provides excellent outcomes with visual improvement in 70 to 85% of cases.[45][1] It leads to the expansion of the bony volume and a relative decrease in the soft tissue volume so that the apical structures decompress. This can be achieved via infero-medial wall decompression, lateral wall decompression, or even a combination of the two (3-wall), with or without fat decompression. The inferomedial orbit can be approached via trans-antral route, trans-cutaneous route, trans-caruncular route, or endoscopically through the nasal approach. In the trans-antral approach, the incision is given along the buccal sulcus and the anterior wall of the maxilla is removed.

A high number of cases with postoperative diplopia (66%) outranks its rate of success (90%). Alveolar nerve hypoesthesia, Cerebrospinal Fluid leak (CSF), and entropion are rare but possible complications.[46] The trans-cutaneous approach involves giving a subciliary incision along the lower eyelid. A trans-cutaneous Lynch incision, a 3 cm curvilinear incision, is given along the nasal area adjacent to the medial canthus. However, this approach often results in a webbed scar and may potentially damage the underlying lacrimal system. A modification involving a smaller-sized (1.5cm) incision, results in minimal webbing and minimizes the risk of iatrogenic damage. Another popular approach is the "swinging lid crease" incision, which not only gives an excellent view of the inferomedial orbit but also provides better visualization of the lateral wall as well as the orbital fat.[47][48][49] A trans-caruncular approach provides a safe, quick, and graded access to the apical area, thus lowering the chances of postoperative diplopia.[50][51] Another safe approach with low rates of postoperative diplopia is the lateral wall decompression, which includes removing the deep lateral wall using a drill or aspirator.[52] 

In fat-centric TED complicated with DON, fat decompression alone, via transconjunctival or transcutaneous approach, can alleviate compression.[22] A novel approach describing a combination of endoscopic trans-ethmoidal medial orbital wall decompression and endoscopic trans-ethmoidal fat decompression has been reported in the literature with low rates of postoperative diplopia that resolved within a few months.[53] Fractionated radiotherapy (2000 rad per eye in ten doses over 10 days) is indicated in patients refractory to medical and surgical decompression or patients with several comorbidities, such as hypertension and diabetic retinopathy.[54] However, the scarcity of evidence-based data regarding its definite use in DON makes it debatable. The use of steroid-sparing immunosuppressive agents such as adalimumab, tocilizumab, and teprotumumab, specifically for DON is yet to be established. 

Differential Diagnosis

The differential diagnoses of DON include other causes of sight-threatening TED, such as ocular surface diseases. Alternative etiologies of optic neuropathy such as those due to toxic and nutritional causes must be ruled out, specifically in the presence of central and paracentral scotomas. Unilateral disc edema with the enlarged blind spot along with electrophysiological changes, may also raise the suspicion of optic neuritis. It is not uncommon to have secondary glaucoma in TED that may be the cause of visual acuity changes, arcuate field defects, RNFL defects, and ocular blood flow changes. A meticulous history, clinical evaluation, and dedicated investigative workup help to differentiate each of the above from DON.

Prognosis

It is imperative to understand that the prognosis of DON largely depends upon whether the treatment was received and the stage or time at which the intervention was initiated. A timely intervention in DON saves vision, with full recovery in about 70% of cases. Young age and an initially elevated CAS are the additional positive prognosticating factors.[45][12]

Complications

More than a disease, DON is itself the gravest complication of TED. Misdiagnosed or left untreated, it leads to permanent loss of visual function. It not only leads to visual disability but also results in major psychosocial trauma.

Deterrence and Patient Education

Elimination of modifiable risk factors and prompt restoration of euthyroidism is indispensable in every patient of TED. Once the disease has progressed to DON, the patients must be counseled to seek treatment as soon as possible, after explaining the risks and benefits of the same. Strict metabolic control and frequent ophthalmological and systemic check-ups must be encouraged for a better prognosis.

Pearls and Other Issues

The occurrence of DON in TED cannot be prevented, but, up to a significant extent, the subsequent blindness is avoidable. A systemic multidisciplinary approach is crucial for detecting the subclinical form of DON in patients of thyroid-related ophthalmopathy. A clinician must maintain a low threshold for an aggressive patient work-up.

Enhancing Healthcare Team Outcomes

Every healthcare institution must be motivated to equip themselves with a joint, multidisciplinary “Thyroid Clinic” comprising at least an ophthalmologist and an endocrinologist. This interprofessional approach is highly encouraged as this will not only enhance the management outcomes but will also reduce the burden of healthcare cost on these patients, especially in lower-to-middle income countries. Owing to the autoimmune nature of the disease, the patients must be counseled regarding the need for a lifelong follow-up. Due to the lack of Level 1 evidence-based data in DON, randomized multi-center trials must be conducted to understand the exact etiopathogenesis of DON, the role of steroid-sparing immunosuppressive drugs, especially in co-morbid conditions, and alternate surgical approaches to maximize healthcare outcomes and enhance the patient's quality of life.