Introduction

What is TED? 

Thyroid eye disease (TED), also known as Graves’ ophthalmopathy or Graves’ orbitopathy, is characterised by chronic inflammation of the eye socket and is the most common cause of proptosis or bulging eyes in adults. It affects 25–50% of Graves' disease cases. TED involves orbital structures such as fibroblasts, adipocytes, and extraocular muscles. TED has an unpredictable course influenced by systemic thyroid status.¹

An accurate clinical assessment of TED is essential for early diagnosis and determining the severity and activity of the condition. This helps identify patients who are at a higher risk of developing serious complications and helps guide appropriate treatments to manage the condition. Proper TED grading ensures timely intervention and better treatment outcomes.³

There are various classification systems for TED, such as NO SPECS, the European Group on Graves Orbitopathy (EUGOGO) severity scale, the Clinical Activity Score (CAS) of Mourits, and the vision, inflammation, strabismus, appearance (VISA) Classification, which are used to grade TED severity. These systems help assess TED presentations and guide treatment decisions.³ In this article, we will discuss the CAS severity classification for TED in detail. 

Pathogenesis (disease process) of TED and treatments 

TED follows a self-limiting course due to the lack of orbital lymphoid tissue, as Rundle’s curve describes. This means the eyes can only deteriorate as much as there is orbital tissue to affect. It progresses through:

• An initial active inflammatory phase of six months to five years (average two years)
• A stable inactive phase where fibrosis persists, and the disease never fully returns to baseline

Early aggressive immunosuppressive treatment in the initial stage can mitigate and prevent further damage. Emerging therapies like monoclonal antibodies and thyroid-stimulating hormone receptor (TSH-R) antagonists have been used to treat TED. However, the inactive phase is less responsive to medical therapy and often requires surgery.¹

The disease is caused by the autoantibodies that attack the extraoccular muscles and ocular fats. The process of this disease includes:

• TED is driven by orbital inflammation due to CD34+ fibroblast activation in ocular tissues, which plays a key role in manifesting the disease
• CD34+ is a hematopoietic stem cell that expresses the CD34 protein on its surface
• These activated fibroblasts express thyroid-related peptides, stimulating the thyroid-stimulating hormone (TSH) receptor and insulin-like growth factor (IGF)-1 complex, leading to adipogenesis and hyaluronic acid synthesis
• Increased orbital adipose tissue and glycosaminoglycan accumulation around the eyes cause soft tissue expansion, intraorbital congestion, and pressure, leading to TED's characteristic symptoms⁴

Clinical activity score (CAS)

TED can be challenging to manage, with treatment options that may be costly or ineffective for some patients. 

Thus, the Clinical Activity Score (CAS) is commonly used to assess disease activity or inflammation and predict a treatment response, but its reliability across different studies remains unclear. One study aimed to evaluate the inter-observer variability of CAS in TED patients.⁵ They found the CAS system effectively predicts responses to immunosuppressive treatment in TED patients. Despite this, it has some limitations as it is examiner-dependent, meaning the characteristics can be subjective and rated differently depending on the clinician. The CAS system has therefore been debated for monitoring disease progression. Some researchers argue that CAS alone does not fully reflect the clinical condition of TED. Integrating imaging studies with CAS can enhance diagnostic accuracy.⁷

Components of CAS

The CAS system was introduced in 1989 based on the signs of inflammation, including:¹

• Pain (Spontaneous or with eye movement)
• Redness (Eyelids or conjunctiva)
• Swelling (Eyelid edema, chemosis, caruncular edema)
• Dysfunction (Impaired eye movement)

Scoring system

The CAS is calculated by assigning one point per item, with equal weighting, resulting in a total score ranging from 0 to 10. The first eight items of the CAS assess soft tissue inflammation, including pain, redness, and swelling.

There are two categories related to this score to identify the disease severity:

• Active Disease: CAS ≥ 3
• Inactive Disease: CAS < 3

The EUGOGO later modified the CAS system. According to the amended CAS, active TED is defined by a score of >3/7 at the first visit or >4/10 at follow-ups.⁶

For the initial CAS assessment, only the first seven criteria are considered. Each of these symptoms indicates active inflammation in TED. These include:

• Spontaneous orbital pain
• Gaze-evoked orbital pain
• Eyelid swelling
• Erythema (red eye)
• Conjunctival redness due to active TED, 
• Chemosis (swelling of conjunctiva)
• Inflammation of the caruncle or plica.

The table below shows the binary scoring pattern in a TED disease:

For follow-up assessments after 1–3 months, the CAS expands to include three additional criteria, making a total of 10 points. These new criteria measure an

• Increase in proptosis (protrusion of eyeball) by more than 2 mm
• A decrease in uniocular ocular movement by over 8°
• A reduction in visual acuity by at least one Snellen line

These indicators help track disease progression and treatment response in TED.

Points to consider when scoring severity

• Orbital pain should be scored only if it lasts more than a few seconds and occurs frequently
• The EUGOGO atlas aids in evaluating soft tissue inflammation, with only moderate or severe eyelid swelling counted as CAS positive
• When swelling or erythema differs between eyelids, the more severe one is used for scoring, though some signs, like conjunctival redness, can be difficult to assess due to nonspecificity
• Only diffuse redness covering at least one quadrant due to active TED should be scored 
• Conjunctival redness caused by corneal stippling or ulceration is not considered a sign of active orbital inflammation
• Mild conjunctival redness should not be included in the CAS score⁶
• Chemosis is assessed using a slit-lamp at 60°, with true chemosis defined as conjunctival separation from the sclera in over one-third of the palpebral aperture or prolapsing past the eyelid's grey line
• It should be distinguished from conjunctivochalasis, which is CAS negative, while prolapsed or inflamed plica and caruncle are considered CAS positive
• An increase in proptosis of ≥2 mm over the past 1 to 3 months is the key indicator of swelling⁶

Severity classification

The management of TED is based on its severity, which is determined by its impact on quality of life and the risk of vision loss. It is classified into mild, moderate, severe, or sight-threatening categories⁶.

Mild

• Minimal impact on daily life
• Symptoms include:
  • Minor lid retraction (<2 mm)
  • Mild soft tissue involvement
  • Exophthalmos <3 mm (above normal range)
  • Transient double vision
  • Corneal exposure is still responsive to lubricants

Moderate to severe

• Significant impact on daily life, may require immunosuppressive medications or surgery
• Symptoms include:
  • Lid retraction (>2 mm)
  • Moderate or severe soft tissue involvement
  • Exophthalmos ≥3 mm (above normal range)
  • Inconstant or constant double vision

Sight-threatening

• Requires immediate intervention due to severe complications regarding vision
• Symptoms include:
  • Dysthyroid optic neuropathy
  • Corneal breakdown due to severe exposure
  •  Eyes popping out of their sockets
  • Severe frozen eye, choroidal folds, or postural visual darkening

The table below helps in understanding the classification, symptoms, and required interventions for different severities of TED.

Summary

Managing TED requires a multidisciplinary approach, with physicians and endocrinologists ensuring early diagnosis and normal thyroid function long-term for prevention. Other precautions, like stopping smoking, psychological support, and counseling, are essential to reduce the impact of this disease. These small steps can improve the disease's impact on mental health, vision, and appearance. 

Treatment options include intravenous glucocorticoids for active moderate to severe cases, orbital radiotherapy as a second-line treatment, surgical decompression for optic neuropathy, rehabilitative surgery in inactive disease, and emerging therapies like monoclonal antibodies and thyroid-stimulating hormone receptor (TSH-R) antagonists.

Ophthalmologists and oculoplastic specialists oversee long-term care, focusing on both medical treatment and cosmetic rehabilitation. The VISA and EUGOGO grading systems, in addition to the CAS system, aid in proper assessment. A simplified activity checklist could help physicians in routine practice.