L.2- Thyroid Eye Disease (TED)

Overview of Thyroid Function and Dysfunction

• Hypothyroidism Definitions and Causes
  • Hashimoto's Thyroiditis: The most common cause of hypothyroidism. It is an autoimmune-mediated attack on the thyroid gland that results in a functional decrease in the production of triiodothyronine ($t3$) and thyroxine ($t4$).
  • Iodine Deficiency: Primarily seen in developing countries as a cause of hypothyroidism.
  • Iodine in Modern Diet: In America, table salt is typically fortified with iodine to prevent deficiency disorders; consequently, iodine-induced hypothyroidism is rare in the US.
• Signs and Symptoms of Hypothyroidism
  • Common manifestations include cold intolerance, fatigue, weight gain, dry skin, and coarse hair.
  • Clinical Metaphor: The patient often presents in a state reminiscent of parasympathetic dominance ("resting, digesting, gaining weight, and always tired").
• Hyperthyroidism Definitions and Causes
  • Characterized by an increased production of thyroid hormones ($t3$ and $t4$).
  • Graves' Disease: The most common cause of hyperthyroidism. It is an autoimmune condition involving thyroid-stimulating autoantibodies that constantly trigger the thyroid gland.
  • Feedback Loop Indices: In hyperthyroidism, the anterior pituitary senses high levels of $t3$ and $t4$, leading to a low measurement of Thyroid-Stimulating Hormone ($TSH$).
• Signs and Symptoms of Hyperthyroidism
  • Manifestations include heart palpitations, weight loss, heat intolerance, and hair loss.
  • Demographics: There is a high predilection for the female population.
  • Clinical Metaphor: The patient presents in a state resembling sympathetic activation.
• Diagnostic Laboratory Values
  • Decreased $TSH$: Resulting from negative feedback mechanism.
  • Increased $t3$ and $t4$: Reflecting hyper-secretion.
  • Antithyroid Antibodies: Present due to the autoimmune nature of the conditions.

Thyroid Eye Disease (TED)

• Terminology and Epidemiology
  • Synonyms: Also known as Thyroid Ophthalmopathy, Thyroid Associated Orbitopathy, or TED.
  • Etiology: While most common in patients with Graves' disease (hyperthyroidism), it can also occur in patients with hypothyroidism or euthyroid status.
  • Demographics: Most frequently affects middle-aged women. The gender ratio is approximately $4$ to $8$ females for every $1$ male.
  • Disease Severity: TED tends to present more severely in males and in patients who are smokers.
  • Prevalence: TED is the most common cause of both unilateral and bilateral proptosis in adults.
• Pathophysiology of TED
  • The autoimmune process specifically targets orbital fibroblasts located in orbital fat and extraocular muscles ($EOM$).
  • Fibroblasts trigger inflammation by stimulating T and B lymphocytes.
  • This leads to the production of pro-inflammatory cytokines and the accumulation of Glycosaminoglycans ($GAGs$) in the interstitial spaces of the $EOM$ and connective tissue.
  • Consequences: Results in orbital fat expansion and physical enlargement of the $EOM$, leading to proptosis and potential diplopia.
• Classification: NOSPECS Mnemonic
  • The disease progression and severity follow the NOSPECS acronym:
    • N: No ocular signs or symptoms.
    • O: Only signs, no symptoms (localized primarily to the eyelids).
    • S: Soft tissue swelling.
    • P: Proptosis.
    • E: EOM involvement.
    • C: Corneal involvement.
    • S: Sight loss (optic nerve head involvement).

Eyelid and Ocular Surface Disorders in TED

• Eyelid Clinical Signs
  • Eyelid Retraction: The upper lid rests abnormally high and the lower lid rests abnormally low.
  • Dalrymple's Sign: Retraction of the upper lid while the patient is in primary gaze.
  • Scleral Show: Superior and inferior sclera become visible. (Note: High myopes, above $-8.00$ diopters, may naturally have more eye elongation/proptosis).
  • Enroth's Sign: Eyelid edema or puffiness, typically worse upon awakening and more prominent on the upper lid.
  • Stellwag's Sign: Reduced frequency of blinking.
  • Von Graefe's Sign: A dynamic marker characterized by lid lag; the upper eyelid remains retracted and stays up while the patient attempts to look down.
• Ocular Surface Manifestations
  • Dry Eye and Exposure Keratopathy: Increased evaporation of tears occurs due to proptosis and lid retraction.
  • Superficial Keratopathy: Identified via fluorescein dye, which pools in areas of epithelial defects (Punctate Epithelial Erosions). The appearance is likened to drizzle on a windshield.
  • Conjunctival Injection/Hyperemia: Vasodilation of the conjunctival vasculature as the eye responds to dryness with inflammation.
  • Superior Limbic Keratoconjunctivitis (SLK): Highly associated with thyroid disease. Characterized by inflammation and friction-induced chafing at the superior portion of the bulbar conjunctiva and limbus. A clinician must pull the lid up and have the patient look down to view the injection.

Proptosis and Extraocular Muscle Involvement

• Measurement of Proptosis
  • Measured using an Exophthalmometer, recording protrusion from the orbit in millimeters ($mm$) relative to a specific base measurement.
  • Normal Ranges by Ethnicity:
    • Whites: $12$ to $22\,mm$.
    • Blacks: $12$ to $24\,mm$.
    • Asians: $12$ to $18\,mm$.
  • Abnormality Threshold: Any difference of $\ge 3\,mm$ between the two eyes is considered abnormal, even if the values fall within standard ranges.
• EOM Restriction and Infiltration
  • Infiltration of muscle bellies causes mechanical restriction rather than a neurological palsy.
  • Frequency of Muscle Involvement Mnemonic: "I'm So Lazy" (Inferior Rectus $>$ Medial Rectus $>$ Superior Rectus $>$ Lateral Rectus).
  • Mechanism: The muscle becomes "tethered." For example, an infiltrated inferior rectus prevents the eye from looking upward (supraduction deficit) because the eye is stuck, not because the superior rectus is weak.
• Forced Duction Testing
  • Used to differentiate between nerve palsy (paresis) and mechanical restriction (infiltration).
  • Negative Forced Duction: The eye moves when physically pulled by forceps, indicating the nerve is paralyzed but the muscle is not physically blocked. Found in CN $III$, $IV$, or $VI$ palsies.
  • Positive Forced Duction: The eye does not move even with physical force, indicating a mechanical or infiltrative restriction.
• Compensatory Findings
  • Resistance to Retropulsion: Difficulty pushing the globe posteriorly into the orbit due to increased volume/pressure.
  • Intraocular Pressure ($IOP$): May be elevated in certain gazes due to restricted muscles compressing the globe.

Sight-Threatening TED and Management

• Compressive Optic Neuropathy
  • Occurs when orbital inflammation and fat expansion compress the optic nerve ($CN II$).
  • Clinical Findings: Severe decrease in visual acuity (e.g., $20/400$, count fingers), reduced color vision (dyschromatopsia), visual field defects, and a Relative Afferent Pupillary Defect ($RAPD$).
  • Note on Bilateral Disease: An $RAPD$ may be absent if both optic nerves are equally compressed, as the defect is "relative."
• Diagnostic Imaging
  • CT Scan: Shows muscle enlargement with a distinct "Coke bottle" appearance (swelling of the muscle belly while sparing the tendons).
  • Contrast with IOI: Idiopathic Orbital Inflammation ($IOI$) typically involves both the muscle belly and the tendon.
• Management Sequence
  • General Rule: Defer irreversible surgeries until a stable interval of $6$ months is achieved.
  • Order of Surgeries: 1. Orbital bony decompression (creating space for tissue to recede), 2. Strabismus surgery (recessing recti muscles), 3. Eyelid reconstruction.
  • Emergency Interventions: Indicated immediately for optic neuropathy or severe corneal ulceration (may involve systemic steroids or tarsorrhaphy).
• Pharmacological and Supportive Care
  • Topical: Preservative-free artificial tears, gels, and immunomodulators like Restasis, Xiidra, or Sequa.
  • Mechanical: Punctal occlusion (collagen plugs), lid taping, or moisture goggles.
  • Teprotumumab (Tepezza): FDA approved in Jan 2020. An IV infusion administered every $3$ weeks for $8$ cycles. Reduces proptosis but carries a risk of ototoxicity (hearing loss).
  • Diplopia Management: Fresnel prisms (stick-on plastic prisms) are preferred during active disease as the amount of required prism may change frequently.

Orbital Tumors and Lesions

• Orbital Cavernous Hemangioma
  • Profile: The most common benign neoplasm in adults ($20$ to $40$ years old), primarily in females.
  • Presentation: Slow, progressive, painless proptosis. Usually located within the common tendinous ring.
  • Imaging: Visualized via MRI, CT, or TRIX ($Time Resolved Imaging with Contrast Kinetics$).
  • Management: Monitoring for small/asymptomatic lesions; surgical excision for large/symptomatic lesions.
• Rhabdomyosarcoma
  • Profile: The most common primary orbital malignancy in children (average age $7$).
  • Clinical Sensation: Rapidly progressive proptosis mimicking an inflammatory process.
  • Key Diagnostic Clue: Frequent nosebleeds due to the release of Vascular Endothelial Growth Factor ($VEGF$) and leaky tumor vessels.
  • Differentiation from Cellulitis: Skin is not warm to the touch, and there is usually no fever.
  • Prognosis: $95\%$ cure rate if confined to the orbit; requires radiation and chemotherapy.

Orbital Surgeries: Enucleation, Evisceration, and Exenteration

• Enucleation
  • Procedure: Complete removal of the entire eyeball, including the scleral shell and intraocular contents; extraocular muscles are detached.
  • Indications: Intraocular malignancy, severe trauma, or a "blind painful eye" recalcitrant to palliative treatment.
  • Follow-up: A spherical implant is placed to maintain volume. A conformer (plastic shell) is worn for $2$ months to prevent the conjunctiva from fusing, followed by a custom prosthetic ($6$ to $8,000\,USD$).
• Evisceration
  • Procedure: Removal of intraocular contents only; the scleral shell and EOM attachments are preserved.
  • Advantages over Enucleation: Shorter surgery, less complex, more cost-efficient, improved prosthetic mobility, and less painful.
  • Disadvantage: Risk of Sympathetic Ophthalmia or dissemination of undetected tumors.
• Exenteration
  • Procedure: Radical removal of the eyeball and all surrounding orbital tissues, including eyelids, fat, muscles, and nerves.
  • Indication: Aggressive malignant tumors involving the eyelid or posterior orbital structures to prevent metastatic spread.