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Eye Signs in Hyperthyroidism (Thyroid Eye Disease / Graves Ophthalmopathy)

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Lid Signs

Key distinction: Lid retraction and lid lag are not the same as exophthalmos. In lid retraction, the upper eyelid is higher than normal but the eyeball is not displaced forward. In exophthalmos, the eyeball itself is pushed forward. - S Das Manual on Clinical Surgery, p. 387-388

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Exophthalmos / Proptosis

• Can be unilateral or bilateral (and is often asymmetric)
• When severe, leads to lagophthalmos (inability to fully close the eye)
• Complications: exposure keratopathy, corneal ulceration, bacterial keratitis

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Soft Tissue Signs

• Periorbital and eyelid oedema
• Conjunctival injection (Goldzeiher's sign - conjunctival redness)
• Chemosis - oedema of the conjunctiva (becomes thickened, crinkled) due to obstruction of venous and lymphatic drainage by raised retro-orbital pressure
• Tearing, photophobia, orbital discomfort
• Superior limbic keratoconjunctivitis

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Restrictive Myopathy (Ophthalmoplegia)

• I - Inferior rectus (most common) → defective elevation (mimics superior rectus palsy)
• M - Medial rectus → defective abduction (mimics 6th nerve palsy)
• S - Superior rectus → defective depression
• O - Oblique muscles
• Lateral rectus is rarely involved; an exotropia in thyroid disease should raise suspicion of concurrent myasthenia gravis

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Optic Neuropathy (Most Serious Complication)

• Critical point: Optic nerve compression can occur with little or no proptosis
• Presents with reduced visual acuity, colour desaturation, afferent pupillary defect
• Patients should be advised to self-monitor by alternately occluding each eye and checking colour perception

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Summary Table (All Named Signs)

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Important Notes

• Lid retraction is the single most common clinical feature of Graves ophthalmopathy - Localization in Clinical Neurology, 8e, p. 428
• Sympathetic signs (Dalrymple's, Von Graefe's, Stellwag's, Joffroy's, Moebius') can occur in any cause of thyrotoxicosis
• Infiltrative signs (proptosis, restrictive myopathy, optic neuropathy, chemosis) are specific to Graves disease
• Ophthalmopathy may appear before, during, or after thyroid disease and can even occur in the absence of thyroid dysfunction
• Radioiodine therapy may worsen ophthalmopathy

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Mechanism of Proptosis in Hyperthyroidism (Graves Ophthalmopathy)

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The Core Problem: Fixed Space, Expanding Contents

1. Enlarged extraocular muscles (dominant contributor)
2. Increased orbital fat volume

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Step-by-Step Mechanism

Step 1 - Loss of Immune Tolerance

Step 2 - T Cell Infiltration of the Orbit

• Interferon-γ (IFN-γ)
• Tumour necrosis factor (TNF)
• Interleukin-1 (IL-1)

Step 3 - Orbital Fibroblast Activation (Key Step)

• Secrete large amounts of glycosaminoglycans (GAGs) - particularly hyaluronic acid - and deposit collagen fibrils in the extraocular muscles and orbital fat
• These GAGs are extremely hydrophilic and can bind many times their weight in water
• This causes massive water retention, oedema, and swelling of the extraocular muscles

"Retrobulbar fibroblasts secrete glycosaminoglycans, causing engorgement of the extraocular muscles and orbital fat and increasing the volume of the orbital contents." - Cummings Otolaryngology, p. 2429

Step 4 - IGF-1R Pathway (Additional Mechanism)

Step 5 - Orbital Volume Expansion

• Extraocular muscles become massively engorged and swollen
• Orbital fat volume increases
• Intra-orbital pressure rises
• The eyeball is displaced forward = proptosis

Step 6 - Late-Stage Fibrosis

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Diagram of Mechanism

TSH-R autoantibodies (TRAb/TSI)
          ↓
Autoreactive T cells sensitised to TSH-R
(shared antigen: thyroid + orbital tissues)
          ↓
T cell infiltration of orbit + cytokine release
(IFN-γ, TNF, IL-1) + IGF-1R co-signalling
          ↓
Orbital fibroblast activation
          ↓
↑ Glycosaminoglycan synthesis (hyaluronic acid)
+ collagen deposition in extraocular muscles & fat
          ↓
GAGs bind water → oedema + muscle swelling
+ Increased orbital fat volume
          ↓
↑ Intra-orbital pressure in rigid bony orbit
          ↓
Eyeball displaced forward = PROPTOSIS
          ↓ (late)
Irreversible fibrosis → restrictive myopathy

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Consequences of Raised Intra-orbital Pressure

Important: Optic nerve compression can occur in the absence of significant proptosis - the apex of the orbit is where the muscles are most crowded and compression of the optic nerve can occur even when forward displacement is minimal. - Kanski's Clinical Ophthalmology, p. 135

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Therapeutic Relevance

• Corticosteroids / IV methylprednisolone - suppress the inflammatory cytokine phase
• Orbital radiation - targets infiltrating lymphocytes
• Teprotumumab (monoclonal antibody) - blocks TSH-R/IGF-1R complexes on orbital fibroblasts, directly targeting the fibroblast activation step; reduces proptosis significantly
• Orbital decompression surgery - physically enlarges the bony orbit to reduce pressure
• Smoking cessation - smoking upregulates inflammatory cytokines and increases orbital venous congestion, worsening disease by 7-8 fold

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Approach to Paraparesis

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Step 1 - Define the Pattern of Weakness

Note: In acute spinal cord injury ("spinal shock"), a UMN lesion presents initially as a flaccid areflexic paraplegia before spasticity develops over days-weeks.

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Step 2 - Localise the Lesion

A. Is the lesion in the SPINAL CORD (most common) or elsewhere?

• Bilateral cerebral/parasagittal lesions (e.g., meningioma compressing both motor strips, bilateral anterior cerebral artery infarcts) - rare, but brain imaging will show it
• Peripheral - bilateral peripheral neuropathy, Guillain-Barré syndrome (ascending flaccid paralysis)
• Neuromuscular junction - rare
• Muscle - myopathy (proximal weakness, no sensory loss)

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B. If spinal cord - what level?

• The sensory level (highest dermatomal level of impaired sensation on trunk) identifies the approximate cord level - but the actual lesion is typically a few segments above the sensory level
• Root pain / radicular pain and focal back tenderness are the most reliable guides to the exact vertebral level
• The motor deficit level is less reliable than the pain/sensory level

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C. If spinal cord - is the lesion Extradural, Intradural-Extramedullary, or Intramedullary?

"The findings of segmental amyotrophy and sensory loss of dissociated type (loss of pain and temperature with preservation of tactile sensation) point to an intramedullary lesion." - Adams & Victor's Neurology, p. 1278

"If root pain developed early and is bilateral, pain and aching in the spine are prominent, percussion tenderness is marked, and motor symptoms below the lesion preceded sensory ones, and sphincter disturbances were late - suspect extradural lesion." - Adams & Victor's Neurology, p. 1278

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Step 3 - Differential Diagnosis by Mode of Onset

Acute Paraparesis (hours to days)

Subacute Paraparesis (days to weeks)

Chronic/Progressive Paraparesis (months to years)

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Step 4 - Important Clinical Syndromes

Brown-Séquard Syndrome (hemisection of cord)

• Ipsilateral: UMN weakness + loss of proprioception/vibration (dorsal column)
• Contralateral: loss of pain and temperature (spinothalamic tract - crosses at entry level)
• Causes: trauma, MS, tumour, disc herniation

Conus Medullaris Syndrome

• Mixed UMN + LMN features (both cord and nerve root involved)
• Early bladder/bowel dysfunction (urinary retention, constipation)
• Saddle anaesthesia (S3-S5)
• Loss of bulbocavernosus and anal reflexes
• Impotence

Cauda Equina Syndrome

• Pure LMN - flaccid, areflexic, wasting
• Asymmetric weakness (roots compressed differentially)
• Saddle anaesthesia
• Bladder: flaccid retention with overflow incontinence
• Causes: central disc prolapse (L4/5, L5/S1), tumours, trauma - surgical emergency

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Step 5 - Investigations

Urgent (if acute)

• MRI whole spine (with contrast) - investigation of choice; shows cord, lesion, level
• CT spine if MRI unavailable (good for bone/fractures)
• Bloods: FBC, CRP/ESR, coagulation, cultures if infective cause suspected

Routine workup

• MRI brain (if bilateral cerebral cause suspected, or to look for MS plaques)
• CSF analysis: protein (elevated in cord compression - Froin's syndrome in complete block), cells (inflammatory/infective), oligoclonal bands (MS), cytology (malignancy)
• Nerve conduction studies + EMG: differentiate cord from peripheral nerve/root cause
• Evoked potentials: SEPs (sensory) and MEPs (motor) - assess cord conduction
• Bloods: vitamin B12, folate, copper, HTLV-1 antibodies, ANA/ANCA, AQP4-IgG (NMO), HIV
• Bone scan / CT chest-abdomen-pelvis: if metastatic disease suspected

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Step 6 - Flowchart Summary

PARAPARESIS
     |
     ├── ACUTE onset (< 24h) → Emergency: trauma, infarct, haematoma, abscess
     ├── SUBACUTE (days-weeks) → Myelitis, metastases, TB, MS, NMO
     └── CHRONIC (months-years) → Spondylosis, tumour, B12 def, HSP, HTLV-1
     
     ↓
UMN pattern (spastic) vs LMN pattern (flaccid)
     ↓
Sensory level? → Yes → Spinal cord lesion
     ↓
Determine vertebral level (sensory level, root pain, percussion)
     ↓
Extradural vs Extramedullary-Intradural vs Intramedullary
     ↓
MRI spine (with contrast) → Definitive anatomical localisation

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