Inclusion Criteria:

1. Confirmed TED (as defined by Bartley and Gorman19)

   - Eyelid retraction (upper eyelid margin at or above the superior corneoscleral limbus in primary gaze without frontalis muscle contraction) in association with any one of the following:

   • Thyroid dysfunction or abnormal regulation (increased serum thyroxine or triiodothyronine level, decreased serum thyroid stimulating hormone level, absence of thyroid radioiodine uptake suppression after administration of triiodothyronine, or the presence of thyroid stimulating immunoglobulins in serum)
   • Exophthalmos (Hertel measurement of at least 20mm)
   • Extraocular muscle involvement (restrictive myopathy or objective evidence of enlarged muscles)
   • Optic nerve dysfunction (abnormal visual acuity, colour vision, pupillary reaction or perimetry not attributable to other causes)

   OR

   - Thyroid dysfunction or abnormal regulation in association with any one of the following:

   -Exophthalmos

   - Extraocular muscle involvement

   - Optic nerve dysfunction

2. Active disease

Inflammatory Index

Inflammatory Index

Soft tissue feature Rating Chemosis 0 Absent

1. Moderate (up to lid margin)
2. Severe (over lid margin; persists on closing eye)

Conjunctival injection 0 Absent 1 Present

Lid injection 0 Absent

1 Present

Lid edema 0 Absent

1. Moderate
2. Severe (festoons, overhang)

Pain at rest (clearly defined as retrobulbar aching) 0 Absent 1 Present

Pain on movement 0 Absent

1 Present

Total possible 8

Active disease is defined as an inflammatory index of at least 3 together with acute or subacute onset (3 months and under) and/or evidence of progression (from history or clinical observation).

(3) Moderate or severe disease

Primary Criteria

Mild Moderate Severe Inflammatory Index <3 3-5 >5

Motility <1/3 1/3 to 2/3 >2/3 (involving any one muscle) limitation limitation Limitation

Elevation, depression, adduction and abduction of the individual eyes will be measured with a modified Aimarck perimeter with input from both patient and the orthoptist who performs the test 20.

Secondary Criteria 21,22,23,24

Mild Moderate Severe Exophthalmos (mm) <21 21-24 25 or more

Best corrected vision (Logmar) - - 0.6 or worse

CT criterion (Muscle Diameter Index) 21-24 25-30 31 and above

These criteria are not considered absolutes and emphasize measurable indices based on previous studies.

The presence of at least 1 primary criterion and at least 1 secondary criterion places the patient in the more advanced disease group (in the situation where 1 primary criterion is mild and the other severe, the presence of 1 severe secondary criterion will yield a severe grade whereas absence of this criterion will result in a mild grade) eg 1) a patient with an inflammatory index of 6 and moderate limitation of extraocular motility, 21mm proptosis, 0.3 vision and MDI of 26 has moderate disease as the secondary criteria for severe disease was not present eg 2) a patient with an inflammatory index of 5 and mild limitation of extraocular motility, 21mm proptosis, 0.3 vision and MDI of 30 has moderate disease as 1 primary and 2 secondary criteria for moderate disease were present eg 3) a patient with inflammatory index of 6 and mild limitation of extraocular motility, 20mm proptosis, 0.3 vision and MDI of 21 has mild disease as the secondary criterion for severe disease was absent and the other primary parameter (motility) was graded mild.

(4) Age between 21 - 60

(5) Written informed consent is obtained

Exclusion Criteria:

1. Previous treatment for TED

   • Oral steroids (e.g. immunosuppressive dose) for last 3 months, radiotherapy
   • Intravenous pulsed steroid or methrotrexate therapy

2. Medically unfit to receive I/V high-dose pulsed methylprednisolone or methotrexate

   • History of cardiac arrthymias, recent acute myocardial infarction
   • History of seizure
   • History of acute bleeding peptic ulcer
   • History of pulmonary tuberculosis, Hepatitis B carrier, Hepatitis C positivity, HIV
   • Uncontrolled diabetes or hypertension (to be eligible for the trial, random blood glucose must be < 11.1 mmol/L and blood pressure must be 140/90 or lower#. If above these limits, patients can be treated and reviewed at 2 weeks for enrolment when criteria are met – provided the patient does not have optic neuropathy)
   • Hepatic dysfunction (Alb, AST, ALT and Alkaline phosphates levels must be within normal range for eligibility)
   • Renal impairment (Urea and Creatinine levels must be within normal range)
   • Abnormal blood count (outside normal range)

3. Others

   • Fertile females considering becoming pregnant during the course of the study and those not willing to take precautions to avoid pregnancy
   • Both female and male planning to start a family during the trial period or within 6 months of stopping the drugs
   • History of seizure
   • History of mental / psychiatric disorder
   • Patients with clinical features of optic nerve disc pallor at primary presentation will be excluded