Workup and Management of Elevated Protein C, Neuritis, and Retinal Hemorrhages
Immediate Priority: Rule Out Giant Cell Arteritis (GCA)
If the patient is over 50 years old with neuritis (optic neuritis) and retinal hemorrhages, immediately initiate high-dose corticosteroids (prednisone 40-60 mg daily or methylprednisolone 1g IV) before any diagnostic testing to prevent irreversible bilateral blindness from GCA. 1, 2, 3, 4
Critical Clinical Assessment for GCA
- Ask specifically about new-onset persistent headache (especially temporal), jaw claudication, scalp tenderness, and constitutional symptoms (fever, weight loss, fatigue) 1, 3, 4
- Palpate temporal arteries for tenderness, thickening, or decreased pulse 3
- Perform funduscopy to assess for optic disc edema and the pattern of retinal hemorrhages 1
- Do not delay corticosteroids while awaiting laboratory results or temporal artery biopsy—this is the most dangerous error and the strongest risk factor for permanent blindness 1, 3, 4
Urgent Laboratory Testing (Draw Before Treatment, But Do Not Wait for Results)
- ESR and CRP immediately (elevated in >95% of GCA cases, but 11% have normal inflammatory markers) 1, 3, 4
- Complete blood count with platelets (assess for thrombocytosis or anemia) 4
- If GCA is suspected based on age >50, visual symptoms, and headache, treat immediately regardless of laboratory results 2, 3, 4
Secondary Differential: Systemic Lupus Erythematosus (SLE) with Neuropsychiatric Manifestations
When to Consider SLE-Related Optic Neuritis
- If patient is younger (<50 years), female, or has known autoimmune disease history 1
- Optic neuritis with retinal hemorrhages can occur in SLE, particularly with antiphospholipid antibody syndrome 1
- Funduscopy showing optic disc edema (30-40% of cases) with peripapillary and peripheral retinal hemorrhages suggests inflammatory optic neuritis 1
Diagnostic Workup for SLE-Related Disease
- Brain and orbital MRI with gadolinium contrast (shows optic nerve enhancement in 60-70% of inflammatory optic neuritis) 1
- Antiphospholipid antibodies (lupus anticoagulant, anticardiolipin antibodies, anti-β2-glycoprotein I) 1
- Visual evoked potentials to detect bilateral optic nerve involvement 1
- Fluorescein angiography if vaso-occlusive retinopathy suspected 1
Treatment for SLE-Related Optic Neuritis
- Pulse intravenous methylprednisolone combined with intravenous cyclophosphamide 1
- Consider anticoagulation if antiphospholipid antibodies are positive and patient does not respond to immunosuppressive therapy 1
- Prognosis is poor: only 30% maintain visual acuity >20/25, and relapses are common requiring chronic immunosuppressive therapy 1
Thrombophilia Workup: Elevated Protein C Context
Understanding the Protein C Finding
The phrase "elevated protein C" is unusual—protein C deficiency (not elevation) causes thrombotic complications including retinal vascular occlusions 5, 6, 7. If the laboratory report truly shows elevated protein C, this may represent:
- Acute phase reactant elevation (inflammatory state) 6
- Laboratory error requiring repeat testing 6
- Acquired elevation from oral contraceptives, pregnancy, or other hormonal states 6
If Protein C Deficiency is Present (Corrected Interpretation)
- Protein C deficiency causes retinal arteriolar occlusions and can present with retinal hemorrhages 5, 6
- Prevalence of protein C/S deficiency in retinal vascular occlusion is low overall, but important in young patients (<50 years) 6, 7
- Screen for factor V Leiden mutation (resistance to activated protein C)—present in 29% of central retinal vein occlusions 7
Comprehensive Thrombophilia Panel
- Protein C activity and antigen levels 6, 7
- Protein S (free and total) 6, 7
- Antithrombin III 6
- Factor V Leiden mutation (R506Q) by PCR 7
- Antiphospholipid antibodies (lupus anticoagulant, anticardiolipin, anti-β2-glycoprotein I) 1, 7
- Homocysteine level 8
- Testing should be performed when patient is not acutely ill and not on anticoagulation 6
Retinal Vascular Occlusion Workup
Immediate Ophthalmologic Assessment
- Visual acuity testing and visual field examination 1
- Slit-lamp biomicroscopy with iris examination for neovascularization 1
- Intraocular pressure measurement 1
- Dilated funduscopy to characterize hemorrhage pattern (peripapillary vs. peripheral, presence of Roth spots) 1, 9
- Fluorescein angiography to assess for vaso-occlusive retinopathy and areas of non-perfusion 1
Stroke/TIA Workup (Retinal Artery Occlusion = "Eye Stroke")
- Immediate referral to emergency department with stroke center capability—retinal artery occlusion has the same silent cerebral ischemia rate as hemispheric TIA 1, 2
- Brain MRI with diffusion-weighted imaging to evaluate for acute cerebral infarction 1, 4
- Carotid ultrasound or CTA/MRA to evaluate for carotid stenosis 1, 4
- Echocardiography to assess for cardiac embolic sources 1
- Antiplatelet therapy (aspirin) and statin therapy apply to the vast majority of patients 1
MOG Antibody-Associated Disease (MOGAD)
When to Consider MOGAD
- Optic neuritis with severe optic disc edema, peripapillary hemorrhages, peripheral retinal hemorrhages, and Roth spots 9
- Typically presents with painful visual loss 9
- More common in younger patients 9
Diagnostic Testing
- Serum MOG (myelin oligodendrocyte glycoprotein) antibodies 1, 9
- Orbital MRI showing hyperintensity in optic nerve with gadolinium enhancement 9
- If co-existing transverse myelitis, also test for NMO IgG (aquaporin-4) antibodies 1
Treatment
- Early intravenous high-dose corticosteroids rapidly improve visual acuity and fundus abnormalities 9
- Retinal hemorrhages resolve rapidly with treatment 9
Treatment Algorithm Based on Age and Presentation
Age >50 Years with Optic Neuritis and Retinal Hemorrhages
- Immediately start prednisone 40-60 mg daily (or methylprednisolone 1g IV if severe) 3, 4
- Draw ESR/CRP but do not wait for results 3, 4
- Same-day ophthalmology and rheumatology consultation 3, 4
- Arrange temporal artery biopsy within 2 weeks (remains diagnostic after steroid initiation) 3, 4
- Brain MRI to exclude stroke 4
Age <50 Years with Optic Neuritis and Retinal Hemorrhages
- Urgent brain and orbital MRI with gadolinium 1, 9
- Serum MOG antibodies and comprehensive autoimmune panel (ANA, anti-dsDNA, antiphospholipid antibodies) 1, 9
- Thrombophilia panel if retinal vascular occlusion pattern present 6, 7
- Pulse IV methylprednisolone (typically 1g daily for 3-5 days) 1, 9
- Consider IV cyclophosphamide if SLE-related 1
Any Age with Retinal Artery Occlusion Pattern
- Immediate ED referral to stroke center 1, 2
- Brain MRI with DWI sequences 1, 4
- Carotid imaging and echocardiography 1, 4
- Antiplatelet and statin therapy 1
- Monitor for neovascularization requiring panretinal photocoagulation 1
Critical Pitfalls to Avoid
- Never attribute new-onset headache with visual symptoms to migraine in patients >50 years—always rule out GCA first 3
- Never delay corticosteroids for GCA while pursuing neuroimaging or awaiting biopsy 3, 4
- Never assume "elevated protein C" is protective—verify the result and consider protein C deficiency as the actual pathology 5, 6
- Never dismiss retinal hemorrhages in optic neuritis as benign—they indicate severe inflammation or vascular occlusion requiring urgent treatment 1, 9
- Never forget that retinal artery occlusion requires the same urgent stroke workup as hemispheric TIA 1, 2