This episode of “Experts InSight,” hosted by Dr. Ben Young, delves into the complexities of intraocular inflammation (IOI) following intravitreal injections, a rare but significant complication. Dr. Young is joined by combined uveitis specialists and vitreoretinal surgeons, Dr. Chris Conrady and Dr. Akbar Shakoor, who share their expertise on diagnosis, management, and long-term considerations.
What is Intraocular Inflammation (IOI)?
IOI refers to an inflammatory response within the eye after an intravitreal injection.
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Signs and Presentation: Signs can range from mild anterior chamber cells (most common) to severe inflammation resembling endophthalmitis, including hypopyon (pus in the anterior chamber) and obscured posterior views.
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Types: Dr. Conrady distinguishes between:
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Acute Reaction: Occurring within the first five days, typically presenting as anterior chamber inflammation.
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Delayed Onset: More concerning, manifesting as retinal vasculitis or vasculopathy, which can lead to severe vision loss.
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Incidence: Rates vary but are generally low (e.g., 0.09% to 1.1% for bevacizumab). All anti-VEGF agents and complement inhibitors have reported incidences.1
Differentiating IOI from Endophthalmitis
A critical challenge is distinguishing IOI from endophthalmitis (intraocular infection), which is the more common and urgent inflammatory event post-injection.
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No Definitive Acute-Phase Distinction: There’s no single sign that definitively rules out endophthalmitis in the acute phase. Endophthalmitis can present mildly and progress.
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“When in doubt, do a tap and inject”: Dr. Shakoor strongly advises always performing a vitreous tap and inject (administering intravitreal antibiotics) if infection is suspected. This is a crucial first step, as delaying treatment for endophthalmitis can lead to devastating vision loss.2
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Diagnosis of Exclusion: IOI is often a diagnosis of exclusion: symptoms improve with anti-inflammatory therapy but without antimicrobial therapy (or after negative cultures confirm no infection following a tap and inject).
Understanding Retinal Vasculitis
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HORVE (Hemorrhagic Occlusive Retinal Vasculitis): Classically associated with intravitreal vancomycin, believed to be a delayed type IV hypersensitivity reaction.
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IOI-Associated Vasculitis: In some newer anti-VEGF agents and complement inhibitors, occlusive retinal vasculitis can occur with minimal hemorrhage. Fluorescein angiography often reveals profound lack of blood supply to the retina (e.g., no signal beyond first-order arterioles).
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Mechanism:
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Acute (First 5 Days): Likely a different, less severe mechanism.
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Delayed (e.g., 18-20 days mean onset for brolucizumab): Strongly hypothesized to be a delayed type hypersensitivity reaction, often following an initial “sensitization” event to the drug. This involves the immune system “remembering” the antigen and mounting a more robust, but unfortunately damaging, response upon re-exposure. Anti-drug antibodies (ADAs), whether pre-existing or induced, may play a role.
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Drug-Specific Rates: While most anti-VEGF agents have very low IOI rates, brolucizumab is an outlier with a quoted rate over 2% for occlusive retinal vasculitis. Complement inhibitors (e.g., pegcetacoplan) may have similar overall IOI rates to anti-VEGFs, but a higher proportion of these cases manifest as occlusive retinal vasculitis (up to 79% in some series).
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Asymptomatic IOI: While rare, some colleagues have reported finding early vasculitis on detailed examination in asymptomatic patients. However, Drs. Conrady and Shakoor have not personally encountered truly asymptomatic cases, noting that most patients report at least some eye irritation. This highlights the importance of thorough examination for any patient reporting post-injection irritation, not simply attributing it to povidone-iodine.
Initial Management of IOI
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Steroids are Key: Once infection is ruled out, anti-inflammatory therapy, primarily steroids, is crucial.
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Oral Steroids Preferred: Both doctors favor oral steroids (e.g., prednisone 0.5-1 mg/kg initially) over periocular/intraocular injections. Oral steroids offer the advantage of being quickly adjusted or discontinued if the diagnosis changes or side effects occur.
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Combination Therapy: For inflammation in both the anterior and posterior segments (e.g., AC cell with vitritis or retinal involvement), a combination of topical and systemic steroids is often used.
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Early Initiation: For severe cases like occlusive retinal vasculitis, early and aggressive initiation of oral steroids is vital to mitigate retinal damage, but only after adequate antimicrobial coverage is ensured.
Long-Term Management and Future Injections
After an IOI episode, managing subsequent treatment for underlying conditions (e.g., AMD, DME) is complex:
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Patient Counseling: Extensive discussion with the patient about the event, future risks, and the need for close monitoring is essential.
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Switching Agents: The general consensus is to avoid re-injecting the same agent that caused the IOI. Switching to a different anti-VEGF agent is a common approach.
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Immunological Overlap: While switching is often safe, there’s a theoretical concern of immunological overlap between some drugs. However, agents with different molecular structures (e.g., brolucizumab and faricimab lack an Fc fragment, unlike bevacizumab or aflibercept) might have different mechanisms of inflammation, making a switch safer.
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Alternative Therapies: For very recalcitrant cases or those with severe IOI, alternative treatments like photodynamic therapy (PDT) might be considered to reduce the frequency of intravitreal injections and minimize exposure to anti-VEGFs. However, PDT is not a primary treatment for AMD due to its potential for macular damage.
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No Role for Pre-medication: Currently, there is no established role for pre-medicating patients with systemic steroids or antihistamines to prevent IOI, as the underlying mechanism is likely a delayed immune response rather than an acute allergic reaction.
