HORD

Here’s a concise, structured summary of the article “Hyperacute Outer Retinal Dysfunction – HORD ” from JAMA Ophthalmology (2025):

🧾 Overview

• Condition described: Hyperacute Outer Retinal Dysfunction (HORD) — a proposed new pediatric retinal disease entity.
• Key features: Sudden, severe bilateral vision loss in children after a febrile illness, with diffuse ellipsoid zone (EZ) and external limiting membrane (ELM) disruption on OCT.
• Study type: Multicenter case series of 8 children (16 eyes) in China, aged 3–7 years.
• Timeframe: November 2022 – May 2023, with ~1 year follow-up.

🔍 Clinical Presentation

• Onset: Mean 16 days after fever (often from common cold–like illness).
• Symptoms:
  • Sudden severe vision loss (all patients)
  • Visual field constriction (100%)
  • Nyctalopia (50%)
  • Color vision abnormalities (25%)
• Initial VA: Mostly hand motion or light perception.
• Fundus: Often normal early; mild vascular attenuation in some.
• OCT early signs:
  • Angular sign of Henle fiber layer hyperreflectivity (ASHH)
  • Hyperreflective dots (HRD)
  • Blurred EZ and intact ELM initially, progressing to EZ/ELM loss.

📊 Disease Course & Imaging

• Progression:
  • Rapid outer retinal layer loss → gradual macular recovery starting ~3–4 weeks.
  • Peripheral EZ/ELM remained absent; macula often recovered.
• 1-year outcomes:
  • VA recovery: 7/8 patients (88%) reached ≥20/40; 4/8 (50%) reached ≥20/25.
  • OCT: Macular EZ intact in 75%, ELM intact in 88%; persistent peripheral loss.
  • ERG: Rod and cone responses extinguished in all patients, even with VA recovery.
  • Fundus: Peripheral pigmentary changes, vessel attenuation.

🧪 Workup & Findings

• Systemic: No evidence of infectious, autoimmune, or inherited retinal disease.
• Genetics: Whole-exome sequencing negative for pathogenic mutations.
• Serology: Mostly negative for antiretinal antibodies; 2 patients positive for anti–PKCγ or anti-Ri.
• Viral testing: Negative in tested cases (including COVID-19, influenza, RSV).

💊 Treatment

• All received corticosteroids (oral or IV); most received IVIG; some had immunosuppressants.
• Recovery timing appeared unrelated to treatment initiation — suggesting possible self-limited course.

🧠 Interpretation & Significance

• Proposed as a distinct entity — different from non-paraneoplastic autoimmune retinopathy (np-AIR) and retinitis pigmentosa (RP) due to:
  • Younger age (mean 5 years)
  • Male predominance
  • Hyperacute onset (within 1 day)
  • Post-febrile trigger
  • Macular recovery with good central vision prognosis
• Possible mechanism: Acute inflammatory process targeting photoreceptors.
• Prognosis: Good central vision recovery, but persistent peripheral dysfunction.

⚠️ Limitations

• Small sample size, no control group, short follow-up (~1 year).
• Causality between febrile illness and HORD not proven.
• Long-term course unknown.

📌 Conclusion

HORD is a likely underrecognized pediatric retinal disorder characterized by:

• Sudden post-febrile bilateral vision loss
• Outer retinal disruption with macular recovery
• Good central vision prognosis despite persistent peripheral retinal dysfunction

Early recognition may improve understanding and guide management, but optimal treatment remains unclear.

🗂 Timeline Highlights

Day 2

• Fundus: Peripheral vascular sheathing

• OCT: Angular sign of Henle fiber layer hyperreflectivity (ASHH), hyperreflective dots (HRD), blurred EZ/ELM

• Clinical: Sudden severe bilateral vision loss

Week 3–4

• OCT: EZ becomes clearer

• Clinical: Visual acuity begins to improve

Month 2–4

• OCT: EZ restored but still disrupted

• Clinical: VA stabilizes

Month 8

• OCT: Intact macular EZ and ELM

• Clinical: Central vision largely recovered

Month 12

• OCT: Recovery of cone outer segment tips (COST)

• ERG: Rod and cone responses remain extinguished

• Autofluorescence: Persistent peripheral changes

• Clinical: Good central VA, but peripheral dysfunction persists

🩺 Condition Overview

• Hyperacute Outer Retinal Dysfunction (HORD): Newly described syndrome in 8 otherwise healthy children (ages 3–7) following a febrile illness.
• Presentation:
  • Sudden, severe, bilateral vision loss (counting fingers or worse).
  • Minimal early fundus changes but OCT showed ellipsoid zone and external limiting membrane disruption.
  • Electroretinography: extinguished photopic and scotopic responses → primary photoreceptor injury.
• Outcome:
  • Partial recovery of central vision (≥20/40 in most) after 1 year.
  • Persistent outer retinal thinning and absent ERG responses.

🔍 Possible Mechanism

• Likely immune-mediated: Viral prodrome in all cases, onset ~2 weeks later → suggests antibody-driven inflammation rather than direct viral infection.
• Early cases showed vitritis, vascular sheathing, and intraretinal hyperreflective dots (inflammatory cells or photoreceptor debris).
• Infectious/inflammatory workups and respiratory viral antigen tests were negative despite concurrent influenza A outbreak.

💊 Treatment

• All received corticosteroids (oral or IV); 7/8 also got IV immunoglobulin.
• No antiviral therapy reported.
• Effectiveness of treatment uncertain due to lack of untreated/control cases.

🔬 Differential Diagnosis & Comparisons

• Shares features with:
  • MEWDS – but HORD is bilateral, more severe, and leaves permanent damage.
  • AZOOR – similar OCT signs but different age group and distribution.
  • Nonparaneoplastic autoimmune retinopathy (np-AIR) – possible molecular mimicry, but rare in children and differs in course.
• Possible analogy to autoimmune encephalitis (“brain on fire”) → antibody-mediated neuroinflammation.

🧪 Research Gaps

• No known antiretinal antibodies detected; possible novel antibody.
• Whole-exome sequencing found no pathogenic variants, but a two-hit hypothesis (genetic susceptibility + inflammatory trigger) is possible.
• Further immune profiling and genetic studies needed.

📌 Takeaway

HORD may be a new pediatric retinal inflammatory disorder causing rapid photoreceptor destruction after viral illness, with partial visual recovery but lasting structural damage.
Future cases could clarify:

• Pathogenesis (immune targets, genetic predisposition)
• Optimal treatment timing and type
• Long-term prognosis and recurrence risk

JAMA Ophthalmol. 2025;143(3):222-229. doi:10.1001/jamaophthalmol.2024.6372