Garcia-Martin 2016 — FM is correlated with retinal nerve fiber layer thinning

One-paragraph summary

Cross-sectional case-control study of 116 fibromyalgia patients vs. 144 age-matched healthy controls, using two independent spectral-domain OCT devices (Cirrus and Spectralis) to measure retinal nerve fiber layer (RNFL) thickness, ganglion cell layer (GCL) thickness, and inner plexiform layer (IPL) thickness. FM patients showed significant thinning across multiple retinal layers measured by both devices, with regional thinning concentrated in nasal-inferior, temporal-inferior, and temporal-superior sectors. Representative effect size: minimum IPL thickness 74.99 ± 16.63 μm (FM) vs. 79.36 ± 3.38 μm (controls), p = 0.023. The methodological strength — large cohort, dual-instrument confirmation, age-matched controls, multiple retinal layer measurements — is unusual for FM biomarker work and makes this the project's foundational established-tier FM-retinal anchor. The interpretation supported is that FM is associated with retinal ganglion cell axon loss, consistent with chronic excitotoxic injury at the RGC-NMDA-Ca²⁺ interface (the project's I-4 calcium intersection in the v0.2 calcium hypothesis) and/or with the broader neurodegenerative signature of long-standing central sensitization.

Claims as triples

• fibromyalgia — correlates_with → retinal_nerve_fiber_layer_thinning [evidence: dual-device replication, Tables 2-3; confidence: established]
• fibromyalgia — correlates_with → ganglion_cell_layer_thinning [evidence: Cirrus OCT analysis; confidence: emerging]
• fibromyalgia — correlates_with → inner_plexiform_layer_thinning [evidence: 74.99 vs 79.36 μm, p=0.023; confidence: emerging]
• OCT_RNFL_thickness — predicts → fibromyalgia [evidence: cross-sectional discrimination, n=116+144; confidence: emerging — replication-pending for diagnostic claim]
• retinal_ganglion_cell — present_in → fibromyalgia [the affected substrate; inferred from RNFL axon-thinning + GCL-thinning; confidence: emerging]
• central_sensitization — modulates → retinal_ganglion_cell_loss [inferred from chronic-NMDA-excitotoxicity literature; confidence: inferred]

Methods note

Single-site cross-sectional study at a Spanish ophthalmology/rheumatology consortium. 116 FM patients (mean age 53.7) recruited from rheumatology clinic; 144 age-matched healthy controls. Inclusion criteria: ACR 1990 FM diagnostic criteria; exclusion of confounding ocular disease (glaucoma, diabetic retinopathy, prior optic neuritis). Two SD-OCT devices used in parallel: Cirrus HD-OCT (Carl Zeiss Meditec) for macular cube analysis with ganglion-cell-layer + IPL segmentation; Spectralis (Heidelberg Engineering) for peripapillary RNFL analysis. Statistical analysis: t-tests for between-group comparisons, with Bonferroni correction for multiple regional comparisons.

Limitations

• Single-site, single-country cohort — replication priority (see Q-Re-1).
• ACR 1990 criteria predate the project's chain framework — no subtype stratification (anti-SGC IgG status, HαT, etc.) available.
• Medication exposure is reported but the modern observation that long-term pregabalin further thins RNFL was not stratified in the original analysis — implies the FM-vs-control effect size may be partially confounded by FM-treatment exposure.
• Cross-sectional design cannot distinguish whether RNFL thinning precedes FM (constitutive vulnerability) or develops with FM (acquired neurodegenerative signature).
• The retinal nerve fiber layer represents RGC axons; the cause of thinning (axonal degeneration, RGC loss, both) cannot be distinguished by OCT alone.

Open questions raised

• Does the finding replicate independently? (Q-Re-1)
• Does RNFL thinning correlate with anti-SGC IgG titer, CAMKV expression, or other chain-stratification markers in the same patients? (Q-Re-2)
• Is the effect size larger or smaller in newly-diagnosed treatment-naive FM patients than in long-term-medicated patients? Stratification by medication exposure essential.
• Does RNFL thinning track with disease duration and severity?

Triangulation notes

• Anchors §4 of retinal-biomarker-diagnostic-priority.md: this is the established-tier FM-retinal foundation that the rest of the multi-chain retinal-imaging framework rests on.
• Connects directly to the I-4 calcium intersection (calcium-dysregulation-hypothesis.md v0.2): RGC axon loss is mechanistically consistent with chronic NMDA-mediated excitotoxicity at retinal ganglion cells, which is a Ca²⁺-permeable receptor-driven process. CAMKV (Kerrebijn 2025 GWAS hit) operates at the Ca²⁺→transcription step in the same cell type.
• Connects to the H3 / central-sensitization chain: RNFL thinning is consistent with the CNS-distributed long-term-potentiation-driven neuroplastic load that central sensitization predicts. The retina-as-CNS-tissue framing makes this finding mechanistically expected, not surprising.
• Connects to Tan 2025 V2M-LP visual circuit anchor: the green-light analgesia circuit operates on the same retinal-input pathway; chronic alterations to RGC populations would affect that circuit's responsiveness.
• Connects to Coluzzi 2025 (TSPO-PET microglial activation): retinal microglia would be the in-vivo imageable counterpart of TSPO-PET-positive brain microglia. Co-measurement would resolve whether retinal layer thinning correlates with TSPO signal.

Bridges

• B-Re-1 (Fibromyalgia ↔ retinal neurodegenerative signature). Both endpoints FM-anchored (FM = this paper's cohort; retinal neurodegenerative signature = RNFL/GCL/IPL thinning replicated across two devices). Confidence: emerging at population level; reaches established once independently replicated. Status: open replication.