Ocular Sjögren / ME/CFS Overlap - Ocular Surface
1 Lépine et al. 2024 — Sjögren Tear Proteomics Biomarkers
Full Citation:: Lépine M, Robert M-C, Sleno L. Discovery and Verification of Sjögren’s Syndrome Protein Biomarkers in Tears by Targeted LC-MRM. Journal of Proteome Research. 2024;23(6):2219–2229. (Lépine, Robert, and Sleno 2024) DOI:: 10.1021/acs.jproteome.4c00163 PMID:: 38682820 Study Design:: Discovery/verification of tear protein biomarkers; targeted LC-MRM across 3 cohorts Key Findings::
- Identified tear protein panel discriminating Sjögren's dry eye from non-Sjögren's dry eye
- Targeted LC-MRM methodology established for tear proteomics verification
- Demonstrates feasibility of tear-based biomarker approach for autoimmune dry eyeConclusion:: Tear proteomics can distinguish Sjögren’s from non-autoimmune dry eye. Limitations:: Moderate sample size; single center; needs independent validation. ME/CFS Relevance:: Provides the methodological framework for tear proteomics as non-invasive diagnostic window into systemic immune dysregulation. If analogous tear proteomic signatures exist in ME/CFS, this approach could enable non-invasive stratification. Certainty Assessment::
- *Score:* 0.502 George et al. 2023 — Tear Proteomics to Discriminate SjS from Non-SjS Sicca
Full Citation:: George CT, Kurien BT, Scofield RH. The Potential Utility of Salivary and Tear Proteomics to Discriminate Sjögren’s Disease from Non-Sjögren’s Sicca. International Journal of Molecular Sciences. 2023;24(24):17497. (George, Kurien, and Scofield 2023) DOI:: 10.3390/ijms242417497 PMID:: 38139325 Study Design:: Narrative review of salivary and tear proteomics Key Findings::
- Tear proteomic signatures in SjS include T-cell activation proteins, immune response markers, β-2 microglobulin
- Proteomics can distinguish SjS from non-SjS sicca
- Salivary and tear proteomics show promise for non-invasive diagnosisConclusion:: Tear proteomics is a practical tool for classifying Sjögren’s disease and distinguishing it from non-SjS sicca. Limitations:: Narrative review; no quantitative synthesis; heterogeneous methods across studies. ME/CFS Relevance:: The sicca phenotype in CFS/ME may overlap with SjS without meeting full diagnostic criteria. Tear proteomics could help distinguish ME/CFS-associated sicca from true Sjögren’s overlap, guiding workup. Certainty Assessment::
- *Score:* 0.503 Wu et al. 2024 — Sjögren Dry Eye Diagnostics Review
Full Citation:: Wu KY, Serhan O, Faucher A, Tran SD. Advances in Sjögren’s Syndrome Dry Eye Diagnostics: Biomarkers and Biomolecules beyond Clinical Symptoms. Biomolecules. 2024;14(1):80. (Wu et al. 2024) DOI:: 10.3390/biom14010080 PMID:: 38254680 Study Design:: Comprehensive narrative review Key Findings::
- Documents tear film biomarkers for SjS-DED: IL-6, IL-17, MMP-9, BAFF, IFN-γ
- Corneal confocal microscopy parameters (CNFD, CNFL, DC density) differentiate SjS from non-SjS dry eye
- Tear proteomics, metabolomics, and imaging modalities reviewed
- IL-6 and MMP-9 in tears correlate with systemic disease activityConclusion:: Multi-modal biomarker approach improves SjS dry eye diagnosis beyond clinical assessment. Limitations:: Narrative review; no systematic methodology; biomarker panels need validation. ME/CFS Relevance:: The tear inflammatory markers (IL-6, IL-17, MMP-9) that track SjS disease activity are the same markers elevated systemically in ME/CFS. This establishes the biochemical bridge: ocular surface cytokines reflect systemic neuro-immune status. Corneal confocal microscopy parameters provide a non-invasive window into small-fiber pathology analogous to ME/CFS. Certainty Assessment::
- *Score:* 0.554 Luzu et al. 2022 — CCM in Sjögren’s with/without SFN
Full Citation:: Luzu J, Labbé A, Réaux-Le Goazigo A, Rabut G, Liang H, Dupas B, Baudouin C. In vivo confocal microscopic study of corneal innervation in Sjögren’s Syndrome with or without small fiber neuropathy. The Ocular Surface. 2022;25:155–162. (Luzu et al. 2022) DOI:: 10.1016/j.jtos.2022.07.003 PMID:: 35872076 Study Design:: Cross-sectional IVCM study Key Findings::
- Corneal subbasal nerve parameters differed significantly between SS-SFN+ and SS-SFN- groups
- CCM detected corneal nerve changes correlating with SFN status in SS patients
- Corneal nerve loss is a marker of systemic small-fiber involvement in autoimmune diseaseConclusion:: CCM can identify the presence of SFN in Sjögren’s syndrome patients. Limitations:: Moderate sample; single center; SFN diagnosis by clinical criteria not skin biopsy. ME/CFS Relevance:: Directly analogous to ME/CFS: both conditions have a subset with SFN, and CCM can detect it non-invasively. The SS-SFN+ CCM profile may match the ME/CFS SFN subset profile. Certainty Assessment::
- *Score:* 0.555 Wang et al. 2025 — CCM Predicts Serological Activity in Sjögren’s
Full Citation:: Wang Y, Jiang X, Li J, Li X. Predictive value of dry eye disease signs and corneal in vivo confocal microscopy on serological activity in primary Sjögren disease. Medicine. 2025;104(14):e42054. (Wang et al. 2025) DOI:: 10.1097/MD.0000000000042054 PMID:: 40193661 Study Design:: Cross-sectional study comparing IVCM findings in SjS-DED vs non-SjS DED Sample Size:: 42 pSS patients (84 eyes), 41 non-pSS DED patients (82 eyes) Key Findings::
- pSS patients had significantly lower corneal nerve density (CND, $p \\< 0.0001$)
- pSS patients had higher corneal dendritic cell density (DCD)
- IVCM parameters combined with clinical signs predicted serological activity (anti-Ro/La, IgG)Conclusion:: CCM helps differentiate SjS-DED and predicts autoimmune activity. Limitations:: Cross-sectional; moderate sample; single center; Asian population only. ME/CFS Relevance:: Demonstrates CCM parameters track autoimmune disease activity. For ME/CFS, CCM could similarly track neuro-immune activity and stratify patients into SFN+ vs SFN- subsets. Certainty Assessment::
- *Score:* 0.556 Vergés et al. 2025 — Fibromyalgia-Associated Dry Eye: CCM + Genetics
Full Citation:: Vergés C, Giménez-Capitán A, Ribas V, Martínez-Pérez E, González MJ, March de Ribot F. Clinical and genetic profiling of fibromyalgia-associated dry eye: A multifactorial approach. The Ocular Surface. 2025;38:377–387. (Vergés et al. 2025) DOI:: 10.1016/j.jtos.2025.10.012 PMID:: 41177509 Study Design:: Cross-sectional multifactorial study (IVCM + genetics + clinical) Key Findings::
- FM-DED patients had corneal nerve abnormalities on IVCM
- COMT and MTHFR polymorphisms associated with dry eye severity in FM
- Corneal nerve changes suggest neuro-immune phenotype in FM dry eyeConclusion:: FM-associated dry eye is a neuro-immune condition with detectable corneal nerve changes. Limitations:: Cross-sectional; moderate sample; novel finding requiring replication. ME/CFS Relevance:: Directly demonstrates that fatigue-spectrum conditions (FM) have measurable ocular surface abnormalities. Provides evidence for the ocular surface as window into neuro-immune status. ME/CFS may show similar patterns given high FM-ME/CFS overlap (~47%). Certainty Assessment::
- *Score:* 0.507 Tavakoli et al. 2015 — Normative Values for Corneal Confocal Microscopy
Full Citation:: Tavakoli M, Ferdousi M, Petropoulos IN, et al. Normative values for corneal nerve morphology assessed using corneal confocal microscopy: a multinational normative data set. Diabetes Care. 2015;38(5):838–843. (Tavakoli et al. 2015) DOI:: 10.2337/dc14-2311 PMID:: 25633665 Study Design:: Multicenter multinational cross-sectional normative data study Sample Size:: Large multinational cohort of healthy participants Key Findings::
- Established age-adjusted normative reference values for corneal nerve fiber density (CNFD), branch density (CNBD), fiber length (CNFL), and tortuosity
- Multicenter collaboration providing worldwide reference standards
- Values enable clinical translation and wider use of CCM across peripheral neuropathiesConclusion:: Age-adjusted normative CCM values are essential for interpreting corneal nerve morphology across disease states. Limitations:: Limited ethnic diversity; need for device-specific reference ranges. ME/CFS Relevance:: Provides the reference framework for interpreting CCM findings in ME/CFS patients. Our CNFD comparisons against normative data depend on these reference values. Certainty Assessment::
- *Quality:* High (multinational, multicenter, large sample)
- *Sample:* Large
- *Replication:* Established standard in the field
- *Score:* 0.808 Cao et al. 2022 — Corneal Nerve Reference Values for Chinese Adults
Full Citation:: Cao J, Qu J, Odilov B, et al. Corneal nerve parameter reference values for Chinese adults assessed by corneal confocal microscopy. Journal of Diabetes Research. 2022;2022:4913031. (Cao et al. 2022) DOI:: 10.1155/2022/4913031 PMID:: 35265718 Study Design:: Cross-sectional reference value study Sample Size:: Healthy Chinese adults Key Findings::
- Established CCM reference values specific to Chinese adults
- Identified age and sex associations with CNFD and CNFL
- Confirms normative values generalize across ethnic populationsConclusion:: Ethnicity-specific reference ranges may be needed for CCM interpretation. Limitations:: Single ethnic group; moderate sample size. ME/CFS Relevance:: Supports use of population-appropriate normative data when interpreting CCM in diverse ME/CFS cohorts. Certainty Assessment::
- *Quality:* Medium
- *Sample:* Moderate
- *Replication:* Consistent with Tavakoli 2015
- *Score:* 0.609 Oreskovic et al. 2026 — CCM as Paraclinical Test in Neurodegenerative Disease
Full Citation:: Oreskovic I, Petzold A, Petropoulos IN, Hau S. Corneal confocal microscopy as a paraclinical test in neurodegenerative disease: a scoping review. British Journal of Ophthalmology. 2026. (Oreskovic et al. 2026) Study Design:: Scoping review Key Findings::
- Comprehensive mapping of CCM evidence across neurodegenerative diseases (PD, MS, AD, ALS)
- CCM shows promise as cross-disease neurodegeneration biomarker
- Identified major research gaps: longitudinal data, standardized protocols, disease-specific signaturesConclusion:: CCM is a promising paraclinical test for neurodegeneration but requires methodological standardization. Limitations:: Scoping review — does not provide pooled quantitative estimates. ME/CFS Relevance:: Directly supports the argument for CCM as a cross-disease biomarker applicable to ME/CFS. Identifies the same gaps present in ME/CFS literature. Certainty Assessment::
- *Quality:* High (systematic scoping review methodology)
- *Sample:* Large literature base
- *Replication:* Systematic synthesis
- *Score:* 0.7010 Ranathunga et al. 2026 — Small Fibre Pathology in Non-Neuropathic Chronic Pain
Full Citation:: Ranathunga N, Sterling M, Sierra-Silvestre E, et al. Small nerve fibre pathology in non-neuropathic chronic pain conditions: a systematic review and meta-analysis. Pain. 2026;167(3):577–590. (Ranathunga et al. 2026) DOI:: 10.1097/j.pain.0000000000003826 PMID:: 41114676 Study Design:: Systematic review and meta-analysis Key Findings::
- Significant small fiber pathology across ICD-11 non-neuropathic chronic pain conditions
- Reduced IENFD and abnormal CCM metrics in fibromyalgia and related conditions
- Provides strong evidence for SFN as a transdiagnostic feature in chronic painConclusion:: Small fiber pathology is a transdiagnostic feature of chronic pain conditions not traditionally classified as neuropathic. Limitations:: Heterogeneity across studies; limited longitudinal data. ME/CFS Relevance:: Directly supports the transdiagnostic SFN framework into which ME/CFS fits. Fibromyalgia findings are highly relevant given ME/CFS-FM overlap. Certainty Assessment::
- *Quality:* High (systematic review with meta-analysis)
- *Sample:* Large (multiple studies pooled)
- *Replication:* Consistent across conditions
- *Score:* 0.7511 Sommer and Üçeyler 2025 — Small Fiber Pathology in Fibromyalgia
Full Citation:: Sommer C, Üçeyler N. Small fiber pathology in fibromyalgia syndrome. Pain Reports. 2025;10(1):e1223. (Sommer and Üçeyler 2025) PMID:: 39726855 Study Design:: Narrative review with evidence synthesis Key Findings::
- ~50% of women with fibromyalgia have reduced skin innervation
- CCM detects SFN in ~59% of FMS patients
- Microneurography shows spontaneous C-fiber activity, mechanosensitivity, enhanced activity-induced slowing
- Consistent across cohorts from different global regionsConclusion:: Converging evidence supports a neuropathic SFN subset in fibromyalgia. Limitations:: Narrative review; no quantitative synthesis. ME/CFS Relevance:: Parallel evidence to the SFN subset in ME/CFS. CCM detection rate (59%) provides benchmark for expected detection in ME/CFS. Certainty Assessment::
- *Quality:* High (authoritative authors, consistent evidence)
- *Sample:* Evidence from multiple cohorts
- *Replication:* Global consistency
- *Score:* 0.7512 Kubat et al. 2026 — CCM in Fibromyalgia: SFN and Treatment Outcomes
Full Citation:: Kubat B, Ozkan G, Sanal Toprak C, Demirci M, Akkaya Turhan S. Corneal confocal microscopy in fibromyalgia syndrome: small fiber neuropathy, and treatment outcomes. Eye. 2026;40(2):279–286. (Kubat et al. 2026) DOI:: 10.1038/s41433-025-04132-2 PMID:: 41318851 Study Design:: Cross-sectional with treatment sub-study Sample Size:: FMS patients and healthy controls Key Findings::
- Reduced CNFD and CNFL with increased corneal dendritic cell density in FMS vs controls
- SNRI (duloxetine) treatment partially reversed corneal nerve changes
- Corneal sensitivity reduced in FMSConclusion:: CCM detects SFN in FMS and may track treatment response. Limitations:: Moderate sample; single center; treatment effect preliminary. ME/CFS Relevance:: Demonstrates CCM can detect treatment response in SFN-associated chronic pain. Same SNRIs used in ME/CFS — suggests potential monitoring tool. Certainty Assessment::
- *Quality:* Medium-low (moderate sample, preliminary treatment data)
- *Sample:* Moderate
- *Replication:* Single center
- *Score:* 0.4513 Akowuah et al. 2025 — CCM in Multiple Sclerosis: Meta-Analysis
Full Citation:: Akowuah PK, Botchway E, Owusu E, et al. Are corneal nerve and dendritic cell parameters assessed via corneal confocal microscopy good markers for multiple sclerosis? A systematic review and meta-analysis. Journal of Neuroimmunology. 2025;407:578697. (Akowuah et al. 2025) DOI:: 10.1016/j.jneuroim.2025.578697 PMID:: 40729966 Study Design:: Systematic review and meta-analysis Key Findings::
- Significant corneal nerve loss (reduced CNFD, CNFL) in MS vs controls
- Increased dendritic cell density in MS — corneal immune activation
- CCM parameters correlate with EDSS disability scoresConclusion:: CCM is a promising biomarker for neurodegeneration and neuroinflammation in MS. Limitations:: Moderate heterogeneity; limited longitudinal data. ME/CFS Relevance:: MS shares immune-mediated neurodegeneration with ME/CFS. Demonstrates CCM captures both nerve loss and immune activation relevant to ME/CFS pathophysiology. Certainty Assessment::
- *Quality:* High (meta-analysis)
- *Sample:* Multiple studies pooled
- *Replication:* Consistent effect across studies
- *Score:* 0.7214 Yin et al. 2025 — Corneal Nerve Loss Predicts Pain in Parkinson’s Disease
Full Citation:: Yin P, Guan C, Niu X, et al. Corneal nerve loss measured by corneal confocal microscopy predicts pain severity in Parkinson’s disease. Neurobiology of Disease. 2025;217:107197. (Yin et al. 2025) DOI:: 10.1016/j.nbd.2025.107197 PMID:: 41260307 Study Design:: Cross-sectional with pain phenotyping Key Findings::
- CNFD independently predicted pain severity in PD
- Corneal nerve loss correlates with small fiber involvement in PD
- Links central neurodegeneration to peripheral small fiber pathologyConclusion:: CCM-derived CNFD is a predictor of pain severity in PD-associated SFN. Limitations:: Moderate sample; cross-sectional. ME/CFS Relevance:: Pain-SFN correlation in PD parallels pain mechanisms in ME/CFS. Supports CCM as tool to quantify SFN contribution to symptom severity. Certainty Assessment::
- *Quality:* Medium
- *Sample:* Moderate
- *Replication:* Consistent with broader PD-CCM literature
- *Score:* 0.6515 Niu et al. 2024 — CCM Distinguishes MSA from Parkinson’s Disease
Full Citation:: Niu X, Yin P, Guan C, et al. Corneal confocal microscopy may help to distinguish Multiple System Atrophy from Parkinson’s disease. NPJ Parkinson’s Disease. 2024;10(1):75. (Niu et al. 2024) PMID:: 38493181 Study Design:: Cross-sectional diagnostic accuracy study Sample Size:: 63 PD, 30 MSA, 31 healthy controls Key Findings::
- CCM distinguished MSA from PD using differential corneal nerve loss patterns
- Disease-specific CCM signatures beyond simple nerve loss
- CNFD and CNFL differed between MSA and PDConclusion:: CCM may aid differential diagnosis of parkinsonian disorders. Limitations:: Moderate sample; single center; needs replication. ME/CFS Relevance:: Disease-specific CCM signatures raise the possibility of CCM distinguishing ME/CFS from overlapping conditions (fibromyalgia, post-COVID). Certainty Assessment::
- *Quality:* Medium
- *Sample:* Moderate
- *Replication:* Novel finding requiring replication
- *Score:* 0.5516 Yang et al. 2025 — CCM Differentiates Secondary Parkinsonism from Idiopathic PD
Full Citation:: Yang H, Xin R, Che N, et al. Corneal confocal microscopy differentiates patients with secondary parkinsonism from idiopathic Parkinson’s disease. NPJ Parkinson’s Disease. 2025;11(1):93. (Yang et al. 2025) DOI:: 10.1038/s41531-025-00969-2 PMID:: 40325027 Study Design:: Cross-sectional diagnostic accuracy study Sample Size:: 45 PD, 25 secondary parkinsonism Key Findings::
- CCM distinguished idiopathic PD from secondary parkinsonism with good diagnostic accuracy
- Disease-specific CCM signatures
- Supports CCM as differential diagnostic toolConclusion:: CCM has diagnostic utility beyond simple neuropathy detection. Limitations:: Moderate sample; needs external validation. ME/CFS Relevance:: Demonstrates CCM specificity at differential diagnosis — relevant for distinguishing ME/CFS from phenotypically similar conditions. Certainty Assessment::
- *Quality:* Medium
- *Sample:* Moderate
- *Replication:* Consistent with Niu 2024
- *Score:* 0.6017 Baghdasaryan et al. 2026 — CCM Detects Early Chemotherapy-Induced Polyneuropathy
Full Citation:: Baghdasaryan N, Hettlich H, Katz M, Navasardyan V, Borggrefe J, Fan W. In Vivo Confocal Microscopy of Corneal Subbasal Nerve Plexus Detects Early Chemotherapy-Induced Polyneuropathy. Cornea. 2026;45(5). (Baghdasaryan et al. 2026) DOI:: 10.1097/ICO.0000000000003948 PMID:: 40757907 Study Design:: Prospective pilot study Key Findings::
- CCM detected chemotherapy-induced polyneuropathy earlier than clinical assessment
- Demonstrates utility for treatment monitoring and early intervention
- Subbasal nerve plexus changes precede clinical symptomsConclusion:: CCM enables early detection of toxic neuropathy. Limitations:: Pilot; small sample; single chemotherapy type. ME/CFS Relevance:: Demonstrates CCM sensitivity to detect early/subclinical nerve damage — relevant for detecting SFN in ME/CFS where symptoms may precede objective findings. Certainty Assessment::
- *Quality:* Low-Medium (pilot study)
- *Sample:* Small
- *Replication:* Single center, needs replication
- *Score:* 0.4018 Ghadban et al. 2025 — CCM vs Skin Biopsy in Mixed Etiology Polyneuropathy
Full Citation:: Ghadban R, Bay-Smidt M, Bjørnkær T, et al. The Correlation Between Functional and Morphometric Small Fiber Assessment in Mixed Etiology Polyneuropathy. Journal of the Peripheral Nervous System. 2025;30(2):e70005. (Ghadban et al. 2025) PMID:: 40791097 Study Design:: Cross-sectional method comparison study Key Findings::
- Direct head-to-head comparison of CCM vs skin biopsy (IENFD) vs QST
- CCM and IENFD showed moderate correlation
- CCM offers non-invasive alternative to skin biopsy for SFN diagnosis
- Both measures correlated with functional assessmentsConclusion:: CCM is a valid non-invasive alternative to skin biopsy for SFN assessment. Limitations:: Moderate correlations; mixed etiologies. ME/CFS Relevance:: Provides the method comparison data needed to argue CCM over skin biopsy in ME/CFS (less invasive, more acceptable to patients). Certainty Assessment::
- *Quality:* Medium
- *Sample:* Moderate
- *Replication:* Consistent with prior comparison studies
- *Score:* 0.6019 van Welie et al. 2026 — CCM in Migraine
Full Citation:: van Welie FC, van Welie S, Dahan A, Tavakoli M, van Velzen M, Terwindt GM. Corneal confocal microscopy reveals nerve fiber alterations in migraine irrespective of subtype or visual hypersensitivity. Cephalalgia. 2026. (Welie et al. 2026) PMID:: 41603452 Study Design:: Cross-sectional case-control study Key Findings::
- CCM detected corneal nerve alterations in migraine vs controls
- Effect independent of migraine subtype or visual hypersensitivity
- Demonstrates trigeminal small fiber involvement in migraineConclusion:: Trigeminal small fiber pathology is present in migraine. Limitations:: Cross-sectional; moderate sample. ME/CFS Relevance:: Extends CCM cross-disease utility to primary headache disorders — relevant given high headache/migraine comorbidity in ME/CFS. Certainty Assessment::
- *Quality:* Medium
- *Sample:* Moderate
- *Replication:* Novel finding
- *Score:* 0.5520 Gharib et al. 2025 — CCM as Biomarker of SFN in SLE
Full Citation:: Gharib M, Ponirakis G, Dafaalla M, et al. Corneal confocal microscopy: a novel biomarker of small fibre neuropathy in SLE. Lupus Science & Medicine. 2025. (Gharib et al. 2025) PMID:: 41130614 Study Design:: Cross-sectional study Key Findings::
- CCM detected small fiber damage in SLE correlating with disease activity
- Correlated with neuropathic pain severity and quality of life
- Expands cross-disease evidence to autoimmune connective tissue diseaseConclusion:: CCM is a valid biomarker for SFN in SLE. Limitations:: Moderate sample; cross-sectional. ME/CFS Relevance:: SLE shares autoimmune features with ME/CFS. Demonstrates CCM captures autoimmune-mediated SFN, relevant to ME/CFS autoimmune hypotheses. Certainty Assessment::
- *Quality:* Medium
- *Sample:* Moderate
- *Replication:* Consistent with earlier SLE-CCM literature (Bitirgen 2021)
- *Score:* 0.6021 Cantrell et al. 2025 — CCM in POTS
Full Citation:: Cantrell S, Rilinger J, Stallkamp Tidd C, Wilson R. Corneal Confocal Microscopy in Postural Orthostatic Tachycardia Syndrome (POTS) as a Diagnostic Tool for Small Fiber Neuropathy. Cureus. 2025. (Cantrell et al. 2025) PMID:: 40271232 Study Design:: Cross-sectional pilot study Key Findings::
- CCM identified SFN in POTS patients
- Links autonomic dysfunction to corneal nerve abnormalities
- Supports CCM utility in dysautonomia-associated SFNConclusion:: CCM may be a useful diagnostic tool for SFN in POTS. Limitations:: Small sample; Cureus (lower-tier journal); preliminary. ME/CFS Relevance:: POTS is highly comorbid with ME/CFS. CCM detection of SFN in POTS provides indirect evidence for shared SFN mechanisms. Certainty Assessment::
- *Quality:* Low
- *Sample:* Small
- *Replication:* Single center, preliminary
- *Score:* 0.3522 Lalive et al. 2009 — IVCM for Treatment Response in Autoimmune Neuropathy
Full Citation:: Lalive PH, Truffert A, Magistris MR, Landis T, Dosso A. Peripheral autoimmune neuropathy assessed using corneal in vivo confocal microscopy. Archives of Neurology. 2009;66(3):403–405. (Lalive et al. 2009) DOI:: 10.1001/archneurol.2008.587 PMID:: 19273761 Study Design:: Longitudinal case report Sample Size:: 1 patient Key Findings::
- Corneal nerve morphology on IVCM paralleled clinical and electrophysiological recovery in anti-MAG neuropathy
- Patient underwent IVIG, plasma exchange, rituximab, corticosteroids sequentially
- IVCM captured nerve fiber changes at peak disease and recovery phaseConclusion:: IVCM can track treatment response in autoimmune peripheral neuropathy — prototype for IVIG response stratification by CCM. Limitations:: Single case; multiple concurrent treatments; no blinding. ME/CFS Relevance:: Establishes proof-of-concept that CCM can stratify IVIG response in immune-mediated SFN, directly applicable to designing IVIG trials in ME/CFS patients with SFN. Certainty Assessment::
- *Quality:* Low (case report)
- *Sample:* n=1
- *Replication:* None
- *Score:* 0.3023 Karakus et al. 2025 — Ocular Surface and CCM in POTS
Full Citation:: Karakus S, Huang JJ, Yashar M, et al. Eye pain and ocular surface characteristics in Postural Orthostatic Tachycardia Syndrome (POTS): The role of autonomic dysfunction. The Ocular Surface. 2025;38:359–364. (Karakus et al. 2025) DOI:: 10.1016/j.jtos.2025.10.009 PMID:: 42183595 Study Design:: Retrospective observational study Sample Size:: 43 POTS patients (39 female; mean age 45.1 yr) Key Findings::
- 38/43 reported ocular pain/dryness; proparacaine testing identified neuropathic origin in 34
- IVCM in 6 cases: reduced nerve density and microneuromas
- Migraine comorbidity (76.7%) strongly associated with pain without staining (OR=15.0)Conclusion:: POTS patients have neuropathic ocular pain driven by altered corneal nerve function rather than classic dry eye. Limitations:: Retrospective; IVCM only in 6/43 (subset bias); no control group for IVCM. ME/CFS Relevance:: More robust evidence than Cantrell 2025 for SFN in POTS. Supports CCM-detected SFN as shared substrate in POTS, which is highly comorbid with ME/CFS. Migraine association relevant to ME/CFS pain phenotypes. Certainty Assessment::
- *Quality:* Medium (observational, higher-impact journal)
- *Sample:* Moderate (n=43)
- *Replication:* Consistent with Cantrell 2025 findings
- *Score:* 0.4524 Carmichael et al. 2022 — CCM in Primary Care for Diabetic Neuropathy Screening
Full Citation:: Carmichael J, Fadavi H, Ishibashi F, Howard S, Boulton AJM, Shore AC, Tavakoli M. Implementation of corneal confocal microscopy for screening and early detection of diabetic neuropathy in primary care alongside retinopathy screening: Results from a feasibility study. Frontiers in Endocrinology. 2022;13:891575. (Carmichael et al. 2022) DOI:: 10.3389/fendo.2022.891575 PMID:: 36313738 Study Design:: Prospective feasibility study Sample Size:: 450 consecutive T1/T2DM subjects in primary care optometry settings Key Findings::
- First study introducing CCM to primary care as DPN screening tool alongside existing retinopathy screening
- CCM completed successfully in 427/450 (94.9%)
- 12.9% had sub-clinical neuropathy (abnormal CNFL) despite no prior neuropathy diagnosis
- 9.2% of short-duration T2DM had abnormal CNFL
- 12.0% had abnormal CNFL despite no diabetic retinopathy
- Significant reductions in CNFD, CNBD, CNFL vs healthy subjects ($p \\< 0.001$)Conclusion:: CCM is feasible in primary care optometry and can detect sub-clinical DPN before traditional signs appear. Limitations:: Single region (UK); optometry-setting specific; automated vs semi-automated analysis concordance evaluated. ME/CFS Relevance:: Demonstrates that CCM can be deployed outside academic ophthalmology centers, making it a realistic screening tool for SFN in ME/CFS patients seen in primary care and community settings. Feasibility rate (94.9%) supports translation to routine clinical use. Certainty Assessment::
- *Quality:* High (prospective, large n, pragmatic design)
- *Sample:* Large (n=450)
- *Replication:* Single study — needs replication in other settings
- *Score:* 0.6025 Stache et al. 2023 — Longitudinal Taxane CIPN with CCM and OCT
Full Citation:: Stache N, Bohn S, Sperlich K, et al. Taxane-Induced Neuropathy and Its Ocular Effects — A Longitudinal Follow-up Study in Breast Cancer Patients. Cancers. 2023;15(9):2444. (Stache et al. 2023) DOI:: 10.3390/cancers15092444 PMID:: 37173911 Study Design:: Prospective longitudinal observational study Sample Size:: 14 paclitaxel-treated BC patients, 10 controls; 4 timepoints (T0: pre-treatment, T1/T2: during, T3: post-treatment) Key Findings::
- First longitudinal study combining oncological exams with CCM + OCT in CIPN
- Largest published CCM mosaics (large-area CLSM) with identical-area re-identification
- Corneal nerve morphology remained stable during treatment
- Retinal thickening detected on OCT (deviation maps)
- No patients developed severe CIPN in this small cohortConclusion:: Advanced biophotonic imaging is a powerful tool for objective assessment of neurotoxic events, with ocular structures as potential biomarkers. Limitations:: Small sample (n=14); minimal CIPN severity in cohort; no significant corneal nerve loss detected (may reflect small sample or protective effect). ME/CFS Relevance:: Demonstrates longitudinal CCM feasibility for monitoring chemotherapy-induced nerve injury. CIPN trajectory (rapid onset, partial recovery) provides an accelerated model for understanding SFN dynamics that may inform ME/CFS SFN progression patterns. Certainty Assessment::
- *Quality:* Medium (small longitudinal, advanced methods)
- *Sample:* Small (n=14)
- *Replication:* Single study
- *Score:* 0.4526 Sterenczak et al. 2021 — Longitudinal Dendritic Cell Burst During Chemotherapy
Full Citation:: Sterenczak KA, Stache N, Bohn S, et al. Burst of Corneal Dendritic Cells during Trastuzumab and Paclitaxel Treatment. Diagnostics. 2021;11(5):838. (Sterenczak et al. 2021) DOI:: 10.3390/diagnostics11050838 PMID:: 34066952 Study Design:: Longitudinal case report with 3 timepoints and region re-identification Sample Size:: 1 HER2+ breast cancer patient Key Findings::
- Same corneal SNP regions re-identified at baseline, 6wk, and 11wk of therapy
- Subbasal nerve morphology remained stable
- Dendritic cell density increased dramatically with a local burst at 11wk
- Demonstrates CCM can track immune cell dynamics, not just nerve morphologyConclusion:: Corneal DC density may serve as biomarker of chemotherapy-induced ocular inflammation. Limitations:: n=1; cannot generalize; DC burst not linked to CIPN severity. ME/CFS Relevance:: Demonstrates CCM’s capacity to monitor immune-nerve interactions longitudinally. In ME/CFS, where neuroinflammation and immune activation are hypothesized drivers of SFN, tracking both corneal nerves and dendritic cells could reveal immune-mediated nerve damage dynamics. Certainty Assessment::
- *Quality:* Low (case report)
- *Sample:* n=1
- *Replication:* None
- *Score:* 0.3027 Tyler et al. 2022 — COCO Study: CCM in Oxaliplatin CIPN
Full Citation:: Tyler EF, McGhee CNJ, Lawrence B, et al. Corneal Nerve Changes Observed by In Vivo Confocal Microscopy in Patients Receiving Oxaliplatin for Colorectal Cancer: The COCO Study. Journal of Clinical Medicine. 2022;11(16):4770. (Tyler et al. 2022) DOI:: 10.3390/jcm11164770 PMID:: 36013010 Study Design:: Longitudinal observational study with 12-month follow-up Sample Size:: 23 patients receiving oxaliplatin for GI cancer Key Findings::
- CCM, corneal sensitivity, and clinical neuropathy assessed at baseline, during, and post-treatment
- CNFD did not change significantly overall but correlated with clinical neuropathy at 20 weeks (r=0.61, p=0.01)
- Corneal sensitivity correlated with neuropathy at 12 weeks (r=0.55, p=0.01) and 20 weeks (r=0.64, p=0.006)
- Modest association supports CCM potential for monitoring oxaliplatin CIPNConclusion:: Corneal changes on CCM show moderate association with peripheral neuropathy, indicating potential to identify oxaliplatin-induced CIPN. Limitations:: No significant CNFD group change over time; modest correlations; single-center. ME/CFS Relevance:: Establishes CCM timepoints for CIPN detection (12-20 weeks) relevant to designing accelerated SFN model studies. Oxaliplatin produces predictable, dose-dependent neuropathy that can serve as positive control for CCM sensitivity. Certainty Assessment::
- *Quality:* Medium (prospective longitudinal, moderate n)
- *Sample:* Moderate (n=23)
- *Replication:* Needs confirmation
- *Score:* 0.5528 Chiang et al. 2026 — Dose-Dependent CIPN with CCM
Full Citation:: Chiang JCB, Makrynioti D, Goldstein D, et al. Dose-dependent neurotoxic chemotherapy and corneal nerve morphological changes. Clinical and Experimental Optometry. 2026;109(5):929–937. (Chiang et al. 2026) DOI:: 10.1080/08164622.2025.2606161 PMID:: 41570248 Study Design:: Prospective longitudinal study with 3 timepoints + 12-month follow-up Sample Size:: 15 taxane-treated, 18 oxaliplatin-treated cancer patients Key Findings::
- Dose-dependent corneal nerve reduction per 100 mg/m² neurotoxic chemotherapy (p=0.02)
- Average nerve fibre length (central + inferior whorl) changed earlier and more sensitively than CNFD alone
- Post-treatment, CIPN patients had lower CNFL at mid and end of treatment vs those without persistent neuropathy (p=0.02, p=0.006)
- Inferior whorl imaging improved sensitivity over central cornea aloneConclusion:: Average nerve fibre length loss may have clinical utility as early marker of CIPN progression; wider-area imaging including inferior whorl is more beneficial. Limitations:: Modest sample; heterogeneous chemotherapy regimens; no blinding. ME/CFS Relevance:: Most methodologically rigorous longitudinal CCM-CIPN study. Dose-response relationship provides quantitative template for modelling SFN progression. Inferior whorl > central cornea finding directly applicable to ME/CFS CCM protocol design. Supports the “accelerated model” concept: CIPN compresses years of SFN progression into weeks. Certainty Assessment::
- *Quality:* Medium-high (prospective longitudinal, dose-response analysis, adequate n)
- *Sample:* Moderate (n=33 total)
- *Replication:* Converges with Tyler 2022, Stache 2023
- *Score:* 0.55