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. Author manuscript; available in PMC: 2025 Jan 1.
Published in final edited form as: Clin Exp Ophthalmol. 2023 Nov 12;52(1):10–21. doi: 10.1111/ceo.14313

Dry eye symptoms and signs in United States Gulf War era veterans with myalgic encephalomyelitis / chronic fatigue syndrome

Victor Sanchez 1, Colin Kim 2, Elyana VT Locatelli 3, Adam Cohen 4, Kimberly Cabrera 3, Kristina Aenlle 3,5, Nancy Klimas 5,6, Robert O’Brien 7, Anat Galor 6,7
PMCID: PMC10873051  NIHMSID: NIHMS1937118  PMID: 37953685

Abstract

Background:

To examine ocular symptoms and signs of veterans with myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) diagnosis, ME/CFS symptoms, and controls.

Methods:

This was a prospective, cross-sectional study of 124 South Florida veterans in active duty during the Gulf War Era. Participants were recruited at an ophthalmology clinic at the Miami Veterans Affairs Hospital and evaluated for a diagnosis of ME/CFS, or symptoms of ME/CFS (intermediate fatigue, IF) using the Canadian Consensus criteria. Ocular symptoms were assessed via standardized questionnaires and signs via comprehensive slit lamp examination. Inflammatory blood markers were analyzed and compared across groups.

Results:

Mean age was 55.1±4.7 years, 88.7% identified as male, 58.1% as White, and 39.5% as Hispanic. Ocular symptoms were more severe in the ME/CFS (n=32) and intermediate fatigue (IF) (n=48) groups compared to controls (n=44) across dry eye (DE) (Ocular Surface Disease Index (OSDI): 48.9 ± 22.3 vs. 38.8 ± 23.3 vs. 19.1 ± 17.8, p<0.001; 5 item Dry Eye Questionnaire (DEQ-5): 10.8 ± 3.9 vs. 10.0 ± 4.6 vs. 6.6 ± 4.2, p<0.001) and pain-specific questionnaires (Numerical Rating Scale 1–10 (NRS) right now: 2.4 ± 2.8 vs. 2.4 ± 2.9 vs 0.9 ± 1.5 ; p=0.007; Neuropathic Pain Symptom Inventory modified for the Eye (NPSI-E): 23.0 ± 18.6 vs. 19.8 ± 19.1 vs. 6.5 ± 9.0, p<0.001). Ocular surface parameters and blood markers of inflammation were generally similar across groups.

Conclusion:

Individuals with ME/CFS report increased ocular pain but similar DE signs, suggesting that mechanisms beyond the ocular surface contribute to symptoms.

Keywords: chronic fatigue syndrome, myalgic encephalomyelitis, chronic ocular pain, neuropathic pain, dry eye

1. INTRODUCTION

Myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) is clinically defined as persistent and unexplainable post-exertional fatigue which presents with a wide range of cognitive, immunological, endocrinological, and autonomic symptoms.1 Approximately 836,000 to 2.5 million individuals are affected in the United States (US), generating a substantial personal and societal burden.2 The Canadian Consensus Criteria (CCC) is often used to diagnose ME/CFS and is based on the Depaul3 and short form-36 questionnaires (SF-36).4 The CCC assigns a diagnosis of ME/CFS based on functional impairment as noted by the SF-36 and the presence of longstanding fatigue as well as additional symptoms including sleep problems, pain, and cognitive, and immune dysfunction as documented by the DePaul.5

As noted above, chronic fatigue is a prominent feature of ME/CFS along with a wide variety of other symptoms across several organ systems. For example, individuals with ME/CFS may experience muscle pain, unrefreshing sleep, and impaired memory and concentration.6 However, the symptom profile of individuals with ME/CFS can overlap with other diseases, such as fibromyalgia and functional neurological disorders. For example, one review paper found that individuals with ME/CFS, functional neurologic disorder, and fibromyalgia have similar cognitive profiles including shared symptoms (e.g., forgetfulness, distractibility, word-finding difficulties) accompanied by inconsistent objective neurophysiological deficits (e.g., Cambridge Neuropsychological Test Automated Battery, Paced Auditory Serial Addition Test).7 Psychological stress and personal traumatic events has also been found to be associated with ME/CFS, suggesting that psychiatric mechanisms may also be contributory.8 In veteran populations, Gulf War Illness (GWI), a multi-symptom illness prevalent in veterans of the Gulf War Era, has overlapping features with ME/CFS.9,10

The etiology of ME/CFS is poorly understood. One hypothesis is that viral infection triggers the condition.11,12 Other hypotheses link ME/CFS to hypothalamic-pituitary-adrenal (HPA) axis dysfunction,13 neuro-abnormalities,14 chemical exposures15, and genetic predisposition.16 War time exposures may play a major role in the development of ME/CFS in veteran populations and mediate the relationship between ME/CFS and chronic multisystem diseases such as GWI. One study of 2189 Gulf War era veterans found that the proportion of deployed veterans who had been diagnosed with ME/CFS (n=1061) was significantly higher (1.6% vs 0.1%, OR: 40.6, CI: 10.2–16.1) when compared to non-deployed veterans (n=1128).17 Thus triggers for GWI, such as pesticide exposure18 and pyridostigmine pills (a reversible acetylcholinesterase inhibitor used as pretreatment to nerve agent exposures)19 may also contribute to ME/CFS pathophysiology in veteran cohorts.

Given its association with viral illnesses, activation of the immune system and inflammation have been implicated in the pathogenesis of ME/CFS. Cytokines are inflammatory signaling molecules which have been studied as evidence of immune system activation in ME/CFS. Some, but not all studies, have noted elevations in various interleukins (IL), tumor necrosis factors (TNF) and interferons in patients with ME/CFS compared to controls.20 One US study found that individuals with ME/CFS (n=117) had significantly higher blood IL-1β (38.8 ± 70.2 vs. 20.9 ± 38.5, p<0.03) and IL-6 levels (11.9 ± 19.4 vs. 7.2 ± 12.3, p<0.05) compared to controls (n=95) (units not provided).21 Other studies have reported elevations in other cytokines in ME/CFS22–24, yet others did not observe differences between groups.25 The heterogeneity of the data regarding blood cytokine profiles in ME/CFS warrants continued assessment of their role as a marker of disease, particularly in the context of different ME/CFS symptoms such as ocular discomfort/pain.

Ocular symptoms have been less well characterized in ME/CFS, although both visual disturbances and ocular discomfort have been linked to the syndrome.26 In fact, ocular symptoms are included in the DePaul questionnaire, which prompts patients on the frequency and severity of eye pain, sensitivity to bright lights, inability to focus vision, and loss of depth perception. One study evaluated 59 individuals living in the United Kingdom (UK) with ME/CFS and found a high frequency of sensitivity to bright lights (92%), difficulty focusing (88%), and eye pain (86%), as captured by the DePaul questionnaire.27 Ocular discomfort is often lumped within the diagnosis of DE and in fact, DE and ME/CFS have been linked. One study examined national health insurance records from Taiwan and identified 884 individuals diagnosed with DE and 3536 gender- and age-matched controls. None of the individuals had a diagnosis of ME/CFS at baseline. The authors noted an increased risk of ME/CFS development in individuals with a DE diagnosis compared to controls over a two-year period (hazard ratio (HR): 1.6, 95% confidence interval (CI), 1.0–2.6, p<0.05).28

To better characterize ocular manifestations of ME/CFS and examine the contribution peripheral markers of inflammation, we examined a cohort of veterans split into categories by ME/CFS status and examined which DE metrics and blood inflammatory markers most closely related to disease.

2. METHODS

2.1. Study population and ME/CFS Diagnosis

The study population included 124 prospectively enrolled veterans who previously served during the Gulf War Era (1990–91) and were seen at the Miami Veterans Affair Hospital Eye Clinic between October 1, 2020 and October, 2023. Inclusion criteria included being active duty during the 1990–91 Gulf War and having normal eyelid, conjunctival, and corneal anatomy. Study exclusions included the use of topical medications (e.g., glaucoma medications), devices (e.g., contact lens use), and anatomical abnormalities (e.g., pterygium) that could confound DE. All individuals signed an informed consent form prior to study enrollment.

Cases were diagnosed based on the CCC criteria for ME/CFS which requires evidence of sub substantial reduction in function defined by low scores in 2 of 3 SF-36 domains: physical (<50), social functioning (<62.5), or vitality (<35).29 In addition, based on the DePaul questionnaire, cases had to have ≥6 months of fatigue (question 69) which was not lifelong or the result of exertion (questions 67, 69, 77, and 89), post-exertional malaise (at least one symptom from questions 14–18), sleep problems (at least one symptom from questions 19–24), pain in any of multiple compartments (at least one symptom in questions 19–24), neurological/cognitive problems including but not limited to problems with memory, concentration, and word finding (at least two symptoms from questions 32–44) and at least one symptom from two of the following areas: autonomic (questions 45–51), neuroendocrine (questions 52–61), and immune (questions 62–66).29 Individuals who met either the SF-36 criteria, or the DePaul criteria, but not both were grouped into an intermediate fatigue (IF) group.

This study included human participants and was approved by the Miami VA Institutional Review Board (ID: 1570449, Board Reference # 3011.0) The study was conducted in accordance with the principles of the Declaration of Helsinki and complied with the requirements of the United States Health Insurance Portability and Accountability Act.

2.2. Collected data

2.2.1. Demographics and comorbidities

All patients were surveyed on previously diagnosed medical comorbidities, medications, and deployment status. Patients were additionally asked to complete the Patient Health Questionnaire-9 (PHQ-9)30 and Post-traumatic stress disorder checklist military version (PCL-M)31 to quantify symptoms of depression and post-traumatic stress disorder respectively (PTSD). Participants were surveyed using the Kansas criteria32 to evaluate for comorbid GWI symptoms.

2.2.2. Ocular symptoms

All individuals filled out standardized questionnaires regarding ocular symptoms. DE symptoms were measured using the Ocular Surface Disease Index (OSDI, range 0–100)33 and 5-Item Dry Eye Questionnaire (DEQ-5, range 0–22).34 Ocular pain intensity was graded using a Numerical Rating Scale (NRS, range 0–10). NRS scores were acquired for pain felt “right now,” “averaged over the last week,” and “worst over the last week.” Neuropathic features of pain were captured using the Neuropathic Pain Symptom Inventory modified for the Eye (NPSI-E, total score: range 0–100; sub-score range 0–10).35 Convergence insufficiency was assessed using the Convergence Insufficiency Symptoms Survey (CISS, 0–60).36

2.2.3. Ocular surface signs

DE signs were assessed by one provider that was masked to the clinical symptoms for each patient. DE signs included, in the order assessed:

  1. Qualitative assessment of ocular surface inflammation via InflammaDry matrix metalloproteinase 9 detection (Quidel, San Diego).37 The intensity of the pink stripe was qualitatively graded as none, mild, moderate, or severe.

  2. Tear break-up time (TBUT), 5μl of fluorescein was placed on the inferior fornix, and 3 measures were recorded and averaged for each eye;

  3. Fluorescein corneal staining graded to the National Eye Institute (NEI) scale.38

    The cornea was divided into five areas and staining was graded in each area on a scale of 0=none to 3=severe, and the scores summed.

  4. Pain intensity rating pre and post anesthetic placement, assessed using a 10-point NRS after application of 10 μL of proparacaine hydrochloride 0.5%;

  5. Anesthetized Schirmer’s test at 5 min

  6. Eyelid and Meibomian gland assessments. Eyelid vascularity was graded on a scale of 0 to 3 (0 none; 1 mild engorgement; 2 moderate engorgement; 3 severe engorgement) and meibum quality on a scale of 0 to 4 (0 = clear; 1 = cloudy; 2 = granular; 3 = toothpaste; 4 = no meibum extracted).39

2.2.4. Inflammatory marker assessment

Participants underwent a blood draw followed by measurement of a panel of inflammatory markers. Among these were C-reactive protein (CRP), glutamic acid, and brain derived neurotrophic peptide (BDNF) which were run with serum. Cytokines, which included, tumor necrosis factor alpha (TNFα), tumor necrosis factor beta (TNFβ), tumor necrosis factor receptor 1 (TNF-RI), tumor necrosis factor receptor 2 (TNF-RII), Inteferon gamma (IFNy); and a series of Interleukins (IL) 1a, 1b, 2, 4, 5, 8, 12, 23, 15, 17, and 10 were run on ethylenediaminetraacetic acid (EDTA) plasma using a Quansys™ Multiplex assay.

2.5. Data analysis

Statistical analysis was performed using SPSS 29.0 (IBM Corp, Armonk, NYU) statistical package. Descriptive statistics were used to summarize patient demographic and clinical information. Normality of the data was assessed using the Kolmogorov-Smirnov test. An ANOVA test was used to calculate differences in continuous variables between the three groups. Chi square was used for categorical variables. The robustness of our findings was then evaluated using forward stepwise multivariable linear regression to evaluate the relationship between DE symptom questionnaire scores and ME/CFS status, when including potential confounders such as age, gender, race, ethnicity, medical comorbidities, and DE signs. For all DE signs, the more severe value from each eye was used. For all analyses, missing data were not including. In this paper, we opted to give information on all variables being compared as opposed to correcting the p-value (e.g., Bonferroni) since the latter methodology has its own limitations.40

3. RESULTS

3.1. Study population

The mean age of the population was 55.1 ± 4.7 years, 88.7% of participants identified as male, 58.1% as White, and 39.5% as Hispanic. Thirty-two participants met the criteria for ME/CFS, 48 were included in the IF group, and 44 in the control group. Demographics (Table I) were similar between all three groups. Medical comorbidities, and medication use were similar between groups with the exception of depression (both self-reported diagnosis and PHQ-9 score), and PTSD (both self-reported diagnosis and PCL-M score) which were more frequent in the ME/CFS and IF groups compared to controls. GWI symptoms was also more frequent in the ME/CFS and IF groups compared to controls (Table II).

Table I.

Demographic information for the myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS), intermediate fatigue (IF), and control groups.

ME/CFS (n = 32) IF (n= 48) Control (n=44) P-value
Demographics
Age, mean years ± SD 54.3 ± 4.4 56.3 ± 4.5 55.5 ± 4.8 0.17
Male gender % (n) 87% (28) 92% (44) 86% (38) 0.70
White % (n) 38% (12) 46% (22) 41% (18) 0.75
Hispanic ethnicity % (n) 38% (12) 40% (19) 41% (18) 0.96
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ME/CFS myalgic encephalomyelitis/chronic fatigue syndrome, IF Intermediate fatigue, SD standard deviation, n number in group.

*

Statistically significant difference at p-value < 0.05.

a

Statistically significant difference compared to controls

b

Statistically significant difference compared to IF

c

Statistically significant difference compared to controls and IF

Table II.

Co-morbidities, medication use, and deployment history for the myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS), intermediate fatigue (IF), and control groups

ME/CFS (n = 32) IF (n= 48) Control (n=44) P-value
Co-morbidities
PTSD % (n) 41% (13)a 40% (19)a 16% (7) 0.03*
PCL-M, mean ± SD 56.1 ± 16.6c 43.6 ± 16.7a 34.1 ± 16.3 <0.001
Depression % (n) 56% (18)a 42% (20) 23% (10) 0.01*
PHQ-9, mean ± SD 16.2 ± 5.5c 10.0 ± 6.1a 5.6 ± 5.2 <0.001
TBI % (n) 4% (2) 9% (3) 0% (0) 0.13
Arthritis % (n) 31% (10) 35% (17) 33% (14) 0.92
Sleep Apnea % (n) 66% (21) 65% (31) 47% (20) 0.14
BPH % (n) 9% (4) 21% (10) 16% (7) 0.37
Hypertension % (n) 42% (13) 42% (20) 32% (14) 0.55
Hyperlipidemia % (n) 53% (17) 52% (25) 34% (15) 0.14
Medication use
NSAID % (n) 52% (16) 33% (16) 42% (18) 0.27
Anti-depressant % (n) 32% (10) 29% (14) 12% (5) 0.06
Anti-anxiety % (n) 23% (7) 10% (5) 16% (7) 0.34
Antihistamine % (n) 39% (12) 23% (11) 23% (10) 0.24
Gabapentin % (n) 13% (4) 10% (5) 12% (5) 0.94
Fish oil % (n) 23% (7) 23% (11) 23% (10) 0.99
Multivitamin % (n) 32% (10) 46% (22) 34% (15) 0.38
Betablocker % (n) 19% (6) 17% (8) 5% (2) 0.12
Statin % (n) 32% (10) 54% (26) 37% (16) 0.11
Aspirin % (n) 13% (4) 21% (10) 16% (7) 0.65
Military
Deployment status % (n) 81% (26) 75% (35) 65% (28) 0.29
GWI symptoms % (n) 59%a (19) 48% (23)a 18% (8) <0.001*
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ME/CFS Myalgic encephalomyelitis/chronic fatigue syndrome, IF Intermediate fatigue, SD standard deviation, n number in group. PTSD Post-Traumatic Stress Disorder, PCL-M Post-traumatic stress disorder checklist military, PHQ-9 Patient Health Questionnaire-9, TBI Traumatic Brain Injury, BPH Benign Prostatic Hyperplasia, NSAID Nonsteroidal anti-inflammatory drug, GWI Gulf War Illness

*

Statistically significant difference at p-value < 0.05.

a

Statistically significant difference compared to controls

b

Statistically significant difference compared to IF

c

Statistically significant difference compared to controls and IF

3.2. Ocular symptoms in the ME/CFS and control groups

Ocular symptoms were compared across the ME/CFS, IF and control groups (Table III). Generally, individuals in the ME/CFS and IF groups reported more severe ocular symptoms compared to controls. This was true across the different measures including DE (OSDI, DEQ-5), pain specific (NRS), and neuropathic pain specific (NPSI-E) questionnaires. Specific questions within the NPSI-E, including burning pain and sensitivity to light, were also higher in the ME/CFS and IF groups compared to controls. Convergence insufficiency symptoms were increased in the ME/CFS and IF groups compared to controls. When comparing the ME/CFS and IF groups, OSDI and convergence insufficiency scores were higher in the ME/CFS versus IF group.

Table III.

Ocular symptom scores in the myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS), intermediate fatigue (IF), and control groups

ME/CFS (n=32) IF (n=48) Control (n=44) P-value
Symptom severity assessed with DE questionnaires (mean ± SD)
OSDI (0–100) 48.9 ± 22.3c 38.8 ± 23.3a 19.1 ± 17.8 <0.001
DEQ-5 (0–22) 10.8 ± 3.9a 10.0 ± 4.6a 6.6 ± 4.2 <0.001
Symptom severity assessed with pain specific questionnaire (mean ± SD), (0–10)
NRS (right now) 2.4 ± 2.8a 2.4 ± 2.9a 0.9 ± 1.5 0.007
NRS (last week average) 2.9 ± 2.5a 2.6 ± 2.8a 1.1 ± 1.8 0.002
NRS (last week worst) 3.5 ± 3.1a 2.9 ± 3.0a 1.3 ± 2.0 0.001
Symptom severity assessed with neuropathic pain specific questionnaires (mean ± SD)
NPSI-E total (0–100) 23.0 ± 18.6a 19.8 ± 19.1a 6.5 ± 9.0 <0.001
NPSI-E burning (0–10) 2.8 ± 2.6a 2.8 ± 2.9a 0.8 ± 1.6 <0.001
NPSI-E pressing (0–10) 4.3 ± 4.6a 4.3 ± 4.6a 1.3 ± 2.1 <0.001
NPSI-E paroxysmal (0–10) 3.6 ± 4.1a 3.0 ± 4.4a 1.1 ± 2.6 0.01
NPSI-E evoked (0–10) 8.8 ± 6.8a 7.0 ± 7.5a 2.3 ± 3.5 <0.001
NPSI-E paresthesia dysesthesia (0–10) 3.5 ± 5.3a 2.7 ± 3.8 1.1 ± 2.3 0.02
Light sensitivity, % (n)
Any light sensitivity, %>0 on 0–10 scale 81% (26)a 65% (31)a 39% (17) <0.001
Binocular function (mean ± SD)
Convergence insufficiency 29.9 ± 12.4c 23.3 ± 12.3a 13.2 ± 9.9 <0.001
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ME/CFS Myalgic encephalomyelitis/chronic fatigue syndrome, IF Intermediate fatigue OSDI Ocular Surface Disease Index, DEQ-5 5 item Dry Eye Questionnaire, NRS Numerical Rating Scale NPSI-E Neuropathic Pain Symptom Inventory modified for the Eye, SD standard deviation, n number in group.

*

Statistically significant difference at p-value < 0.05.

a

Statistically significant difference compared to controls

b

Statistically significant difference compared to IF

c

Statistically significant difference compared to controls and IF

3.3. Ocular surface signs in the ME/CFS and control groups

Overall, signs of ocular surface and tear dysfunction were similar between groups (Table IV), with the exception that a greater proportion of individuals in the ME/CFS group reported persistent eye pain after administration of proparacaine compared to controls.

Table IV.

Ocular surface signs in the myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS), intermediate fatigue (IF), and control groups

DE signs* ME/CFS (n=32) IF (n=48) Control (n=44) P-value
MMP9 positivity, % (n) 57% (16) 63% (22) 59% (19) 0.90
MMP9 qualitative assessment (0–3), mean ± SD 1.2 ± 1.90 1.1 ± 1.0 1.3 ± 1.6 0.82
TBUT, seconds, mean ± SD 8.7 ± 4.4 8.6 ± 4.1 8.2 ± 5.0 0.84
Corneal staining (0–15), mean ± SD 1.8 ± 2.8 1.0 ± 1.6 1.3 ± 2.2 0.28
Schirmer’s with anesthesia, mm wetting at 5 minutes, mean ± SD 14.6 ± 8.5 13.5 ± 9.0 13.0 ± 9.3 0.74
Schirmer≤5 mm wetting, % (n) 16% (5) 23% (11) 21% (9) 0.70
Ocular pain prior to anesthesia, % (n) 50% (16) 47% (22) 36% (16) 0.44
Persistent pain after anesthesia, % (n) 41% (13)a 28% (13) 14% (6) 0.03
Eyelid telangiectasias (0–3), mean ± SD 0.5 ± 0.8 0.5 ± 0.7 0.6 ± 0.7 0.96
Meibum quality (0–4), mean ± SD 1.3 ± 1.1 1.4 ± 1.0 1.2 ± 0.8 0.70
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ME/CFS Myalgic encephalomyelitis/chronic fatigue syndrome, IF Intermediate fatigue TBUT Tear break-up time, MMP-9 ocular surface matrix metalloproteinase 9, SD standard deviation, n number in group

*

More abnormal sign from right or left eye

a

Statistically significant difference compared to controls

b

Statistically significant difference compared to IF

c

Statistically significant difference compared to controls and IF

3.4. Serum inflammatory markers in the ME/CFS and control groups

Serum inflammatory markers, which included CRP, glutamic acid, BDNF, TNF-RI, TNF-RII, TNFα, TNFβ, and a series of interleukins were similar across the ME/CFS, IF and control groups (Table V).

Table V.

Serum inflammatory markers in the myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS), intermediate fatigue (IF), and control groups

mean ± SD ME/CFS (n=32) IF (n=48) Control (n=44) P-value
CRP (mg/dL) 0.2 ± 0.3 0.8 ± 2.3 0.3 ± 0.6 0.26
Glutamic acid (uM/uL) 1.0 ± 0.6 1.3 ± 0.6 1.2 ± 0.5 0.18
BDNF (ng/mL) 37.7 ± 10.5 42.3 ± 14.2 38.6 ± 11.0 0.24
TNF-RI (pg/mL) 460.1 ± 187.0 480.8 ± 333.5 440.9 ± 146.3 0.76
IL-1α (pg/mL) 12.4 ± 8.9 13.3 ± 9.6 11.0 ± 8.1 0.49
IL-1β (pg/mL) 19.0 ± 6.3 21.7 ± 11.2 21.4 ± 9.7 0.47
IL-2 (pg/mL) 20.3 ± 9.0 20.7 ± 9.6 21.4 ± 11.1 0.90
IL-4 (pg/mL) 2.8 ± 1.4 3.3 ± 2.1 2.9 ± 1.7 0.48
IL-5 (pg/mL) 7.2 ± 4.5 6.2 ± 3.5 7.0 ± 4.3 0.52
IL-6 (pg/mL) 9.6 ± 4.9 10.9 ± 7.1 10.6 ± 7.8 0.73
IL-8 (pg/mL) 4.5 ± 6.3 4.0 ± 3.0 3.7 ± 1.6 0.70
IFNy (pg/mL) 8.0 ± 3.1 8.5 ± 3.4 8.7 ± 4.8 0.74
IL-12 (pg/mL) 3.7 ± 1.9 4.0 ± 4.3 4.5 ± 3.7 0.62
IL-13 (pg/mL) 4.8 ± 2.3 4.5 ± 1.7 4.7 ± 2.7 0.81
IL-23 (pg/mL) 207.8 ± 368.8 100.4 ± 124.1 112.8 ± 144.7 0.09
IL-15 (pg/mL) 4.3 ± 2.2 4.5 ± 1.1 4.3 ± 1.7 0.83
IL-17 (pg/mL) 51.0 ± 89.8 36.9 ± 58.3 48.9 ± 73.6 0.66
IL-10 (pg/mL) 44.6 ± 67.8 37.1 ± 65.9 35.9 ± 66.3 0.86
TNFα (pg/mL) 10.3 ± 6.3 9.7 ± 5.0 8.7 ± 4.1 0.40
TNF-RII (pg/mL) 577.2 ± 251.7 565.1 ± 166.4 533.6 ± 118.3 0.57
TNFβ (pg/mL) 9.8 ± 6.6 10.6 ± 10.1 11.7 ± 11.9 0.72
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ME/CFS Myalgic encephalomyelitis/chronic fatigue syndrome, IF Intermediate fatigue, CRP C-reactive protein, BNDF Brain-Derived Neurotrophic Factor TNF-RI Tumor necrosis factor receptor 1, IL Interleukin, IFNy Inteferon gamma, TNFα Tumor necrosis factor alpha, TNF-RI Tumor necrosis factor receptor 2, TNFβ Tumor necrosis factor beta SD standard deviation, n number in group *Statistically significant difference at p-value < 0.05.

a

Statistically significant difference compared to controls

b

Statistically significant difference compared to IF

c

Statistically significant difference compared to controls and IF

3.5. Multivariable analyses

Next, we evaluated whether relationships between ocular symptoms and ME/CFS remained when considering potential confounders such as demographics, deployment history, GWI status, medical comorbidities, oral medications, and DE signs using multivariable forward stepwise linear regression models. ME/CFS status remained significantly associated with higher questionnaire scores on the OSDI (standardized β: 0.3, p<0.001, R2 = 0.6), DEQ5 (standardized β: 0.3, p=0.001, R2 = 0.6), and NPSI-E (standardized β: 0.3, p<0.001, R2 = 0.5). No other variables remained significant across all three questionnaires.

4. DISCUSSION

In summary, we found that individuals who met criteria for ME/CFS and those who met partial criteria for ME/CFS (IF) reported more severe ocular symptoms across several questionnaires compared to controls. These included burning pain, light sensitivity, and convergence insufficiency. We also found an increased likelihood of depression, antidepressant use, and PTSD, in individuals with ME/CFS compared to controls. However, signs of ocular surface and tear dysfunction and blood markers of inflammation were comparable across groups. Our findings suggest that ocular symptoms in individuals with ME/CFS cannot be fully attributable to ocular surface or peripheral inflammatory abnormalities and may instead be mediated by peripheral and/or central nerve dysfunction, among other potential factors, such as psychiatric co-morbidities and medication use.

Ocular symptoms have long been associated with ME/CFS. One study examined 190 individuals with ME/CFS (at the time called chronic fatigue and immune dysfunction syndrome) and 198 controls living in the US and surveyed them for ocular burning, itching, grittiness, and dryness (yes/no responses). A greater number of individuals in the ME/CFS group reported symptoms of burning (~60% vs. 26%, p=0.0001), itching (~58% vs. 30%, p=0.0001), grittiness (~35% vs. 18%, p=0.0003), dryness (~44% vs 21%, p=0.0001), and scratchiness (~32% vs 15%, p=0.0002) compared to controls. Individuals in the ME/CFS group were also more likely to report blurriness with distance vision, near vision, and sensitivity to light.26 Only a few studies have examined ocular signs in ME/CFS. One group compared 25 individuals with ME/CFS to 18 controls and found lower Schirmer’s strip scores (< 10 mm/5min) in the ME/CFS compared to control group (40% vs 6%, p= 0.01). Further, 52% of ME/CFS subjects but no controls complained of mucosal dryness (yes/no on a question encompassing skin, oral, and eye dryness). All individuals in the study underwent a labial minor salivary gland biopsy which was graded for the number of inflammatory foci/4-mm2 within gland sections. 44% of individuals in the ME/CFS group had 1 or more inflammatory foci/4-mm2 compared to 17% in the control group (p<0.05). Interestingly, no individuals in the study had elevated anti-Sjogren-syndrome type A or type B antibodies (anti-SSA, and anti-SSB respectively).41 These findings are in agreement with a study of 32 individuals with ME/CFS living in Japan who were described as having a “seronegative Sjogren’s type phenotype”, based on a combination of complaints of mucosal dryness, histologic evidence of Sjogren’s on lip biopsy, and abnormal Schirmer and Rose Bengal test results (exact criteria not given).42 This contrasts with our findings of similar tear, ocular surface, and blood inflammatory markers across groups. This reality speaks to potential heterogeneity within ME/CFS, which can occur both with and without objective evidence of mucosal dryness/inflammation.

Beyond ME/CFS, a discordance between ocular symptoms and signs has been observed across various chronic pain conditions43,44, and is thought to reflect generalized hypersensitivity due to neuropathic mechanisms.45 One example is fibromyalgia, a neurological disorder with significant symptom overlap with ME/CFS.7 One study assessed symptoms of ocular pain in 66 individuals who met the criteria for fibromyalgia. Sixty-seven percent (95% CI = 56–78%) of individuals reported at least some degree of ocular pain, with an average eye pain intensity score of 2.6 ± 2.4 on a 1–10 NRS over a four week recall in the entire cohort. Eleven percent (11%) of individuals with fibromyalgia also had evidence of aqueous tear deficiency (Schirmer<5 mm), suggesting that in this cohort, the frequency of ocular pain was greater than the frequency of tear deficiency.9 Similar findings were noted in a study that compared individuals with FM (n=53) to controls (n=53) in Turkey. OSDI scores were more severe in the FM compared to control group (32.0 ±18.6 vs. 13.7 ±8.2, p<0.001). In this study, the FM group had lower TBUT (9.1 ±3.2 vs. 11.7 ± 2.9, p<0.001) and Schirmer scores (8.6 ±3.5 vs. 11.4 ±3.3, p<0.001) compared to controls, although mean values were normal in both groups, so the clinical significance of the findings are unclear.46 Similar findings have also been in individuals with migraine.47

An ocular phenotype of symptoms out of proportion to signs has also been noted in individuals with GWI symptoms.48 In our prior study, OSDI scores were higher in 30 individuals with GWI compared to 41 controls (41.2 ±22.9 vs. 28.0 ±8.2, p<0.01), while ocular surface signs such TBUT and Schirmer scores were similar between groups.49 In our current study, ME/CFS more closely associated with ocular symptoms severity than GWI symptoms on multivariable analysis, which may point to fatigue as a common denominator to the ocular pain experienced in both diseases. The shared findings between various pain conditions and an ocular phenotype of discordance between symptoms and signs suggests that similar mechanisms may underlie ocular pain across these conditions.50–52

Neuroinflammation is one possible pathophysiological mechanism that may link fatigue across multiple conditions, including ME/CFS. One study used 11C-(R)-PK11195, a ligand for a translocator protein expressed by microglia or astrocytes, and PET to investigate the presence of neuroinflammation in ME/CFS. In 9 ME/CFS patients and 10 controls, BPND values (a measure of 11C-(R)-PK11195 density) were higher in the midbrain (0.2 ± 0.03 vs 0.1 ± 0.02, p<0.001), pons (0.2 ± 0.03 vs 0.1 ± 0.03, p=0.002), thalamus (0.1 ± 0.02 vs. 0.06 ± 0.02, p=0.001) and cingulate (0.01 ± 0.008 vs 0.003 ± 0.003, p=0.04) regions of the brains of ME/CFS patients compared to controls.53 Neuroinflammation has also been linked to ocular pain. One mouse model of DE (excision of extra orbital lacrimal and harderian gland) examined spontaneous eye closing ratios (height /width of eye, lower values indicate a grimace response used as an index of ocular discomfort) in cases compared to controls (sham surgery). The closing ratio was similar in the groups prior to surgery (0.8 ± 0.02 vs. 0.8 ± 0.01, P > 0.05), but significantly decreased in DE mice 21 days after surgery (0.6 ± 0.02 vs 0.7 ± 0.02, P < 0.0001), indicating more discomfort than in controls. In addition to a difference in pain behavior, DE mice had evidence of neuro-inflammation in the ipsilateral trigeminal ganglion compared to control mice based on higher immunoreactivity based on staining of glial fibrillary acidic protein (GFAP, marker for satellite cell activity: 2.2 ± 0.4 vs. 0.8 ± 0.2, P < 0.05) and Iba1 (marker of macrophage activity: 2.0 ± 0.2 vs 0.7 ± 0.2, P < 0.01).54 This model supports a relationship between ocular pain and neuro-inflammation, which may be relevant in ME/CFS.

On the other hand, in our paper, peripheral markers of inflammation and neuroinflammation were not different between groups. This is not entirely unexpected as previous research has suggested that cytokines propagate inflammation locally via autocrine and paracrine signaling not as endocrine signalers flowing through blood.55,56 This property likely contributed to the heterogenous findings regarding peripheral cytokines and ME/CFS seen in previous studies conducted in various geographic locations.20,57 Specifically, some studies, like ours, did not find differences in inflammatory markers in MF/CFS vs control patients. In one study, cytokine expression levels by peripheral blood mononuclear cells (TNFα: 89 [68–125] vs. 87 [73–103]; IL-1α: 186 [113–278] vs. 200 [153–245]; IL-10: 42 [31–54] vs. 41 [32–45]) was similar between 22 individuals with ME/CFS and fibromyalgia and 19 controls. Similar findings were also noted after the cells were stimulated with IFNγ (TNFα: 77 [62–89] vs. 87 [73–103]; IL-1α: 183 [113–278] vs. 122 [106–170]; IL-10: 42 [31–53] vs. 45 [32–45]) (all units in mean intensity of fluorescence with [median interquartile range], all p-values > 0.05).58 On the other hand, other studies have noted differences in serum inflammatory markers in ME/CFS compared to controls, with differences in the specific markers noted across studies. One Belgian study conducted compared circulating blood cytokines in 16 patients with ME/CFS and 14 controls, and found that the ME/CFS group had significantly higher IL-1β (655.7 ± 47.8 femtogram/milliliter (fg/mL) vs. 87.6 ± 21.8 fg/mL), IL-8 (19,056.5 ± 8254.0 fg/mL vs. 86.1 ± 18.1 fg/mL), IL-10 (318.8 ± 1028.3 fg/mL vs. 86.04 ± 17.9 fg/mL), and TNFα (534.0 ± 1,782.4 fg/mL vs. 89.2 ± 19.4 fg/mL) levels (p<0.05).23 Overall, findings of our and previous studies suggest that while inflammation may play a role in MF/CFS, the value of blood cytokine profiling has yet to be established.55

Our results also demonstrate an increased frequency of depression, antidepressant use, and PTSD in individuals with ME/CFS when compared to controls. This finding is consistent with prior studies.59–61 One US study examined the co-occurrence of ME/CFS and PTSD in 8,544 individuals. After adjusting for age, sex, and race, individuals with PTSD were 7.5 times more likely to report ME/CFS than those without PTSD (95% CI: 5.0–11.0).60 Similar findings have been observed for ME/CFS and depression.61 Notably, ocular surface symptoms, observed more frequently in our ME/CFS cohort, have also been related to psychiatric comorbidities. One Canadian meta-analysis, which included 32 studies, found a depression prevalence of 40% (95% CI: 0.29–0.52) in DE patients (variably defined), with a 1.81 times higher odds of depression in individuals with DE (95% CI: 1.61–2.02).62 Missing from the literature are studies that examine the direction of the association. It is unclear if ME/CFS and ocular surface symptoms are distressing, leading to a psychiatric condition, whether psychiatric conditions pre-dispose to ME/CFS and ocular surface symptoms, or if a common contributor underlies these disparate manifestations. Another potential confounder is the use of psychiatric medications, which may in themselves impact symptoms, furthering obscuring the noted relationships.63

As with all studies, our findings need to be examined considering the study limitations. These included the cross-sectional study design and geographically restricted sample size of predominantly male veterans. However, ME/CFS has mostly been studied in women64, and as such, we provide a novel population to examine disease manifestations and study potential pathophysiological contributors. A strength of our study is its prospective nature, and the robustness of symptoms and signs collected from participants. Areas that warrant further research include studying peripheral and central nerve function in individuals with ME/CFS and examining different therapeutic strategies, including neuro-modulation, in individuals who do not respond to therapies targeting ocular surface health and have a symptom profile that outweighs signs of ocular surface disease. Treatments targeting central nerve abnormalities, such as with anticonvulsants and tricyclic antidepressants (TCAs) may offer a therapeutic benefit in this population.65,66 While there is limited evidence on its use in ME/CFS, previous trials have shown pregabalin to have good effect in the treatment of pain in fibromyalgia. One randomized placebo controlled trial in the US which included 529 individuals diagnosed with fibromyalgia found that treatment with 450 milligrams of pregabalin daily resulted in a greater proportion of patients experiencing a greater than 50% reduction in their initial pain rating (measured on a 1–10 scale) compared to those treated with placebo (29% vs 13%, p=0.003).67 Similar studies are needed in individuals with ME/CFS and comorbid ocular symptoms. Our study findings, which highlight an ocular phenotype of pain out of proportion to signs of tear dysfunction in a veteran cohort, suggest that such approaches could be considered in individuals with ME/CFS and ocular pain.

Funding sources:

Supported by the Department of Defense Gulf War Illness Research Program (GWIRP) W81XWH-20-1-0579 (Dr. Galor).

Other support:

Department of Veterans Affairs, Veterans Health Administration, Office of Research and Development, Clinical Sciences R&D (CSRD) I01 CX002015 (Dr. Galor), Biomedical Laboratory R&D (BLRD) Service I01 BX004893 (Dr. Galor), Rehabilitation R&D (RRD) I21 RX003883 (Dr. Galor), and Vision Research Program (VRP) W81XWH-20-1-0820 (Dr. Galor), National Eye Institute U01 EY034686 (Dr. Galor), R61EY032468 (Dr. Galor), NIH Center Core Grant P30EY014801 (institutional) and Research to Prevent Blindness Unrestricted Grant GR004596-1 (institutional).

Footnotes

Conflict of interest: None

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