Small Fiber Neuropathy in Patients with Dry Eye Disease

doi:10.21203/rs.3.rs-4927462/v1

Download PDF

Research Article

Small Fiber Neuropathy in Patients with Dry Eye Disease

https://doi.org/10.21203/rs.3.rs-4927462/v1

This work is licensed under a CC BY 4.0 License

Version 1

posted

You are reading this latest preprint version

Purpose: Small-fiber neuropathy (SFN) refers to a range of peripheral neuropathic conditions affecting small-caliber sensory and/or autonomic nerve fibers. This study aims to determine the prevalence and characteristics of SFN symptoms in patients with dry eye disease (DED).

Design: Cross-sectional study at two academic eye centers

Methods: 31 patients with DED and an Ocular Surface Disease Index (OSDI) greater than 13 were included. SFN symptoms were determined using the Small-Fiber Symptom Survey (SSS), a validated questionnaire, and positive symptoms were defined as having a score of 15.7 or higher (two standard deviations from the mean of healthy individuals without SFN). DED symptoms and ocular pain were assessed using the OSDI and the Ocular Pain Assessment Survey (OPAS), respectively. DED signs were assessed clinically and patient response to standard DED treatment was evaluated 6-12 months after the administration of the questionnaires.

Results: The prevalence of SFN symptoms among DED patients was 77.4%. Positive correlations were found between SSS and OSDI (r=0.43, p=0.017), and between SSS and OPAS (r=0.62, p=0.0003). A negative correlation was observed between SFN symptoms and corneal fluorescein staining (CFS, r=-0.42, p=0.018) but not with tear break-up time or Schirmer’s test results. Despite more intense topical treatment and stable clinical signs of DED, patients with severe SFN symptoms (high SSS scores) had a less favorable subjective response to DED treatment, compared to those with low and moderate SSS scores.

Conclusion: There is a high prevalence of SFN symptoms in patients with DED. SFN symptoms are strongly associated with ocular pain and DED symptoms and are negatively correlated with CFS. Patients with severe SFN symptoms have a less favorable subjective response to standard DED treatment, suggesting the presence of neuropathic conditions that warrant further neurological assessment.

Ophthalmology

Dre eye disease

DED

small fiber neuropathy

neuropathy

neuropathic pain

Dry eye disease (DED) is a prevalent eye condition affecting approximately 6.8% of adults in the United States [1]. It occurs mainly when there is an impairment in the tear film or the lacrimal functional unit, leading to various symptoms such as dryness, foreign body sensation, eye fatigue, fluctuating vision, tearing, irritation, and neuropathic symptoms including dysesthesia, hyperalgesia, hypoalgesia, and allodynia [2 3]. These symptoms can be attributed to the activation of sensory corneal nerves triggered by factors such as tear film hyperosmolarity, inflammatory mediators, or sensory nerve hypersensitivity [4]. While increasing tear volume and stability can alleviate many of these symptoms, many patients with neuropathic symptoms do not experience such relief [5].

Notably, analysis of corneal nerves in DED patients using in vivo confocal microscopy (IVCM) has revealed altered nerve morphology characterized by lower density, increased tortuosity, and beading, compared to those without DED [6]. Additionally, there is a higher occurrence of DED in patients with diabetic neuropathy, attributed to a decrease in corneal sensory nerves in some studies [7 8]. Moreover, a high prevalence of neuropathy has been observed in patients with Sjogren’s syndrome (SS), an autoimmune disease with the hallmark symptoms of dry eyes, ranging from 1.8–64% [9 10]. Among the neuropathies associated with SS, small fiber neuropathy (SFN) is the most prevalent, accounting for at least 30% of cases [11].

SFN is a condition characterized by damage to small, myelinated A-delta fibers and unmyelinated nociceptive C fibers, which have both somatic and autonomic components [12]. This nerve injury can manifest in various ways, including hyperesthesia, allodynia, paresthesia, and hypoesthesia, and impact multiple body systems, particularly the cardiovascular, gastrointestinal, and integumentary systems [13]. SFN patients frequently exhibit symptoms of DED, indicating a notable association between the two conditions [14 15]. Moreover, studies have shown that SFN diagnosis is associated with reduced corneal nerve density, shorter nerve fiber length, loss of neural complexity, and variations in nerve bundle size observed by IVCM [16–18]. These observations raise the possibility that neuropathy may be a critical component of DED and a possible contributor to DED symptoms.

While the causes and symptoms of SFN and DED have been explored individually and the two conditions are theoretically linked via sensory nerve changes, their clinical correlation remains unclear. Understanding the prevalence and characteristics of SFN symptoms in patients with DED can shed light on the pathogenesis of DED and potentially lead to improved treatment approaches. Treister et al. have developed and validated the Small-Fiber Symptom Survey (SSS), a 1-page questionnaire concerning the full spectrum of SFN symptoms, in 179 participants with SFN diagnosed with objective tests and healthy controls [19]. In this study, we utilized the SSS and assessed the prevalence of SFN in patients with DED. In addition, we determined the correlation between SFN symptoms and ocular symptoms/signs of DED and evaluated patient response to standard DED treatment based on their SFN symptom severity.

A cross-sectional questionnaire-based study was conducted at the Mass Eye and Ear (MEE) and Beth Israel Deaconess Medical Center (BIDMC) in Boston, MA. The study obtained approval from the Institutional Review Board at MEE and BIDMC and adhered to the principles of the Declaration of Helsinki and the Health Insurance Portability and Accountability Act of 1996.

Subjects:

Between 2017 and 2021, consecutive patients presented with DED to the eye clinics were assessed for eligibility. The inclusion criteria were an age of 18 years or older, an Ocular Surface Disease Index (OSDI) score of 13 or greater [20] and the ability to understand English. Patients with graft-versus-host disease, contact lens wear, diabetes, Parkinson's disease, previous corneal diseases, previous corneal or refractive surgery, or cataract surgery within the past 6 months were excluded. A total of 31 subjects were enrolled.

Ocular Surface Disease Index (OSDI) assessment:

The OSDI questionnaire evaluates ocular surface symptoms related to DED [20 21]. The questionnaire consists of 12 items divided into three sections: ocular symptoms, visual function, and environmental triggers. Responses are rated on a scale of 0 to 4 for each item. The overall OSDI score is calculated using a standardized formula: OSDI= [(sum of all scores for all questions answered) x100]/[(total number of questions answered)x4]. The total OSDI is scored on a scale of 0 to 100, with higher scores representing greater disability.

Ocular pain assessment:

Patients completed the Ocular Pain Assessment Survey (OPAS), a validated questionnaire for neuropathic pain that integrates patient responses concerning both ocular and non-ocular pain intensity, effects on quality of life, aggravating factors, and associated factors [22]. Each test question is scored on a scale of 0–10, or 0–100, with increments of 1 or 10 units, respectively. The mean for each category was calculated by dividing the sum of the scores by the number of questions answered [22].

Assessment of clinical signs of DED:

Schirmer test: A calibrated sterile strip was placed in the conjunctival fornix for 5 minutes after topical anesthesia (0.5% proparacaine hydrochloride), and the wetting in millimeters was recorded.

Tear break-up time (TBUT): Sodium fluorescein dye was instilled, and the tear film disruption time was observed under a slit lamp biomicroscope. TBUT > 10 s is considered normal, 5–10 s is considered borderline, and < 5 s is considered low [23].

Corneal fluorescein staining (CFS): CFS was assessed based on the NEI grading scale, ranging from 0 (no corneal epitheliopathy) to 15 (severe epitheliopathy) [24].

For each patient, the average of both eyes was presented as one data point.

Corneal sensitivity testing:

Corneal sensation was evaluated using the Cochet-Bonnet esthesiometer (Luneau Ophthalmologie, Chartres, France). The esthesiometer used a nylon monofilament with a diameter of 0.12 mm and a fully extended length of 60 mm. Each eye's central, superior, inferior, nasal, and temporal cornea was gently touched once with the filament, starting at a length of 60 mm. If no positive response was observed, the filament length was reduced in 5 mm increments, and the process was repeated until a positive response was elicited. The corneal sensation was then determined as the mean value obtained from the five corneal areas on each eye [25]. The average of both eyes was presented as one data point.

SFN symptom assessment:

A validated questionnaire known as the Small-Fiber Symptom Survey (SSS) was employed to evaluate symptoms related to SFN [19]. The one-page SSS questionnaire encompasses five clusters of SFN symptoms, including sensation, circulation, gastrointestinal, pelvic, and miscellaneous. Each of the questionnaire's 34 questions is rated on a scale from 0 to 4, with 0 indicating "never," 1 indicating "rarely", 2 indicating "sometimes", 3 indicating "often", and 4 indicating "always". It also scans for chronic pain severity (0–10). The total score ranges from 0 to 146.

In the initial development of SSS, it was validated in 179 participants including SFN patients diagnosed with objective tests and healthy controls. The SSS score averaged 5.06 ± 5.3 (mean ± SD) in healthy controls and 32.4 ± 14.8 in patients with confirmed SFN. In the current study, we utilized a cutoff value of 15.7, which represents two standard deviations from the mean of healthy individuals, to determine the prevalence of SFN symptoms. In addition, patients with positive SFN symptoms (SSS score > 15.7) were further divided into moderate and high SSS score groups using 32.4 as a cutoff value [19].

DED treatment response:

After the initial cross-sectional questionnaire study was completed, 30 participants continued their DED care in the clinics. Their electronic medical records (EMR) at baseline and 6–12-month follow-up visits were reviewed and DED treatment regimens were recorded. In addition, their DED clinical signs were compared between baseline and follow-up visits. Their subjective response to DED treatments was extracted from the history of present illness section in the EMR and recorded as ‘improved, the same, or worse’.

In Vivo Confocal Microscopy (IVCM):

A random group of patients underwent IVCM imaging using the Heidelberg Retina Tomograph 3 equipped with the Rostock Cornea Module, following an established protocol [26]. Corneal nerve morphology (branching, width) and density were assessed in a masked fashion.

Statistical analysis:

The statistical analysis was conducted using GraphPad Prism 8 (GraphPad Software Inc., USA). The normality of data distribution was assessed using the Shapiro–Wilk test. Spearman’s test was employed to evaluate correlations between SSS score, OSDI score, OPAS score, and clinical parameters. For continuous variables between three groups, a Kruskal Wallis test was performed. The Chi-square test was used for categorical variables. A Wilcoxon signed-rank test was conducted to analyze the difference in CFS scores between baseline and follow-up visits. Data are presented as mean ± standard deviation (SD), and statistical significance was defined as p-values < 0.05.

Study population

This study included 31 patients diagnosed with DED, with a majority of females (80.6%). The average age of the patients was 55.1 ± 16.6 years, ranging from 23 to 87 years. The demographic information of the patients can be found in Table 1.

Table 1

Demographics of the study population
Study Population
Number of patients	31
Sex
Male	6 (19.4%)
Female	25 (80.6%)
Age (year)	55.1 ± 16.6 (23–87)
18–40	8 (25.8%)
41–65	11 (35.5%)
> 65	12 (38.7%)
Race
White	23 (74.1%)
African American	2 (6.5%)
Asian	2 (6.5%)
Unknown	4 (12.9%)
BMI (kg/m²)
18-<25	15 (48.4%)
25-<35	13 (41.9%)
Unknown	3 (9.7%)
Smoking
Never smoked	22 (70.9%)
Previous smoker	3 (9.7%)
Current smoker	3 (9.7%)
Unknown	3 (9.7%)
Comorbidities
Hypertension	8 (25.8%)
Arthritis	6 (19.4%)
Fibromyalgia	4 (12.9%)
Dysautonomia	1 (3.2%)

DED symptoms and pain were evaluated using OSDI (50.9 ± 24.7) and OPAS (20.3 ± 14.3). Additionally, the clinical signs of DED were assessed, including tear film parameters (TBUT and Schirmer test), CFS and corneal sensitivity scores. The clinical characteristics of the patients are presented in Table 2.

Table 2

Clinical characteristics of the study population
Dry eye disease parameters
Ocular surface disease index score*	50.9 ± 24.7 (12.5–97.9)
Ocular pain assessment score (n = 30)	20.3 ± 14.3 (0-55.6)
Dry eye disease signs
Schirmer’s test (mm)*	9.4 ± 8.7 (1.0–35.0)
Tear break-up time (sec, n = 30)	5.2 ± 3.4 (0.0–15.0)
Corneal fluorescein staining (NEI scale)*	2.3 ± 3.3 (0.0-13.5)
Corneal sensitivity (cm, n = 29)	5.6 ± 0.8 (2.5-6.0)
Small fiber neuropathy symptoms assessment (n = 31)
Small Fiber Symptoms survey score (SSS)*	38.9 ± 33.6 (0.0-123.0)
Frequency of SSS score > 15.7	24 (77.4%)
0-15.7 15.8–32.4 ≥ 32.5	7 (22.6%) 12 (38.7%) 12 (38.7%)
*n = 31, Mean ± SD (range)

There is a high prevalence of SFN symptoms among DED patients.

The DED patients were assessed for SFN symptoms using the SSS questionnaire. The mean SSS score for the entire group was 38.9 ± 33.6, ranging from 0.0 to 123.0. To determine the presence of SFN symptoms, a cutoff of 15.7 was used, which represents two SDs from the mean of healthy individuals [19]. As indicated in Table 2, 77.4% of the patients reported positive symptoms of the disease based on this cutoff, with 38.7% reporting a score between 15.8 and 32.4, and another 38.7% reporting a score of ≥ 32.5.

SFN symptoms correlate moderately with OSDI and strongly with ocular pain.

When assessing the relationship between DED symptoms using OSDI and SSS scores, we observed a moderate positive correlation (r = 0.4256, P = 0.017) as depicted in Fig. 1A. However, upon analyzing the OSDI subcomponents, we found a significant correlation with symptoms related to vision alteration, such as poor vision and blurred vision, reporting gritty eyes, light sensitivity, and reading difficulties. No correlation was observed with reporting discomfort from wind, air-conditioning, or humidity, nor with reporting issues related to driving, computer usage, or television viewing, as illustrated in Supplementary Table 1.

When examining the correlation between ocular pain and SFN symptoms, OPAS is strongly correlated with SSS scores (r = 0.6151, P = 0.0003) as depicted in Fig. 1B. This positive correlation was also evident in the OPAS subcomponent, particularly with the reporting of non-ocular pain as shown in Fig. 1C.

Sub-analysis of SFN symptoms in correlation with DED symptoms and ocular pain

The SSS questionnaire has 6 sections: chronic pain, sensation, circulation, gastrointestinal, pelvic, and miscellaneous symptoms. To identify the SFN symptoms most strongly linked to DED symptoms, we conducted a sub-analysis exploring the correlation between each SSS component and OPAS/OSDI. Among these, sensation, gastrointestinal, and miscellaneous symptoms were strongly correlated with the OPAS score, whereas only miscellaneous symptoms were strongly correlated with the OSDI score. Most notably among each SFN symptom, reporting chronic pain on SSS was strongly correlated with OPAS (r = 0.726, p < 0001), but not with OSDI scores. In addition, reporting mental and physical fatigue, and deep internal feeling of vibration on SSS was strongly correlated to both OPAS and OSDI scores, as illustrated in Supplementary Table 2.

Analysis of SFN symptoms in correlation with DED signs.

Our findings established a correlation between SFN symptoms and DED symptoms. Subsequently, we investigated the relationship between SFN symptoms and DED signs. We did not observe a significant correlation between the SSS scores and the Schirmer’s test (tear secretion, P = 0.362), TBUT scores (tear film stability, P = 0.549), or corneal sensitivity (P = 0.484). However, we noted a moderate negative correlation to the CFS (corneal epithelial integrity, r=-0.419, P = 0.018), as illustrated in Fig. 2.

Lack of subjective symptom improvement in patients with severe SFN symptoms with standard DED treatment.

The cohort was divided into three groups, low, moderate, and high SSS scores, based on thresholds of 15.7 and 32.4, established by referencing the average score of healthy and confirmed SFN patients [19]. Supplementary Table 3 indicates that there were no significant differences in age, body mass index (BMI), smoking status, or comorbidities among these subgroups. There was no significant difference in the clinical characteristics either (Supplementary Table 4).

All patients were administered standard ophthalmic treatments for DED, as detailed in supplementary table 5. Comparatively, the high SSS (severe SFN) group appeared to have received more intense topical treatment (cyclosporine, serum tears, and lifitegrast eye drops) than the low SSS group, although statistical significance was not established. A review of the electronic medical records for the 30 patients who continued care in the clinic indicated that the ocular surface remained stable across the three groups, as indicated by CFS in Fig. 3A.

In terms of symptom improvement in the cohort, 41.9% (13 patients) reported positive changes, 25.8% (eight patients) reported no change in symptoms, and 29.0% (nine patients) reported worsened symptoms. Notably, among patients who reported worsened symptoms, 77.8% (n = 7) belonged to the severe SFN symptoms category (high SSS scores). Patients with low SSS scores exhibited either improvement (71.4%, n = 5) or unchanged symptoms (28.6%, n = 2). Among those with moderate SSS scores, 50.0% (n = 6) experienced improvement, 33.3% (n = 4) reported no change, and only 16.7% (n = 2) reported worsened symptoms. Conversely, 63.6% of patients with high SSS scores (seven patients) reported worsened symptoms, 18.2% (two patients) experienced improvement, and 18.2% (two patients) reported unchanged symptoms, as depicted in Fig. 3B.

IVCM shows alterations in corneal nerve morphology in patients with severe SFN symptoms.

As a proof of concept, corneal nerves were assessed using IVCM in three individuals with high SSS scores and compared to an individual with low SSS scores. Interestingly, we noted a decrease in corneal nerve density and an increase in nerve fiber width in those patients, as shown in Fig. 4.

DED is a complex condition that significantly affects the quality of life [27]. While treatment is largely effective for the majority of patients, some DED patients continue to experience persistent symptoms despite escalating therapy [28 29]. In this study, we investigated the relationship between SFN symptoms and DED symptoms and signs. We discovered a high prevalence of SFN symptoms among DED patients and a strong correlation between ocular pain and the severity of SFN symptoms. Interestingly, we observed a negative correlation between SFN symptoms and CFS. Most patients with severe SFN symptoms did not experience symptom improvement during the follow-up. These findings suggest that DED ocular pain in some patients may have a neuropathic origin.

While DED has been historically categorized as being caused by inadequate tear production, excessive tear evaporation, or a combination of both, evidence for a neuropathic origin has been growing [28 30]. Many associations have been established between systemic neuropathic diseases and DED [31]. One study found subjects who had increased forearm pain sensitivity were more likely to have DED [32]. Furthermore, an analysis of patient data from Veteran Affairs showed patients with a chronic pain diagnosis are 1.9 times more likely to have DED compared to patients without a chronic pain diagnosis [30].

SFN is a commonly associated diagnosis in syndromes involving unexplained chronic pain and multi-system symptoms [33]. Previous studies have shown ocular involvement in the SFN population in terms of a high prevalence of DED symptoms and altered ocular nerve density and complexity [16 34]. To diagnose SFN, a validated questionnaire with good reliability and validity was developed as a screening tool before proceeding to invasive testing [19]. Using this questionnaire, we found that 77.4% of DED patients reported positive SFN symptoms and a strong correlation between reporting altered sensation and ocular pain, suggesting a direct correlation between the two conditions (Table 1).

SFN has also been strongly associated with Sjögren's syndrome (SS), an autoimmune disease characterized by dry eyes and dry mouth [35 36]. In a cohort of 509 SS patients, fifteen patients were diagnosed with SFN [35]. The neurological symptoms associated with SS were attributed to the complex interplay of immune cells, and autoantibodies, leading to inflammation, and neurological damage [9 37]. Similarly, DED involves Th17-mediated autoimmunity and complement-dependent autoantibodies causing ocular inflammation and tissue damage [38 39]. These immune-mediated inflammatory processes might explain the association between SFN symptoms and DED.

DED can manifest with various symptoms, from dryness to pain which can be resistant to treatment [40]. DED pain can arise from various sources, including altered tear osmolarity, epithelial damage, or neurosensory dysfunction, which can result in changes in corneal nerve excitability and morphology [30 41]. By utilizing a standardized scoring system to evaluate pain, we observed a significant correlation between ocular pain scores and symptoms of SFN (Figure 1). Patients experiencing severe SFN symptoms reported higher levels of pain and exhibited worse symptoms during follow-ups despite stable clinical parameters (CFS score) (Figure 3). These findings align with the research conducted by Siedlecki et al., who noted that patients with more intense ocular pain showed less response to medical treatments [29], suggesting that traditional treatments may not adequately address all aspects of the disease.

Interestingly, while the SFN symptoms correlated moderately with the OSDI, there was no correlation between DED signs (such as TBUT and Schirmer test) and SFN symptoms. In contrast, a negative correlation was noted between the SFN symptoms and the CFS score. This further confirms that ocular pain in DED may be related to an underlying neurological component rather than surface pathology. We also noted that reporting mental and physical fatigue on the SFN symptom survey correlates strongly to ocular pain (OPAS) and DED symptoms (OSDI). These findings align with previous reports on the association between chronic fatigue syndrome and DED [42].

Corneal nerve analysis via IVCM has proven valuable in diagnosing SFN [16 17 43]. In line with this, our study demonstrated that patients experiencing severe SFN symptoms exhibited notable changes in corneal nerve morphology, including reduced density and branching, and increased nerve fiber width (Figure 4). As noted by Brines et al., an increase in nerve fiber width correlated with neuropathy severity [16]. Our research further indicates that patients with altered nerve morphology reported heightened ocular pain intensity and exacerbated symptoms during follow-up. This reinforces the hypothesis of a neurological component contributing to ocular pain in individuals with DED.

The limitations of this study include the relatively small sample size and the cross-sectional design, which does not establish causality. However, this study is the first to utilize a validated SFN symptom survey in the DED population and correlations found in this study provide the foundation for further investigations. Additionally, our findings may not be generalizable to all DED patients, as the study was conducted in two tertiary eye care centers. While none of the patients included reported having SS, the probability of these patients having underlying undiagnosed SS contributing to this neuropathy cannot be eliminated. The SFN Symptom Survey serves as a tool to identify individuals at high risk for the disease, but it is not a definitive diagnostic tool. Confirmation of SFN requires additional diagnostic evaluations. Lastly, we acknowledge that the IVCM analysis is only performed in a few patients within the cohort and may not provide a comprehensive view.

In conclusion, using a validated SFN symptom survey, our study reveals a high prevalence of SFN symptoms in DED patients and a strong correlation between SFN symptoms and ocular pain. Additionally, SFN symptoms correlate positively with DED symptoms, and negatively with the CFS. Importantly, patients with severe SFN symptoms have significantly less favorable response to standard DED treatments, when compared to those with no or mild SFN symptoms. The validated SFN symptom survey proves to be a valuable tool in evaluating DED patients, particularly those who fail to respond to treatments. These observations suggest that there may be a significant neuropathic component in certain DED patients, highlighting the need for further neurological assessment and posing challenges for effective treatment strategies in this population.

Funding sources

This study did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors.

Declaration of competing interest

No relevant conflicting relationship exists for any author.

Farrand KF, Fridman M, Stillman I, Schaumberg DA. Prevalence of Diagnosed Dry Eye Disease in the United States Among Adults Aged 18 Years and Older. Am J Ophthalmol 2017;182:90-98 doi: 10.1016/j.ajo.2017.06.033[published Online First: Epub Date]|.
Rosenthal P, Borsook D. The Corneal Pain System. Part I: The Missing Piece of the Dry Eye Puzzle∗. The Ocular Surface 2012;10(1):2-14 doi: https://doi.org/10.1016/j.jtos.2012.01.002[published Online First: Epub Date]|.
Stern ME, Beuerman RW, Fox RI, Gao J, Mircheff AK, Pflugfelder SC. The pathology of dry eye: the interaction between the ocular surface and lacrimal glands. Cornea 1998;17(6):584-89
Mcmonnies CW. The potential role of neuropathic mechanisms in dry eye syndromes. Journal of optometry 2017;10(1):5-13
Rosenthal P, Baran I, Jacobs DS. Corneal pain without stain: is it real? The ocular surface 2009;7(1):28-40
Labbé A, Liang Q, Wang Z, et al. Corneal Nerve Structure and Function in Patients With Non-Sjögren Dry Eye: Clinical Correlations. Investigative Ophthalmology & Visual Science 2013;54(8):5144-50 doi: 10.1167/iovs.13-12370[published Online First: Epub Date]|.
Zhang X, Zhao L, Deng S, Sun X, Wang N. Dry Eye Syndrome in Patients with Diabetes Mellitus: Prevalence, Etiology, and Clinical Characteristics. J Ophthalmol 2016;2016:8201053 doi: 10.1155/2016/8201053[published Online First: Epub Date]|.
Zhang X, Zhao L, Deng S, Sun X, Wang N. Dry Eye Syndrome in Patients with Diabetes Mellitus: Prevalence, Etiology, and Clinical Characteristics. Journal of Ophthalmology 2016;2016:8201053 doi: 10.1155/2016/8201053[published Online First: Epub Date]|.
Pavlakis PP, Alexopoulos H, Kosmidis ML, et al. Peripheral neuropathies in Sjögren's syndrome: a critical update on clinical features and pathogenetic mechanisms. J Autoimmun 2012;39(1-2):27-33 doi: 10.1016/j.jaut.2012.01.003[published Online First: Epub Date]|.
Sène D, Cacoub P, Authier FJ, et al. Sjögren Syndrome-Associated Small Fiber Neuropathy: Characterization From a Prospective Series of 40 Cases. Medicine (Baltimore) 2013;92(5):e10-e18 doi: 10.1097/md.0000000000000005[published Online First: Epub Date]|.
Ng Wing Tin S, Zouari HG, Wahab A, Sène D, Lefaucheur J-P. Characterization of neuropathic pain in primary Sjögren’s syndrome with respect to neurophysiological evidence of small-fiber neuropathy. Pain Medicine 2019;20(5):979-87
Terkelsen AJ, Karlsson P, Lauria G, Freeman R, Finnerup NB, Jensen TS. The diagnostic challenge of small fibre neuropathy: clinical presentations, evaluations, and causes. The lancet neurology 2017;16(11):934-44
Oaklander AL, Nolano M. Scientific Advances in and Clinical Approaches to Small-Fiber Polyneuropathy: A Review. JAMA Neurology 2019;76(10):1240-51 doi: 10.1001/jamaneurol.2019.2917[published Online First: Epub Date]|.
Viceconti A, Geri T, De Luca S, et al. Neuropathic pain and symptoms of potential small-fiber neuropathy in fibromyalgic patients: a national on-line survey. Joint Bone Spine 2021;88(4):105153
Bakkers M, Faber CG, Hoeijmakers JG, Lauria G, Merkies IS. Small fibers, large impact: quality of life in small‐fiber neuropathy. Muscle & nerve 2014;49(3):329-36
Brines M, Culver DA, Ferdousi M, et al. Corneal nerve fiber size adds utility to the diagnosis and assessment of therapeutic response in patients with small fiber neuropathy. Scientific reports 2018;8(1):4734
Tavakoli M, Marshall A, Pitceathly R, et al. Corneal confocal microscopy: A novel means to detect nerve fibre damage in idiopathic small fibre neuropathy. Experimental Neurology 2010;223(1):245-50 doi: https://doi.org/10.1016/j.expneurol.2009.08.033[published Online First: Epub Date]|.
Roszkowska AM, Licitra C, Tumminello G, Postorino EI, Colonna MR, Aragona P. Corneal nerves in diabetes—The role of the in vivo corneal confocal microscopy of the subbasal nerve plexus in the assessment of peripheral small fiber neuropathy. Survey of Ophthalmology 2021;66(3):493-513 doi: https://doi.org/10.1016/j.survophthal.2020.09.003[published Online First: Epub Date]|.
Treister R, Lodahl M, Lang M, Tworoger SS, Sawilowsky S, Oaklander AL. Initial development and validation of a patient-reported symptom survey for small-fiber polyneuropathy. The Journal of Pain 2017;18(5):556-63
Miller KL, Walt JG, Mink DR, et al. Minimal clinically important difference for the ocular surface disease index. Archives of ophthalmology 2010;128(1):94-101
Özcura F, Aydin S, Helvaci MR. Ocular surface disease index for the diagnosis of dry eye syndrome. Ocular immunology and inflammation 2007;15(5):389-93
Qazi Y, Hurwitz S, Khan S, Jurkunas UV, Dana R, Hamrah P. Validity and reliability of a novel ocular pain assessment survey (OPAS) in quantifying and monitoring corneal and ocular surface pain. Ophthalmology 2016;123(7):1458-68
Lee JH, Kee CW. The significance of tear film break-up time in the diagnosis of dry eye syndrome. Korean J Ophthalmol 1988;2(2):69-71 doi: 10.3341/kjo.1988.2.2.69[published Online First: Epub Date]|.
Bron AJ, Evans VE, Smith JA. Grading of corneal and conjunctival staining in the context of other dry eye tests. Cornea 2003;22(7):640-50
Draeger J. Corneal sensitivity: measurement and clinical importance: Springer Science & Business Media, 2012.
Cruzat A, Witkin D, Baniasadi N, et al. Inflammation and the Nervous System: The Connection in the Cornea in Patients with Infectious Keratitis. Investigative Ophthalmology & Visual Science 2011;52(8):5136-43 doi: 10.1167/iovs.10-7048[published Online First: Epub Date]|.
Gomes JA, Santo RM. The impact of dry eye disease treatment on patient satisfaction and quality of life: A review. The ocular surface 2019;17(1):9-19
Kheirkhah A, Dohlman TH, Amparo F, et al. Effects of Corneal Nerve Density on the Response to Treatment in Dry Eye Disease. Ophthalmology 2015;122(4):662-68 doi: https://doi.org/10.1016/j.ophtha.2014.11.006[published Online First: Epub Date]|.
Siedlecki AN, Smith SD, Siedlecki AR, Hayek SM, Sayegh RR. Ocular pain response to treatment in dry eye patients. The Ocular Surface 2020;18(2):305-11
Galor A, Levitt R, Felix E, Martin E, Sarantopoulos C. Neuropathic ocular pain: an important yet underevaluated feature of dry eye. Eye 2015;29(3):301-12
Levitt AE, Galor A, Chowdhury AR, et al. Evidence that dry eye represents a chronic overlapping pain condition. Molecular pain 2017;13:1744806917729306
Vehof J, Kozareva D, Hysi PG, et al. Relationship between dry eye symptoms and pain sensitivity. JAMA ophthalmology 2013;131(10):1304-08
Farhad K. Current Diagnosis and Treatment of Painful Small Fiber Neuropathy. Current Neurology and Neuroscience Reports 2019;19(12):103 doi: 10.1007/s11910-019-1020-1[published Online First: Epub Date]|.
Chen A, De E, Argoff C. Small Fiber Polyneuropathy Is Prevalent in Patients Experiencing Complex Chronic Pelvic Pain. Pain Medicine 2018;20(3):521-27 doi: 10.1093/pm/pny001[published Online First: Epub Date]|.
Pavlakis PP, Alexopoulos H, Kosmidis ML, et al. Peripheral neuropathies in Sjogren syndrome: a new reappraisal. J Neurol Neurosurg Psychiatry 2011;82(7):798-802 doi: 10.1136/jnnp.2010.222109[published Online First: Epub Date]|.
Descamps E, Henry J, Labeyrie C, et al. Small fiber neuropathy in Sjögren syndrome: comparison with other small fiber neuropathies. Muscle & Nerve 2020;61(4):515-20
Jamilloux Y, Magy L, Hurtevent JF, et al. Immunological profiles determine neurological involvement in Sjögren's syndrome. Eur J Intern Med 2014;25(2):177-81 doi: 10.1016/j.ejim.2013.10.005[published Online First: Epub Date]|.
Wei Y, Asbell PA. The core mechanism of dry eye disease is inflammation. Eye Contact Lens 2014;40(4):248-56 doi: 10.1097/icl.0000000000000042[published Online First: Epub Date]|.
Chen Y, Dana R. Autoimmunity in dry eye disease - An updated review of evidence on effector and memory Th17 cells in disease pathogenicity. Autoimmun Rev 2021;20(11):102933 doi: 10.1016/j.autrev.2021.102933[published Online First: Epub Date]|.
Barabino S, Labetoulle M, Rolando M, Messmer EM. Understanding symptoms and quality of life in patients with dry eye syndrome. The ocular surface 2016;14(3):365-76
Guerrero-Moreno A, Baudouin C, Melik Parsadaniantz S, Réaux-Le Goazigo A. Morphological and functional changes of corneal nerves and their contribution to peripheral and central sensory abnormalities. Frontiers in Cellular Neuroscience 2020;14:610342
Chen CS, Cheng HM, Chen HJ, et al. Dry eye syndrome and the subsequent risk of chronic fatigue syndrome-a prospective population-based study in Taiwan. Oncotarget 2018;9(55):30694-703 doi: 10.18632/oncotarget.25544[published Online First: Epub Date]|.
Bucher F, Schneider C, Blau T, et al. Small-Fiber Neuropathy Is Associated With Corneal Nerve and Dendritic Cell Alterations: An In Vivo Confocal Microscopy Study. Cornea 2015;34(9):1114-19 doi: 10.1097/ico.0000000000000535[published Online First: Epub Date]|.

The authors declare no competing interests.

Supplementary.docx
Supplementary Tables

Download PDF

Version 1

posted

You are reading this latest preprint version

Small Fiber Neuropathy in Patients with Dry Eye Disease

Status:

Version 1

Abstract

Figures

Introduction

Methods

Subjects:

Ocular Surface Disease Index (OSDI) assessment:

Ocular pain assessment:

Assessment of clinical signs of DED:

Corneal sensitivity testing:

SFN symptom assessment:

DED treatment response:

In Vivo Confocal Microscopy (IVCM):

Statistical analysis:

Results

Study population

Sub-analysis of SFN symptoms in correlation with DED symptoms and ocular pain

Discussion

Declarations

References

Additional Declarations

Supplementary Files

Status:

Version 1