Assessment of ocular neuropathic pain following vitreoretinal surgery using 23-gauge sclerotomy

Objective To investigate the presence of persistent ocular pain after 23-gauge pars plana vitreoretinal surgery Method This is a prospective study including patients who underwent 23-gauge vitrectomy or silicone removal with local or general anesthesia. We evaluated the symptoms of ocular neuropathic pain before and two months after surgery using the Brief Pain Inventory (BPI) questionnaire, and the impact of reported ocular symptoms on quality of life. Correlation between ocular pain and factors such as patient demographics and underlying conditions were also assessed. Result 75 patients with


Introduction
According to the International Association for the Study of Pain, pain is de ned as an unpleasant sensory and emotional experience associated with or resembling that associated with, actual or potential tissue damage.[1] External painful stimuli such as trauma, surgery, or in ammation hurt nerve terminals and induce acute nociceptive pain which is the physiologic function of nociceptors.During a cornea or conjunctival surgery, an injury to the trigeminal nerve and its branches occurs.Also, the density of goblet cells in the conjunctiva will change.
This initial insult to the nerve may lead to a set of pathologic changes that cause an improper nerve signal and a sense of persistent pain in the absence of painful stimuli.Allodynia is de ned as an experience of pain, foreign body sensation, tearing, or photophobia in response to normally benign stimuli such as blinking.[2] This ocular discomfort develops due to modi cation of the normal function of receptors and if continue for two months following surgery, can be considered ocular neuropathic pain.It has several features that overlap with dry eye syndrome.[3][4][5][6] In fact when ocular pain symptoms disproportionally outweigh the clinical signs, i.e. symptoms of pain, foreign body sensation, or irritation are present despite no or minimal objective signs of ocular surface defects or staining, and/or conjunctival injection, it is called ocular neuropathic pain.
Neuropathic ocular pain has sensory, psychic, cognitive, and behavioral elements.[2] Patients with genetic factors as well as bromyalgia or psychiatric disease such as depression are more susceptible to developing persistent postoperative pain.[7,8] Similar to dry eye, the prevalence increases with age and is more common in females.[4,9] In addition to laser refractive surgeries, other operations such as cataract surgery, lid surgery, botulinum toxin usage, and aesthetic surgery can also cause or aggravate symptoms of dry eye syndrome.[4] However, a few studies have been conducted on retinal surgeries.
In this study, we aimed to evaluate the frequency of symptoms of ocular neuropathic pain after vitreoretinal surgeries involving 23-gauge sclerotomy.We have also investigated the effect of different variables such as demographic factors and underlying conditions on post-operative symptoms.

Method
This study is a prospective observational case series conducted on patients who had surgeries involving 23-gauge (23G) sclerotomy incisions including pars plana deep vitrectomy and silicone removal from June 2019 until January 2020 in a tertiary educational hospital.In the operating room, for local anesthesia, a combination of 0.02 mg/kg Midazolam and 1 mcg/kg Fentanyl was administered for IV sedation; and after monitoring for blood pressure, peribulbar injection of Lidocaine 2% and Marcaine was performed.For general anesthesia, Midazolam 0.02 mg/kg, Fentanyl 2 mcg/kg, Atracurium 0.5 mg/kg and Propofol 2 mg/kg were employed.Two to three scleral incisions were placed 3 to 4mm posterior to the limbus, on inferotemporal, superonasal, and superotemporal locations.Vicryl 8 − 0 or 7 − 0 absorbable sutures were placed to close the sclerotomies, in occasional cases that were not watertight at the end of surgery.All surgeries were performed by two surgeons (NE or MI).
We assessed persistent pain in patients using the Persian version of the standardized brief pain inventory (BPI) questionnaire [10], immediately before surgery and two months after surgery.The items evaluated include frequency of deep eye pain, irritation, photophobia, tearing, foreign body sensation, deep head and facial pain, and numbness.All these symptoms were measured on an 11-point numeric rating scale (NRS).The average of all items, de ned as overall eye symptoms, was calculated to evaluate the correlation of ocular manifestations with demographic characteristics and systemic conditions.All patients have also undergone slit-lamp examination and intraocular pressure measurement on day one, week one, month one, and month two after the surgery.
The effect of demographic characteristics (such as patient's age, sex, level of education), as well as background systemic conditions (such as diabetes mellitus (DM), hypertension (HTN), chronic back pain, musculoskeletal pain, migraine headaches, depression), and type of surgery, method of anesthesia on reported ocular symptoms and quality of life were investigated.Items that were questioned for this purpose were whether any disturbance has happened in general activity, mood, relationships, sleep, enjoyment of life, the ability of walking, the ability to perform normal work both outside and inside the home, and the patients rated them via an 11-point numeric scale.
Patients with di culty in communication, a history of psychiatric, cerebrovascular, or neurologic disease, alcohol consumption, or using illicit drugs, analgesics, or opioids within the last 48 hours of the surgery were excluded from the study.
Written consent was obtained from patients who wish to participate.The collected data was analyzed using SPSS software.To evaluate the difference in mean between two independent groups, the Mann-Whitney U test and for comparison of more than two groups, the Kruskal-Wallis test was used.The correlation between quantitative variables was analyzed by the Spearman correlation test.To evaluate the association of a covariate with a dichotomous dependent variable, logistic regression was used.The signi cance level of the test was considered 0.05.
No postoperative complications such as uveitis, corneal epithelial defect, punctate epithelial erosion, signi cant ocular surface in ammation, or conjunctival injection were observed during follow-up examinations.
Table 1 demonstrates the prevalence and intensity of pain-related symptoms pre-and post-operatively.Although the frequency of some symptoms such as deep eye pain, photophobia, and facial numbness increased after surgery, the difference was not statistically signi cant.
Table 2 demonstrates the quality-of-life scores at baseline and two months following surgery which did not show a signi cant alteration.
Patients' overall eye symptoms at baseline did not differ with the presence of systemic diseases such as diabetes and hypertension (0.84 ± 1.29 vs 1.90 ± 2.83, p-value: 0.396).Similarly, two months after surgery, such association was not observed (1.17 ± 1.86 vs 1.21 ± 1.46, p-value: 0.566).
The presence of musculoskeletal pain, migraine headache, and depression did not affect the overall eye scores in the preoperative period.Similarly, these factors except migraine headache (OR: 1.39, CI95%: 1.014-1.918;p-value: 0.041) were not correlated with overall eye scores, postoperatively.
The method of anesthesia (local or general) and type of surgery (vitrectomy or silicone oil removal surgery) did not affect eye symptoms two months after surgery (p-value > 0.05).

Discussion
In the present study, we showed that following 23-gauge sclerotomies, ocular pain scores did not alter signi cantly.However, we observed a signi cant increase in analgesics consumption during two months following surgery.In addition, patients using analgesics after surgery have reported worse quality-of-liferelated items.Patients who reported ocular and facial pain as well as photophobia before surgery had a higher chance of analgesic consumption after surgery.
Severing the enriched nerve plexus in surgeries involving corneal incisions has been shown to induce ocular neuropathic pain and dry eye symptoms.However, few studies exist that investigate ocular pain following surgeries involving solely scleral incisions.[11,12] The prevalence of chronic eye pain following cataract surgery has been reported as high as 34%.[13] Similarly, ocular neuropathic pain after refractive surgery is a well-known complication.[14][15][16][17] One study [17] reported that 20% of patients who underwent laser-assisted in-situ keratomileusis (LASIK) had symptoms of dry eye six months after surgery.
Compared with the cornea which has the highest nerve density in the body, the sclera is less sensitive due to its lower nerve density and the less exposed nerves which are located far from the surface.
[18] The anterior sclera is innervated by two long posterior ciliary nerves which are branches of the ophthalmic division of the trigeminal nerve.[19] These nerves pierce the sclera adjacent to the optic nerve and travel anteriorly to around the ciliary body.The small gauge sclerotomies can injure these nerve endings.Additionally, conjunctival manipulation, desiccation, exposure to microscope light, and toxicity of povidone Iodine or postoperative topical drugs can induce ocular surface abnormalities.A study conducted in 2013, investigated ocular pain after conventional 20-gauge pars plana vitrectomy and reported that the frequency of ocular pain increased from 4.6% before surgery to 49.4% the day after surgery which then gradually decreased.In this study, 12.6% of patients reported persistent ocular pain at the nal report which was two months after surgery.Symptoms of dry eye and foreign body sensation were found in 25% of patients.[11] The insigni cance alteration of pain scores in our study may be related to the use of a smaller gauge device to pierce the sclera with the induction of fewer nerve endings destruction.Interestingly, a retrospective study comparing 20-gauge vs 23-gauge vitrectomy, showed less pain and sleep disturbance, and fewer analgesics consumption in the 23-gauge vitrectomy group one week after surgery.[12] Although ocular pain scores did not alter signi cantly after surgery, a signi cant proportion of our patients used analgesics afterward.This subset of patients scored worse in the items of the quality-oflife questionnaire.In fact, analgesic consumption may have masked the ocular pain symptoms, in exchange for a decrease in quality-of-life.Previous studies have shown that the use of oral analgesics is an independent predictor of lower scores of quality-of-life.[20] Using NSAIDs is associated with fatigue, anxiety, and depression in patients with rheumatoid arthritis.[21] Based on our ndings, higher scores of ocular and facial pain, as well as photophobia before surgery herald higher odds of analgesic use after surgery.Detection of risk factors and appropriate management of postoperative ophthalmic pain may reduce the number of analgesic-dependent patients and may result in a more satisfactory outcome.
Although it is reported that the presence of underlying conditions such as DM, HTN, musculoskeletal pain, and depression may affect the rate of reported pain symptoms [7,8,22], we did not nd any correlation between baseline and postoperative eye pain in this regard.The only underlying factor that could be considered a predictive factor for postoperative eye pain was found to be migraine headaches.
It is known that in neuropathic pain syndromes, social, and psychiatric issues play a signi cant role in the perception of pain by the patients.[23] Our study has several limitations.First, the sample size is relatively small.Second, we did not record the dose and frequency of analgesic used after surgery.Also, although the type of surgery was not associated with post-operative pain, it would be helpful to collect and analyze the data of intraoperative surgical steps such as endolaser photocoagulation or scleral indentation in future studies.

Conclusion
To date, many studies investigated postoperative pain in different anterior segment surgeries, but reports focusing on pain after retinal surgery are quite a few.In this study, we evaluated ocular neuropathic pain in retina surgeries involving 23-gauge sclerotomies.Although the increasing trend of ocular pain at two months after scleral incisions was not signi cant, an increase in analgesic consumption after surgery was observed which affects the quality-of-life scores in this subset of patients.

Declarations
Funding: No funding was received to assist with the preparation of this manuscript.

Figures
Figures

Table 1
Prevalence and intensity of eye symptoms, mean and SD of patient-reported pain score, and other symptoms before and after surgery.

Table 2
Scores of quality-of-life at baseline and 2 months after surgery