Electrodiagnostic Signs of Carpal Tunnel Syndrome in Ocular Pseudoexfoliation Syndrome: A Case-Control Study

Purpose To assess the occurrence and severity of electrodiagnostic signs of carpal tunnel syndrome (ED-CTS) in patients with ocular pseudoexfoliation (PEX) and compare them with normal subjects. Method A 1:1 case-control study was designed and 60 patients with PEX were recruited from May 2019 to February 2021, and the ndings were compared with 59 age- and gender-matched healthy controls. All patients underwent complete ophthalmologic examination and nerve conduction velocity test at the median nerve was used to assess the occurrence and severity of ED-CTS in both hands. Results The mean age of participants was 59.8 ± 4.5 years. Occurrence of ED-CTS was 38.3% in PEX patients and 20.3% in control subjects (P = 0.025). There was also a signicant difference in the severity, and presence of asymptomatic CTS (P < 0.05). Adjusting other variables, including; age, sex and job diculty, having severe ED-CTS showed a 3.49-fold higher chance in the PEX group (P = 0.002). Conclusion There is a direct relation between PEX and the occurrence, as well as severity of ED-CTS.


Introduction
Ocular pseudoexfoliation syndrome (PEX) is a relatively common systemic disorder rst described by Lindberg in 1917 [1]. It mainly affects ocular tissues through the gradual deposition of brogranular material at the anterior segment of the eye and elsewhere. Although the chemical composition is not fully understood, overproduction and abnormal metabolism of glycosaminoglycans have been shown to play a key role [2,3]. PEX is more common in men over 60 years of age. Incidence rates vary greatly by race and geographic region. Studies showed that the incidence of PEX is about 0.3% in the Netherlands, 3% in France, 16% in Russia, 28.7% in Spain, and 42% in Sweden [4,5].
This syndrome manifests as akes on the pupil margin and anterior lens capsule, increased pigmentation of the trabecular meshwork, and open-angle glaucoma. Deposits of extracellular matrix, exfoliative materials and amyloid in PEX have also been found in other organs [3,6]. Associations between PEX and various systemic diseases such as diabetes, ischemic heart disease, systemic hypertension, and cerebrovascular disease have been discussed in the literature [7,8]. It has also been shown that this syndrome can affect peripheral nerves [9,10].
Carpal tunnel syndrome (CTS) is the most common entrapment neuropathy resulting from the median nerve compression in the carpal tunnel [11]. Certain conditions, such as diabetes mellitus, amyloidosis, hypothyroidism, and rheumatoid arthritis, may predispose one to CTS [12]. Obesity, pregnancy, use of birth control pills, menstrual irregularities, aging, and smoking are also risk factors for CTS [13]. Regardless of the risk factors, the prevalence of the condition in the general population is approximately 15% [14].
Indeed, the diagnosis of CTS is based on both clinical ndings and the results of electrodiagnostic tests [15,16]. Regarding the pathophysiology of CTS, protein deposits have been found in some patients [17].
Nerve conduction studies (NCV) and electromyography (EMG) can determine the occurrence and severity of median neuropathy at the wrist [18]. Needle EMG studies are less sensitive than NCV studies in diagnosing CTS. Sensitivities of electrodiagnostic methods range from 49-84% with speci cities of 95% or higher [19].
The severity of CTS is usually rated based on the results of the NCV test, which re ects the degree of demyelination and axonal loss in the median nerve [20]. Asymptomatic individuals with electrodiagnostic evidence of CTS appear more prone to develop CTS later in life than others with a normal NCV [21]. Therefore, it is important to determine the prevalence of electrodiagnostic CTS, especially in asymptomatic individuals who do not have any of the known risk factors. It bears noting that early and accurate diagnosis of CTS is essential for effective non-surgical management and valid identi cation of surgical candidates [22].
The study was designed to investigate an association between PEX and electrodiagnostic signs of CTS (ED-CTS). This may guide future research in identifying new risk factors for CTS.

Design and Setting
From May 2019 to February 2021, we conducted a case-control study in the ophthalmology department of Imam Hossein Hospital, a teaching hospital a liated with Shahid Beheshti University of medical sciences (SBMU), Tehran, Iran. The department is well-equipped, and the hospital is a large referral hospital with a high patient turnover.

Ethical Considerations
Ethical approval was obtained from the Research Ethics Committee of the Faculty of Medicine a liated with SBMU under reference number IR.SBMU.MSP.REC.1398.232.

Eligibility
Men and women aged 55-70 years were included. Diagnosis of PEX was based on an ophthalmic examination by slit-lamp biomicroscopy. Subjects with hypothyroidism and hyperthyroidism alike, diabetes mellitus, amyloidosis, rheumatic diseases, and a positive family history of neuropathy, previous wrist fracture, pregnancy, lactation, and carpal tunnel surgery were excluded. The control group consisted of normal subjects in the same age range who were referred to the clinic for ophthalmological examination.
Recruitment PEX patients and normal subjects were recruited. Initially, patients were invited to attend a screening visit.
At the screening visit, the rationale of the study was explained to all potential participants. If any patient declined to participate, another was invited in the same manner until the required sample was recruited.
We reviewed the patients' medical records and performed ophthalmologic examinations. Participants who gave written informed consent were enrolled in the study. Those subjects who worked heavily with their hands were excluded. A nurse, who had experience in performing work tasks, determined the level of employment hardship. The use of ngers and wrists during daily activities was used to decide whether a subject's employment was di cult or not.

Outcome Measures
All subjects were evaluated by history taking and physical examinations, including pain, paresthesia, weakness, Tinel's sign, and Phalen's maneuver. Physical examinations categorized patients into symptomatic and asymptomatic. The NCV testing at the median nerve of both hands was evaluated using the Nicolet EDX® EMG/NCS/ EP /IOM system (Natus machine, U.S.A). According to the American Association of the Electrodiagnostic Medicine criteria, neurophysiological tests rated CTS as mild, moderate, and severe [21]. All examinations were performed by a well-trained, physiatrist, who were blinded to patients' group.
Sample Size CTS has a prevalence of approximately 3.4% in women and 0.6% in men and the incidence increases with age to such an extent that it reaches 22.2% in those over 55 years of age [13,14]. To the best of our knowledge, no reports were presenting an association between PEX and CTS. Based on the documented medical records from our hospital information system, our research team estimated that the occurrence of CTS in PEX patients was approximately 50%. Considering this rate, we needed 52 samples in each group for a 1:1 independent case-control study to detect a signi cant discrepancy in the presence of CTS between PEX patients and the control group, with a power of 80% and a two-sided con dence level of 95%, using Kelsey's formula. We added eight samples to each group to ensure that the study was adequately powered for a 10% loss to follow-up.

Statistical Analyses
Results are presented as mean (SD) for continuous variables and absolute numbers (%) for categorical data. Means of continuous variables were compared using paired and independent t-tests. Normality of outcome variables was examined with the Shapiro-Wilk test, and homogeneity of variances was examined with Levene's test. To test the differences between study groups for categorical variables, either a χ2 test or Fisher's exact test was used. Also generalized estimating equations (GEEs) were used to analyze the effect of PEX on ED-CTS with adjusting the effect of other variables including: sex, age and job di culty. An exchangeable working correlation matrix was considered as structure of correlation matrix for two hands. The signi cance level was set at two-tailed α < 0.05. All data analyses were performed using SPSS Statistics, version 25 for Windows. The data analysts were masked to the patients' group.

Results
This study involved 119 subjects (238 hands), 60 in the PEX group and 59 in the control group. Results of one subjects of control group excluded at the nal steps of the study, nding a random fasting plasma glucose of more than 200 mg/dL in her laboratory ndings. The mean age was 59.83 ± 4.52 years, and 56 (47%) cases were male. Table 1 shows the baseline characteristics of the participants.  Table 2 shows the severity of ED-CTS per hand of the participants. Adjusting other variables including age, sex and job di culty in multivariate GEE analysis, showed the chance of having higher severity of ED-CTS in the PEX group is 3.49 (P = 0.002) times more than control group. Table 3 shows these associations in both univariate and multivariate models, with more details.

Discussion
PEX is considered an age-related disease that can lead to ocular complications such as cataracts or open-angle glaucoma. Numerous studies of PEX patients have shown that brogranular material is secreted from multiple sites, including the iris pigment epithelium, ciliary epithelium, and anterior lens capsule epithelium. However, the chemical nature of this substance is still unknown despite extensive research [8].
On the other hand, this syndrome is considered a systemic process with a possible increased risk of cardiovascular and cerebrovascular morbidities. Extracellular matrix and exfoliative materials found in other organs such as heart, lung, aorta, liver, kidneys, and peripheral arteries can con rm this idea [3,6].
An association between PEX and systemic diseases such as diabetes, ischemic heart disease, systemic hypertension, asthma, and rheumatoid arthritis has been discussed [7,8]. Manaviat et al. investigated the association between PEX and diabetes. They found that the prevalence of PEX was higher in diabetics [23]. An alteration in collagen metabolism, which is more common in diabetics, may be related to the higher rates of PEX [2].
In addition, Djordjevic et al. reported that PEX is one of the most important clinical parameters associated with abdominal aortic aneurysm, along with diabetes and hypertension [24]. Kovac et al. found a signi cant association between PEX and cardiac ischemia but no association with hypertension, diabetes, and cerebrovascular disease [25]. This discrepancy may be due to geographic differences that contribute to the development of PEX in different communities.
Researchers have noted the association between PEX and some neurological diseases. Singham et al. suggested that the accumulation of pseudoexfoliation material in sensorineural cells could explain the association between PEX and hearing loss [26]. Zojaji et al. also showed a strong association between PEX and sensorineural hearing loss [27]. Turgut Coban et al. showed an association between PEX and polyneuropathy in a case-control study of 31 PEX patients. They suggested, progressive in ltration of amyloid and proteins in the retinaculum exor and synovial tissue was thought to cause neuropathy [10].
To our knowledge, this is the rst study to examine the relationship between PEX and CTS. It seems that the secretion and deposition of protein substances in PEX could cause the compression of the median nerve, and it may have a role in the pathophysiology of CTS. In view of this, this study aimed to investigate the relationship between PEX and ED-CTS.
The results of the current 1:1 case-control study showed an increased risk of developing ED-CTS in PEX patients vis-a-vis the normal group. The severity of ED-CTS was also higher in PEX patients.
The results of this study showed that 16.7% in the control group and 52.2% in the PEX group showed ED-CTS and were asymptomatic. This nding of healthy individuals is consistent with Alrawashdeh's report on CTS patients, which showed that 15% of patients with ED-CTS are asymptomatic [28]. This means that PEX patients not only have a higher chance and severity of ED-CTS, but also a higher percentage of them are asymptomatic. As discussed above, sensory bers of the peripheral nervous system are affected by PEX, so it might explain why PEX patients with their median nerve involved at the wrist are asymptomatic.
According to the present study, the OR of ED-CTS in PEX patients is 2.71 times higher than in healthy subjects. Therefore, since another possible hypothesis for the coexistence of the two disorders is the presence of another underlying systemic disease, further studies should be done to investigate the occurrence of PEX in patients with ED-CTS. In addition, studying the occurrence of PEX in patients with ED-CTS is important because of the possibility of ocular damage due to an increase in intraocular pressure in patients with PEX glaucoma; it can help prevent dangerous ocular complications. Performing in vitro studies on the deposited materials is also suggested to clarify the molecular mechanisms further.

Limitations
The limitation of this study is that the duration of PEX was unknown in the participants as all patients were primary naïve.

Conclusions
Based on the present study results, there seems to be a direct relationship between PEX and the occurrence and severity of CTS-associated electrophysiological changes. Moreover, the occurrence of asymptomatic CTS is higher in PEX patients compared to previous studies.

Declarations
Founding: None Con icts of interest/Competing interests: There is no con ict of interest of any of the authors with the results of this study.
Availability of data and material: All results are available and could be shared if requested.