Introduction

Carpal tunnel syndrome (CTS) is a neurological disorder characterized by paresthesia and pain in the hands due to lesions and ⁄or dysfunction of the median nerve at the wrist [1-4]. The carpal tunnel is located at the base of the palm. CTS is defined as “a symptomatic compression neuropathy of the median nerve at the level of the wrist” by the American Academy of Orthopaedic Surgeons (AAOS) [5]. In the general population, CTS has been found to have a prevalence rate of 3.8% and an incidence rate of 1.8/1,000 [6,7] with more frequency in women than in men; the prevalence rate is 9.2% in women and 6% in men. [5]. CTS is one of the most common upper limb compression neuropathies. CTS accounts for approximately 90% of all entrapment neuropathies. It is due to an entrapment of the median nerve in the carpal tunnel at the wrist [6]. Also, CTS is the most common neuropathy during pregnancy [8].

CTS is associated with compression, some anomalies, autoimmune or hematologic disorders, arthritis, trauma, or neoplasms [9]. The exact pathogenesis of CTS is not clear. There are several theories which have been put forward to explain the symptoms. The mechanical compression, micro-vascular insufficiency, and vibration theories are the most popular ones. According to the mechanical compression theory, symptoms of CTS are due to compression of the median nerve in the carpal tunnel. The micro-vascular insufficiency theory proposes that the lack of blood supply leads to depletion of nutrients and oxygen to the nerve, causing it to slowly lose its ability to transmit nerve impulses. According to the vibration theory, the symptoms of CTS could be due to the effects of long-term use of vibrating tools on the median nerve in the carpal tunnel [10]. Also, some research indicates that biochemical mediators, including the free oxygen radicals prostoglandin E2 (PGE2) and interleukin-6 (IL-6), may ultimately be involved in the pathophysiology of idiopathic CTS by cause of ischemia [11]. While the nature of CTS has been extensively studied, little is known about the genetic background of this disease. Several authors have suggested that genetic factors are associated with CTS [12,13]. The investigations performed to determine the genetic background of CTS focused on proinflammatory cytokines such as IL-1, IL-6 and tumour necrosis factor α (TNF- α). These cytokines are released by peripheral nervous system cells including macrophages, T-cells, and Schwann cells in response to inflammation, tissue injury, and immunological reactions. Subsequently, they initiate a molecular cascade to activate other proinflammatory cytokines and growth factors that contribute to neuropathic pain [14]. They can also directly modulate neuronal hypersensitivity and elicit spontaneous neuronal discharges [15]. While the pro-inflammatory cytokines such as IL-6 and IL-18 have the pronociceptive effect, the anti-inflammatory cytokines such as IL-4 or IL-10 play an important role in nociception, thereby inhibiting the development of neuropathic pain [16]. Additionally, evaluation of nociception was used to monitor the functional recovery of the injured nerve and the nociception increased after median nerve compression [17]. Therefore, it is important to investigate associations between CTS and anti-inflammatory cytokines such as IL-4 that have a role in neuronal hypersensitivity and the nociception process. However, until now, there has been no report about the relationship of IL-4 gene intron 3 VNTR polymorphism and CTS. The aim of the present study is to analyze the association of IL-4 VNTR polymorphism with CTS susceptibility and disease progression in patients with CTS in a Turkish population.

Materials and Methods

Subjects

One hundred fifty-five patients (patient group, 135 females and 20 males) with carpal tunnel syndrome and 140 healthy participants (control group, 106 female and 34 male, without any reported history of CTS symptoms or surgery), were recruited for this study from Physical Therapy and Rehabilitation and the Neurology clinics in the Faculty of Medicine, Gaziosmanpasa University, Tokat, Turkey. The controls and the patients with CTS were matched for type of occupation and years of exposure to wrist activity (Table 1). Prior to participation in this study, the participants were informed about the procedures and gave written informed consent (according to the Declaration of Helsinki). In addition, a questionnaire containing personal details and self-reported personal and family medical history questionnaires were completed by each participant. This study was approved by the Ethics Committee of the Faculty of Medicine, Gaziosmanpasa University (14-KAEK-039).

Genotyping

DNA was extracted from 2 mL venous blood according to kit procedure (Sigma, USA) and stored at -20°C. To detect 70 bp VNTR polymorphism of IL-4 gene PCR assay as described by Mout et al. [18] was used. PCR was performed with a 25 µl reaction mixture containing 50 ng DNA, 0.8 lM of each primer, 200 lM of each dNTP, 2.5 mM MgCl2, 0.5 U Taq polymerase, 109 KCl buffer (MBI, Fermentas). Amplification was carried out using primers F5’ AGGCTGAAAGGGGGAAAGC-3’, R 5’-CTG TTCACCTCAACTGCTCC-3’ with initial denaturation at 95ºC for 5 min, 30 cycles of denaturation at 94ºC for 30 s, annealing at 58ºC for 45 s, extension at 72ºC for 1 min and final extension at 72ºC for 10 min. The PCR products were visualized on 3% agarose gel stained with ethidium bromide. PCR product was of 183 bp for P1 allele and 253 bp for P2 allele. In order to validate the accuracy and reproducibility of this method, each PCR reaction included internal controls for each genotype. A second PCR was performed to confirm samples in which results were not clear. Also, to confirm the accuracy of the genotyping, repeated analysis was performed on randomly selected samples. No discrepancies were found.

Statistical Analysis

Analysis of the data was performed using the computer software SPSS 16.0 (SPSS, Chicago, IL, USA) and OpenEpi Info software package program. Continuous data were given as mean ± SD (standard deviation) and (min–max). The frequencies of the alleles and genotypes in patients and controls were compared with x2 analysis. Odds ratio (OR) and 95% confidence intervals (CIs) were calculated. p value smaller than 0.05 (two-tailed) was regarded as statistically significant. Power analysis was made by using Minitab 15.0 package program. Hardy-Weinberg equilibrium was assessed by Chi-square analysis.

Results

Demographic variables and baseline characteristics of patients are given in Table 1. The mean age ± standard deviation (SD) was 46.85±11.45 years in patients and 46.59±11.03 years in the control group. There were 135 females (87.1) and 20 males (12.9) and 106 female (75.7) and 34 male (24.3) in patient and control groups, respectively. Table 2 presents the distribution of IL-4 70 bp VNTR mutation profiles in patients and control groups. There was no statistically significant difference in the genotype frequencies at IL-4 70 bp VNTR gene (p>0.05), but allele frequencies showed a statistically significant association (p=0.02). Also, many clinical characteristics (gender, age, height, weight, BMI, age onset of disease, dominant hand, time of diagnosis, family history, disease side, Tinel’s sign, Phalen maneuver, EMG findings, and clinical stage) were analyzed. Among the demographic and clinical characteristic of FM patients, no statistically significant difference was found between carriers and non-carriers of IL-4 70 bp VNTR polymorphism (Table 1 and 3). It was concluded that IL-4 70 bp VNTR polymorphism may cause FM especially in P1 allele form.

Discussion

The studies related to carpal tunnel genetic background and future therapeutic strategies are focused on cytokines and proteoglycans [19,20]. It has been reported that proinflammatory cytokines play an important role in the pathophysiology of neuropathic pain syndromes, CTS, and herniated intervertebral disks [21]. Interleukin-6 (IL-6) is a multifunctional bioactive cytokine whose actions include the modulation of proliferation and differentiation. Also, IL-6 has a role in the development, differentiation, regeneration, and degeneration of neurons in the peripheral and central nervous systems [11,15].

In other studies related to the genetics of carpal tunnel syndrome, it has been reported that proteasome modulator 9 gene creates a risk for the development of carpal tunnel syndrome [22]. Lupsi et al showed that Y169H missense variant segregates with an axonal neuropathy, whereas the nonsense R954X mutation is associated with subclinical evidence of carpal tunnel syndrome; therefore, haploinsufficiency of SH3 domain and tetratricopeptide repeats-containing protein 2 may cause susceptibility to carpal tunnel syndrome [23]. These data suggest that multiple cytokines, including IL-1 and IL-6, produced from tenosynovial tissues in patients with dialysis-associated amyloidosis might induce the proliferation of synovial cells and might cause carpal tunnel syndrome [24]. Penas et al reported that the Val158Met polymorphism Catechol-O-methyltransferase that inactive of the catecholamine neurotransmitters seems not to be a risk factor for the development of CTS [2]. In previous studies, the fibrotic factors such as transforming growth factor-beta, connective tissue growth factor, type 1 collagen, and type 3 collagen are effective in CTS susceptibility [25]. Additionally, Burger et al showed that sequence variants of the COL5A1 3′-untranslated region (UTR) are associated with altered risk of CTS [12].

In the present study, we analysed the frequencies of 70 bp VNTR polymorphisms at intron 3 of anti-inflammatory cytokine IL-4 in CTS patients in a Turkish population. Our results show that while there was no statistical significance between the groups with respect to IL-4 genotype distribution (p>0.05), the allele frequencies of the patients and healthy controls are statistically significant (p<0.05). The main findings of this study are that the percentages of IL-4 70 bp VNTR polymorphism alleles are significantly different between patients and controls. We think that it is important to investigate associations between CTS and anti-inflammatory cytokines such as IL-4 that have a role in neuronal hypersensitivity and nociception process.

Conclusion

These findings show that there is an association of IL-4 gene 70 bp VNTR polymorphism P1 allele with susceptibility of a person for the development of carpal tunnel syndrome (p<0.05). The results of this study are important because this is the first report that investigates the relationships between susceptibility to carpal tunnel syndrome and IL-4 gene intron 3 VNTR polymorphisms. Additional analyses with larger populations are required to confirm these findings in different study populations.

Competing interests

The authors declare that they have no competing interests.

References

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2. Fernández-de-las-Peñas C, Ambite-Quesada S, Ortega-Santiago R, Martínez-Perez A, Díaz HF, Martínez-Martín J et al. Catechol-O-methyltransferase Val158Met polymorphism is associated with pain and disability, but not widespread pressure pain sensitivity, in women with carpal Tunnel syndrome. Pain Physician 2013;16(5):591-600.

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Introduction

Fiber optic bronchoscopy (FOB) is widely used in the diagnosis and treatment of pulmonary diseases, particularly in the evaluation, diagnosis, and treatment of endobronchial lesions. FOB is an extremely safe procedure provided basic precautions are taken.

FOB sensitivity is generally low in tumors localized in the outer third of the lung; i.e. in the parenchyma where the airways are generally normal in malignant people. Diagnosis of peripheral pulmonary lesions can be difficult; however, the use of computed tomography (CT)-, fluoroscopy- or ultrasonography (USG)-guided surgery increases the diagnostic rates. However, whether bronchoscopic inspection or percutaneous intervention is the optimal diagnostic medium for peripheral pulmonary lesions is unclear [1].

FOB under fluoroscopy is thought to be an effective and reliable first inspection method for the diagnosis of the pulmonary lesions with a diameter larger than 2 cm [2]. Shiner et al. [3] reported that bronchoscopy carried out on 71 patients with lesions larger than 2 cm did not detect endobronchial lesions and had a diagnostic ratio of 33% (11–76%).

Fluoroscopic guidance is technically less difficult, costs less, and requires less procedure time than CT guidance. The pneumothorax ratio is higher in CT-guided than fluoroscopy biopsies [4-6]; in fact, serious complications are rare in fluoroscopy-guided surgery [7]. The most common complication associated with fluoroscopic guidance is hemorrhage; however, it is generally not serious enough to require treatment. Complications such as pneumothorax, hemomediastinum, and damage to the bronchoscope are rare. The technique has been shown to be reliable for high-risk cases such as older age groups, emphysema, and cardiac disease [8-10].

Endobronchial lesion biopsy has a high diagnostic value for lesions that can be seen using a bronchoscope [11, 12]; however, the diagnostic values for transbronchial biopsy under fluoroscopy and brushing are high for peripheral lesions that cannot be seen using a bronchoscope [12-15].

The present study compared the diagnostic values of C-arm fluoroscopy-guided bronchoscopic lavage, brushing, and biopsy samples obtained in cases where radiological masses or parenchymal lesions were detected, but endobronchial pathology was not found.

Material and Method

The present prospective observational study compared the diagnostic values of routine bronchoscopic sampling methods. The study included patients scheduled for bronchoscopy for various reasons in which samples were obtained using C-arm fluoroscopy. We enrolled 60 consecutive patients with no endobronchial lesions between February-2005 and September-2007.

The study was approved by the Ethics Committee of Ege University, and all patients provided written informed consent prior to entry into the study.

Radiological masses or parenchymal infiltration were detected in the lung and first lavage, followed by brushing and then biopsy sampling on the cases where no endobronchial lesions were observed during FOB under C-arm fluoroscopy guidance.

Biopsy samples were sent to the pathology laboratory in a formalin solution, and brush samples were immediately fixed in 70% alcohol.

Prior to the biopsy, a medical history was taken and a physical examination and chest radiography were performed on all patients. A CT scan was routinely used to determine the location and characteristics of the lesion and to locate the site for the biopsy.

The inclusion criteria were: over the age of 18, a mass lesion or parenchymal infiltration on the chest radiogram, no endobronchial lesion detected using FOB, and cardiopulmonary stability and the ability to tolerate bronchoscopy. Patients with an endobronchial lesion, thrombocyte count <50000/mm3, or neutrophil count <1000/mm3 were excluded from the study.

Prior to surgery, the patients received premedication with subcutaneous morphine HCl (5–10 mg) and 2% lidocaine for local anesthesia. Midazolam was used to achieve deep sedation during surgery. The midazolam dose was adjusted for each patient with a maximum dose of 5 mg.

Patients were placed in the supine position and the FOB (Olympus videobronchoscope CLE-10, USA) was inserted through the transnasal or transoral route. Blood pressure, electrocardiogram (ECG), heart rate, and oxygen saturation were monitored during surgery in all patients. We used a Siemens Siremobil Compact L brand C-arm for fluoroscopy.

We used a registration form to collect demographic, clinical, radiological, and laboratory data and information concerning the cancer and bronchoscopic findings (i.e., view, monitoring, operations carried out, complications, and the results of the measures taken).

The Statistical Package for the Social Sciences 16.0 (SPSS Inc., Chicago, IL, USA) was used to conduct the statistical tests. Chi-squared tests were used to compare non-parametric variables and t-test were used to compare parametric outcomes. A regression analysis was carried out to evaluate factors contributing to diagnostic success.

Results

The study included 60 patients (45 male and 15 female) with a mean age of 61.5 ± 9.6. The most frequent symptoms were cough (56.7%), chest pain (23.3%), and dyspnea (20%). Lesions were most frequently detected in the right upper lobe. A peripheral mass >3 cm was detected on the chest radiogram in 27 patients, a peripheral nodule <3 cm was detected in 22 patients, and peripheral localized consolidation or infiltration was detected in 11 patients. A total of 30 patients (50%) were active smokers and 20 (33.3%) patients were nonsmokers while 10 (17.7%) patients were ex-smokers.

Surgery was performed most frequently on the right upper lobe (43.3%) and the apical segment of the right upper lobe (18.3%; Figures 1 and 2).

More than one biopsy was obtained during bronchoscopic surgery. Five biopsies were obtained from seven (11.7%) cases, four were obtained from 38 (63.3%) cases, three from 11 (18.3%) cases, two from two (3.3%) cases, and one biopsy was obtained from two (3.3%) cases. No statistically significant difference was found between the number of biopsies obtained and the diagnostic ratio. The diagnoses and sampling method used are shown in Table 1.

The diagnostic ratio was 36.7% for biopsy, 20% for bronchoscopic brushing, and 21.7% for bronchoscopic lavage (Figure 3). The total diagnostic ratio combining all sampling methods was 45%. Alternative methods were used for patients who could not be diagnosed using these sampling methods, those diagnostic ratios were: 25% for transthoracic fine-needle aspiration biopsy; 15% for surgery, and 15% for other methods (lymph node biopsy, metastasectomy, radiological detected but not pathologically proven tumor). The various surgeries performed are shown in Table 2.

The radiological sizes of the lesions are shown in Figure 4. Assessment according to tumor diameter revealed diagnostic ratios of 48.1% for lesions >3 cm and 31.8% for the lesions <3 cm (Figures 4 and 5). We found that that brushing did not detect lesions <3 cm. (p = 0.02). The regression analysis revealed no independent factors that contributed to the diagnosis.

Discussion

The present prospective study, carried out over a two and a half years, revealed a diagnostic ratio of 36% for biopsy, 20% for brushing, and 21% for bronchoscopic lavage. The total diagnostic ratio, the combination of all methods, was 45%. No serious surgery-related complications were observed in any patient.

C-arm fluoroscopy is widely used to obtain tissue or cytology samples during FOB for peripheral pulmonary lesions. The total diagnostic rate using fluoroscopy-guided biopsy, brushing, and aspiration has been reported to be 40–80% and the false-positive ratio was low [16, 17]. Evaluation of the bronchoscopic diagnostic methods individually revealed diagnostic ratios of 15–46% for biopsy, 29–50% for brushing, and 42–46% for aspiration [16]. The use of fluoroscopy increases the diagnostic ratio by 10–30% [17].

Cortese et al. [18] assessed 45 patients with pulmonary metastatic, but not endobronchial, lesions, and obtained a total diagnostic rate of 53% and a 47% diagnostic rate for biopsy, 22% for brushing, and 17% for lavage using fluoroscopy. A previous fluoroscopy-guided study conducted in 452 patients revealed a diagnostic ratio of 55.2% for biopsy [19].

The authors reported that as the number of biopsies increased, the diagnostic ratio increased (diagnostic rate of 52% for ≤4 and 70% for >4 biopsies) [19]. In contrast, we obtained three to four bronchoscopic biopsies from 49 cases, but did not find a statistically significant relationship between number of biopsies and diagnostic ratio. This difference may be explained by the fact that the distribution between biopsy numbers and case numbers was not homogenous in our study. Previous studies that have found an association between biopsy number and an increase in diagnostic rate recommend that at least four biopsies are obtained from each patient [19, 20].

Cortese et al. [18] reported diagnostic rates of 64% for tumors larger than 2 cm in diameter, and 28% for lesions smaller than 2 cm. In another study, fluoroscopy-guided diagnostic surgery was found to be ineffective for lesions less than 1.1 cm in diameter [21].

Assessment of diagnostic ratio according to tumor diameter revealed rates of 48.1% for lesions larger than 3 cm and 31.8% for those smaller than 3 cm. The brushing method was not effective for lesions smaller than 3 cm. (p = 0.02).

In a comparison of endobronchial ultrasound (EBUS) and fluoroscopy, Herth et al. [22] found fluoroscopy to be preferable because of its low cost and high diagnostic rate. However, both fluoroscopy and EBUS have been reported to be reliable diagnostic methods for lesions smaller than 3 cm [23].

Herth et al. [24] reported that EBUS detected 48 of 54 lesions smaller than 3 cm that could not be detected using fluoroscopy, and that 38 diagnoses were made resulting in a 70% diagnostic rate.

Ensminger and Prakash [25] reported a 55% diagnostic rate for 107 biopsies obtained using fluoroscopy on patients with diffuse pulmonary disease, but no endobronchial lesions. They found that the technique was clinically useful in 75% of procedures. In another study the authors concluded that fluoroscopy-guided bronchoscopic procedure performed on cases of diffuse lung disease significantly increased the diagnostic rate [26].

Diagnostic rates have been found to be higher at facilities that use EBUS. Using multiple diagnostic methods based on the case and combining sampling techniques increases the success rate of diagnosis [27]. In our study, biopsy was found to be the most effective sampling method with a diagnostic ratio of 36%; however, the addition of brushing and lavage sampling increased the success rate to 45%.

Fluoroscopy increases the reliability of sampling, particularly when obtaining a biopsy from a peripheral lesion for transbronchial biopsy. Fluoroscopy-guided surgery has been reported to decrease the risk of pneumothorax; although the risk of pneumothorax is less than 1.8% when guided by fluoroscopy, it has been reported to be as high as 2.9% when fluoroscopy-guided surgery was not used [28]. A previous study reported a pneumothorax rate of 5.8%, and while 3.8% required a thorax tube, major hemorrhage was observed in 0.2% of the patients [29, 30]. No serious complications were observed in our study.

Fluoroscopic guidance is technically less difficult, costs less, and has a lower complication risk than the CT guidance. Furthermore, the pneumothorax ratio is higher in CT-guided (40–50%) than in fluoroscopy-guided surgery. Finally, fluoroscopy-guided FOB is a reliable method.

Fluoroscopy-guided transbronchial needle aspiration (TBNA) has made a significant contribution to the diagnostic efficacy of fluoroscopy at a ratio of 20% (7–35%); and its diagnostic efficacy varies between 35% and 69%. In general, the bronchoscopy diagnostic rate decreases for lesions smaller than 3 cm located at the lateral end of the midclavicular line.

Conclusions: We observed that C-arm fluoroscopy-guided bronchoscopy reliably increased the diagnostic efficacy for peripheral lesions. Our findings suggest that biopsy was more effective than the other sampling methods; however, combining the methods increased diagnostic sensitivity with the exception that brushing was not effective for diagnosis of lesions smaller than 3 cm.

Authors’ contributions: JCE, TG and GC contributed to study design and execution. JCE, AB and ATO drafted the manuscript. JCE, AB and TG coordinated the study and reviewed the manuscript. TG and GC reviewed and commented on manuscript drafts. All authors read and approved the final manuscript.

Competing interests

The authors declare that they have no competing interests.

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