To measure the duration of nasolacrimal transition in patients with Multiple Sclerosis (MS), to compare the findings with the healthy population and to investigate the relationship between MS-related disability and nasolacrimal transition time.
A total of 73 individuals including 37 patients with relapsing–remitting MS and 36 healthy volunteers were included in the study. In both groups the nasolacrimal transition time was measured using flurosein drops. The degree of disability of MS patients was calculated according to the Expanded Disability Status Scale (EDSS).
There was a significant difference between MS patients and control group in terms of the median value of nasolacrimal transition time in (240 s (min: 85, max: 724) and 58.5 s (min: 21, max: 428), respectively) (p < 0.001). A positive correlation was found between EDSS scores and nasolacrimal transition time of MS patients (r = 0.384, p = 0.019).
This study showed that nasolacrimal transition time is prolonged in MS patients and there is a relationship between the degree of MS-related disability and the nasolacrimal transition time. This is the first study in the literature on this subject and the results of our study have the potential to shed light on the causes of common infections in MS patients. Long-term prospective studies are needed to further investigate the relationship between prolonged nasolacrimal transition and infections in MS patients.
Multiple sclerosis (MS) is an autoimmune, inflammatory, demyelinating and neurodegenerative disease of the central nervous system and is one of the leading causes of unpredictable lifelong disability in young adults today .
With some exceptions, the global distribution of MS generally increases as it moves away from the equator. It is seen with a frequency of 50–300 per 100,000 people, and it is estimated that approximately 2.3 million people worldwide live with MS . MS has a major impact on individuals' quality of life as well as functional, financial aspects of life and this impact increases with increasing disability .
In their study based on big data analysis Persson et al.  reported that people with MS have a higher risk of infection than the general population. In MS patients, infections cause attacks and may lead to progression of the disease and increased disability [4, 5]. Outpatient or inpatient services provided to MS patients due to infection are higher than general population [4, 6]. Therefore, strategies to prevent infections and early diagnosis are crucial in patients with MS. Although ocular infections are more common in MS patients and rare opportunistic ocular infections have also become prevalent, the causes of these infections have not been understood exactly [5, 7, 8].
The tear film consists of three components or layers: mucin, aqueous and lipid. The functions of the tear film include: lubrication of the ocular surface; removal of foreign substances from the ocular surface, protection with antibacterial action, and tissue care and wound healing on the ocular surface . The lacrimal drainage system is an organization of channels that drain tears from the ocular surface to the lower part of the nasal cavity . Stenosis or obstruction in the lacrimal canal makes the lacrimal system a stagnant pool that can be easily infected by bacteria .
In this study, we aimed to compare the nasolacrimal transition time between MS patients and healthy control group. Moreover, we investigated the relationship between MS-related disability and nasolacrimal transition time. To the best of our knowledge, there are no studies in the literature investigating the nasolacrimal transition time in MS patients.
Materials and methods
This prospective, cross-sectional case–control study was conducted between 10 February 2020 and 10 July 2020 in the Ear-Nose-Throat and Neurology clinics of a tertiary hospital. The principles of the Helsinki declaration were followed during the study and written informed consent forms were obtained from all participants. This study has been approved by the local ethics committee (Ethics committee protocol number: 2017-KAEK-189_2019.12.25_14).
Thirty-seven individuals diagnosed with relapsing–remitting MS according to McDonald criteria (2017) and 36 healthy volunteers were included in the study . Each MS patient underwent a complete neurological physical examination and their disability degree was assessed by the Extended Disability Status Scale (EDSS). EDSS is scored between 0 and 10 and higher scores indicate greater disability .
MS patients that had an attack or steroid therapy within the past month were excluded from the study. Moreover, patients with dementia, Parkinson's disease, vascular diseases, metabolic disease (diabetes mellitus or hypertension), epilepsy or psychiatric diseases were excluded from the study. Patients with vitamin B12 and vitamin D deficiency, anemia, folate deficiency, and patients with elevated levels of urea, aspartate aminotransferase, and alanine aminotransferase enzyme were excluded. Patients with acute or chronic infection, congenital anomalies of the brain, history of head trauma within the last year, peripheral neuropathy, heart diseases, thyroid and lung diseases, collagen tissue diseases, liver diseases, kidney failure, and pregnant patients were also excluded. Moreover, patients whose eye examination revealed epiphora, patients that had a history of lacrimal surgery, eyelid contour disorder, and ocular surface disease were not included in the study. Other exclusion criteria were septal deviation, nasal polyposis, antrochoanal polyp, turbinate hypertrophy, upper respiratory tract infection, history of nasal surgery, history of allergies, and history of active or passive smoking.
A detailed medical history was taken from all participants, physical and nasal endoscopic examinations were performed. Data including age, gender, medical and surgical history, current medications, family history and physical examination findings were recorded.
In 1961 Jones proposed a lacrimal system patency test, which revolutionized our understanding of the lacrimal system [14, 15]. An indirect ophthalmoscope or a head mirror and a nasal speculum are used in this test. One or two drops of 2% sodium fluorescein are dropped into the eye and a cotton applicator soaked with topical anesthetic is placed under the inferior turbinate. Patients are asked to sit forward with their eyes open, head bent and elbows on their knees until the staining of the cotton applicator is visualized. This staining is the indicator of nasolacrimal patency. The main disadvantage of the Jones test is the difficulty of seeing the dye in the cotton applicator. Becker proposed using flexible angioscope to eliminate this issue . The flexible angioscope, thanks to its small diameter, flexibility, and maneuverability, provides direct visualization of the opening of nasolacrimal canal in the nose and inferior turbinate and makes the dye test more reliable. The sensitivity provided by the angioscope enables even a small amount of dye to be detected .
In our study, we also used the flexible fiberoptic endoscope (Karl Storz, Germany), which is routinely used in our ear, nose and throat clinic. While the patient was in a sitting position without any local anesthesia, 2 drops of 2% sodium fluorescein were dropped into the conjunctival sac, and the inferior meatus and the opening of the nasolacrimal canal was directly visualized with a flexible fiberoptic endoscope. The time elapsed from administration of flurosein into the eye and visualization of the dye at the lower orifice was measured with a stopwatch and recorded as a nasolacrimal transition time.
Statistical Package for the Social Sciences (version 22.0, IBM Inc., Chicago, IL, USA) software was used for statistical analysis. Conformity of the data to normal distribution was tested with ShaphiroWilk test. Student's t-test was used to compare the properties of 2 independent groups with normal distribution, while Mann Whitney-U test was used to compare the properties of 2 independent groups with non-normal distribution. Chi-square test was used to compare groups according to categorical variables. Pearson correlation test was used for normally distributed data and Spearman correlation test was used for non-normally distributed data. P value less than 0.05 was considered statistically significant.
The mean age of MS group was 38.75 ± 9.48 years, while that of the control group was 39.19 ± 9.39 years. There was no significant difference between the groups in terms of age (p = 0.844). While 64.9% (n = 24) of MS patients were female and 35.1% (n = 13) were male, 69.4% (n = 25) of the healthy control group were female and 30.6% (n = 11) were male. There was no significant difference between the groups in terms of gender distribution (p = 0.867). Patient characteristics for both groups are presented in Table 1. The mean EDSS score of MS patients was 3.06 ± 1.74.
The median value of the nasolacrimal transition time was significantly higher in MS group compared to the control group (240 s (min: 85, max: 724) vs 58.5 s (min: 21, max: 428), respectively) (p < 0.001) (Table 1). No significant correlation was found between the time, since the diagnosis of MS and nasolacrimal transition time (r = 0.1122, p = 0.4471). However, a positive correlation was found between MS group’s EDSS scores and nasolacrimal transition time (r = 0.394, p = 0.019). The scatter plot between EDSS and nasolacrimal transition time is presented in Fig. 1.
In this study, the nasolacrimal transition time was significantly prolonged in MS patients compared to the healthy control group. In addition, a positive correlation was found between increased disability and nasolacrimal transition time in MS patients.
Önerci reported that nasolacrimal drainage is influenced by the tear production, eyelid position, anatomy of the tear system, and pump mechanisms . Deterioration in tear production has been demonstrated in MS patients, especially during clinical exacerbations [18, 19]. Annunziata et al.  reported that oral and ocular dryness may be seen in MS and these tend to increase during MS attacks. They also reported that oral and ocular dryness was higher in MS patients with higher disability .
Örnek et al.  suggested that autonomic dysfunction may be a common pathway of decreased tear production and corneal hypoesthesia in MS patients. In light of this information, it may be said that the prolonged nasolacrimal transition time in MS patients was due to decreased tear production.
The blink reflex and orbicularis oculi muscle are called the lacrimal pump mechanism in the nasolacrimal flow [17, 21]. The lacrimal pump plays an important role in the periodic regeneration of the tear film and the distribution and drainage of tears . Önerci have reported that weak orbicularis oculi muscle tone can lead to physiological dysfunction and impaired lacrimal drainage . The motor neuron of the orbicularis oculi muscle is the facial nerve and is one of the most frequently affected nerves in MS .
Any change in blinking pattern affects tear distribution and drainage . Elongation in blinking reflex in MS patients has been demonstrated in previous studies [24, 25]. Brooks et al.  have shown that prolonged blinking reflex in MS patients was associated with disease duration and degree of disability. Therefore, the prolonged nasolacrimal transition time in MS patients in our study might be the result of prolonged blinking reflex due to MS. On the other hand, the reason of prolonged nasolacrimal transition time in MS patients may be the cumulative effect of decreased tear production and prolonged blinking reflex in MS patients.
Many studies have reported that nasolacrimal duct obstruction may cause bacterial colonization in the lacrimal system and chronic dacryocystism [11, 27, 28]. Moreover, Li et al.  reported that infectious keratitis is closely associated with lacrimal duct obstruction. Lacrimal sac biopsy specimens taken during external dacryocystorhinostomy (DSR) showed positive culture results and bacterial colonization even in patients without a history of dacryocystitis . Sood et al.  have presented a case of 34-year-old MS patient with bilateral acute retinal necrosis (ARN). ARN, which is a rare infectious uveitis caused by members of the herpes family, is characterized by necrotizing retinitis, vitritis, occlusive vasculitis, and rapid progression in the absence of antiviral therapy and can lead to significant visual impairment and blindness despite immediate diagnosis and treatment . Ocular symptoms of MS are not rare and visual disability is a major cause of morbidity associated with the disease. . Toxoplasma, which is not a frequent cause of ocular infection, was reported to be the cause of ocular infection in a 23-year-old male MS patient .
Naiboğlu et al.  evaluated nasal mucociliary clearance in patients undergoing DSR due to epiphora. They observed a dry, crusted nasal mucosa on the side, where the nasolacrimal passage was impaired and showed that the nasal mucociliary clearance was prolonged . Considering the similar biochemical composition of tear film and nasal mucus they suggested that lubricating, antibacterial and hydrative properties of the tear film can contribute to the nasal mucus and may be required for optimal mucociliary clearance . Moreover, Şahin et al. have also demonstrated that mucociliary clearance, which is one of the most important defense mechanisms of the respiratory system, is prolonged in MS patients compared to the healthy control group [32, 33]. The prolonged nasolacrimal transition in MS patients may also cause prolonged mucociliary clearance. The rate of community-acquired pneumonia in MS is 3.6 times higher than in the general population . From this point of view, prolonged nasolacrimal transition in MS patients may create a risk factor for ocular infections with its direct effect, as well as pose a risk for upper and lower respiratory tract infections due to prolonged mucociliary clearance with indirect effect. It has been reported that upper respiratory tract infections can increase MS attacks by 30–40% in MS patients [4, 35]. Therefore, further studies are needed to precisely clarify these relationships.
In our study, we used EDSS, which is a frequently used scale in MS follow-up, to evaluate the disability status of MS patients. A significant positive relationship was found between EDSS score and nasolacrimal transit time in the patient group. However this correlation was not very strong. Although studies have shown a correlation between EDSS value and autonomic dysfunction in MS patients, EDSS is a scale that mainly evaluates motor and sensory functions without emphasizing autonomic involvement . Günal et al.  considered autonomic function tests necessary to detect subclinical parasympathetic and sympathetic autonomic dysfunction in MS patients and emphasized that a standard EDSS follow-up could overlook these changes. In line with this information, the reason for the weak correlation between nasolacrimal transition time and EDSS in our study might be patients’ subclinical autonomic dysfunction and associated asymptomatic decrease in tear production.
When we evaluated our patient group in detail, we found that some patients had lower nasolacrimal transition time. Better autonomic functions and tear production in these patients may be the reason for this lower transition time. Since we did not evaluate autonomic functions of our patients, and limited number of patients we could not make a subgroup analyze and a clear interpretation on this issue. This can be considered as a limitation of our study. Future large scale studies evaluating autonomic functions in more detail may shed light on this issue.
The low sample size due to large exclusion criteria is the limitation of our study. Moreover, since it is a cross-sectional study, it provides less information to establish a cause-effect relationship. However, despite its limitations, this is the first study that evaluated the nasolacrimal transition time in MS patients and, therefore, offers a unique prospective to the medical community.
In this study, the nasolacrimal transition time was significantly prolonged in MS patients compared to the healthy control group. Infections are common in MS patients and can cause MS attacks and increase morbidity. Our findings may contribute to understanding of the etiology of these infections. In addition, our results lead to the hypothesis that the reason for prolonged mucociliary activity seen in MS patients may be due to the prolonged nasolacrimal transition time. Clinicians who follow up MS patients should be aware of the tear changes and lacrimal system pathologies in these patients. Early diagnosis and treatment for these pathologies can reduce the susceptibility of patients to both opportunistic ocular infections and upper respiratory tract infections. This is the first study on this subject and that further studies are needed to establish a cause-effect relationship. Further prospective pathophysiological and biochemical studies on this subject may lead to new horizons in the treatment and follow-up of MS disease.
Kular L, Jagodic M (2020) Epigenetic insights into multiple sclerosis disease progression. J Intern Med 288:82–102
Thompson AJ, Baranzini SE, Geurts J, Hemmer B, Ciccarelli O (2018) Multiple sclerosis. Lancet 391(10130):1622–1636
Persson R, Lee S, Yood MU, Wagner CM, Minton N, Niemcryk S, Lindholm A, Evans AM, Jick SS (2020) Infections in patients diagnosed with multiple sclerosis: a multi-database study. MultSclerRelatDisord 41:101982
Steelman AJ (2015) Infection as an environmental trigger of multiple sclerosis disease exacerbation. Front Immunol 19(6):520
Marrodan M, Alessandro L, Farez MF, Correale J (2019) The role of infections in multiple sclerosis. MultScler 25(7):891–901
Wijnands JM, Kingwell E, Zhu F, Zhao Y, Fisk JD, Evans C, Marrie RA, Tremlett H (2017) Infection related health care utilization among people with and without multiple sclerosis. MultScler 23(11):1506–1516
Heath G, Airody A, Gale RP (2017) The ocular manifestations of drugs used to treat multiple sclerosis. Drugs 77:303–311
Zecca C, Nessi F, Bernasconi E, Gobbi C (2009) Ocular toxoplasmosis during natalizumab treatment. Neurology 73(17):1418–1419
Perry HD (2008) Dry eye disease: pathophysiology, classification, and diagnosis. Am J Manag Care 14(3 Suppl):S79-87
Ali MJ, Paulsen F (2020) Human lacrimal drainage system reconstruction, recanalization, and regeneration. Curr Eye Res 45(3):241–252
Prokosch V, Prokosch JE, Julia P, Idelevich EA, Böhm MRR, Thanos S, Stupp T (2014) Bacterial spectrum and antimicrobial susceptibility patterns in acquired and connatal lacrimal duct stenosis. Curr Eye Res 39(11):1069–1075
Thompson AJ, Banwell BL, Barkhof F, Carroll WM, Coetzee T, Comi G, Correale J, Fazekas F, Filippi M, Freedman MS (2018) Diagnosis of multiple sclerosis: 2017 revisions of the McDonaldcriteria. Lancet Neurol 17(2):162–173
Kurtzke JF (1983) Rating neurologic impairment in multiple sclerosis: an expanded disability status scale (EDSS). Neurology 33(11):1444–1446
Jones LT (1961) An anatomical approach to problems of the eyelids and lacrimal apparatus. Arch Ophthalmol 66(1):111–124
Jones LT, Wobig JL (1991) Surgery of the eyelids and lacrimal system. Birmingham, Alabama: Aesculapius, 1976. Munden PM, Kardon RH, Denison CE, Carter KD. Palpebral fissure responses to topical adrenergic drugs. Am J Ophtalmol 111:706–710
Becker BB (1990) Flexible endoscopy in primary dye testing of the lacrimal system. Ophthalmic Surg Lasers Imaging Retina 21(8):577–580
Onerci M (2002) Dacryocystorhinostomy. Diagnosis and treatment of nasolacrimal canal obstructions. Rhinology 40(2):49–65
Örnek N, Dağ E, Örnek K (2015) Corneal sensitivity and tear function in neurodegenerative diseases. Curr Eye Res 40(4):423–428
Miro J, Peña-Sagredo JL, Berciano J, Insua S, Leno C, Velarde R (1990) Prevalence of primary Sjögren’s syndrome in patients with multiple sclerosis. Ann Neurol 27(5):582–584
Annunziata P, De Santi L, Di Rezze S, Millefiorini E, Capello E, Mancardi G, RizM De, Scarpini E, Vecchio R, Patti F (2011) Clinical features of Sjogren’s syndrome in patients with multiple sclerosis. Acta NeurolScand 124(2):109–114
Jones LT (1973) Anatomy of the tear system. Int OphthalmolClin 13(1):3–22
Palakuru JR, Wang J, Aquavella JV (2007) Effect of blinking on tear dynamics. Invest Ophthalmol Vis Sci 48(7):3032–3037
Zadro I, Barun B, Habek M, Brinar VV (2008) Isolated cranial nerve palsies in multiple sclerosis. ClinNeurolNeurosurg 110(9):886–888
Degirmenci E, Erdogan C, Bir LS (2013) Correlation between blink reflex abnormalities and magnetic resonance imaging findings in patients with multiple sclerosis. Acta Neurol Belg 113(3):265–269
Klissurski M, Novachkova S, Pl T, Alexiev F (2009) Orbicularis oculi reflex abnormalities in patients with multiple sclerosis: a clinical, EMG, and MRI investigation. ElectromyogrClinNeurophysiol 49(1):59–63
Brooks JBB, Jardim MR, Papais-Alvarenga RM, Fragoso YD (2015) There is still a role for the blink reflex in the diagnosis and follow-up of multiple sclerosis. ClinNeurophysiol 126(4):743–747
DeAngelis D, Hurwitz J, Mazzulli T (2001) The role of bacteriologic infection in the etiology of nasolacrimal duct obstruction. Can J Ophthalmol 36(3):134–139
Hartikainen J, Lehtonen O-P, Saari KM (1997) Bacteriology of lacrimal duct obstruction in adults. Br J Ophthalmol 81(1):37–40
Li G, Guo J, Liu R, Hu W, Xu L, Wang J, Cai S, Zhang H, Zhu Y (2016) Lacrimal duct occlusion is associated with infectious keratitis. Int J Med Sci 13(10):800–805
Sood AB, Kumar G, Robinson J (2016) Bilateral acute retinal necrosis in a patient with multiple sclerosis on natalizumab. J Ophthalmic Inflamm Infect 6(1):1–4
Naiboglu B, Devecı I, Kalaycık C, Daylan A, Habesoglu TE, Toros SZ, Devecı SE, Egelı E (2010) Effect of nasolacrimal duct obstruction on nasal mucociliary transport. J LaryngolOtol 124(2):166–170
Sahin E, Hamamcı M, KantekinY, (2020) Measurement of mucociliary clearance in the patients with multiple sclerosis. Eur Arch Otorhinolaryngol 277(2):469–473
Gudis DA, Cohen NA (2010) Cilia dysfunction. OtolaryngolClin North Am 43(3):461–472
Vinogradova Y, Hippisley-Cox J, Coupland C (2009) Identification of new risk factors for pneumonia: population-based case-control study. Br J Gen Pract 59(567):e329–e338
Correale J, Fiol M, Gilmore W (2006) The risk of relapses in multiple sclerosis during systemic infections. Neurology 67(4):652–659
Kale N, Magana S, Agaoglu J, Tanik O (2009) Assessment of autonomic nervous system dysfunction in multiple sclerosis and association with clinical disability. Neurol Int 1(5):15–18
Gunal DI, Afsar N, Tanridag T, Aktan S (2002) Autonomic dysfunction in multiple sclerosis: correlation with disease-related parameters. EurNeurol 48(1):1–5
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All procedures performed in studies involving human participants were in accordance with the ethical standards of the institutional and/or national research committee (Yozgat Bozok University Clinical Researches Ethic Committee Ref No: 2017-KAEK-189ˍ2019.12.25ˍ14) and with the 1964 Helsinki declaration and its later amendments or comparable ethical standards.
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Dağıstan, H., Hamamcı, M. Nasolacrimal transition time in patients with multiple sclerosis. Eur Arch Otorhinolaryngol (2021). https://doi.org/10.1007/s00405-021-06603-0
- Multiple sclerosis
- Nasolacrimal transition