# Advances in the Noninvasive Diagnosis of Dry Eye Disease
###### Abstract  
Dry eye disease (DED) is a multifactorial disease that represents one of the most common ophthalmologic conditions encountered in everyday clinical practice. Traditional diagnostic tests for DED, such as subjective questionnaires, tear film break-up time and the Schirmer test, are often associated with poor reproducibility and reliability, which make the diagnosis, follow-up, and management of the disease challenging. New advances in imaging technologies enable objective and reproducible measurements of DED parameters, thus making the diagnosis a multimodal imaging-based process. The aim of this review is to summarize all the current and emerging diagnostic tools available for the diagnosis and monitoring of DED, such as non-invasive tear breakup time, thermography, anterior segment optical coherence tomography, meibography, interferometry, in vivo confocal microscopy, and optical quality assessment. Although there is not a gold standard imaging technique, new multi-imaging-integrated devices are precious instruments to help clinicians to better cope with the diagnostic complexity of DED.  
dry eye; diagnosis; noninvasive diagnosis; advanced imaging; NIBUT  
1  
Dry eye disease (DED) is one of the most common ophthalmologic conditions encountered in everyday clinical practice [1]. The 2017 report by the Tear Film and Ocular Surface Society (TFOS) Dry Eye Workshop (DEWS II) published the renewed definition of DED, which was defined as an ocular surface disorder in which multiple pathological events, including tear film instability, hyperosomatarity, inflammation and neurosensory abnormalities, lead to the loss of the homeostasis of the entire system [2]. Common symptoms of DED include, among others, irritation, redness, foreign body sensation, blurry vision, tearing, and sensitivity to light. It is a chronic condition that also represents an important economic burden for both patients and society [3].  
Performing a suitable clinical diagnosis of DED can be challenging, as its signs and symptoms are often poorly correlated. Combinations of subjective symptoms evaluated by questionnaires, slit lamp examination and (non-)invasive diagnostic tests have been used to obtain the diagnosis. The TFOS DEWS II Diagnostic Methodology report identified a diagnostic algorithm for a stepwise analysis that includes, after triaging questions, the evaluation of symptoms and homeostasis markers (noninvasive or fluorescein break-up time, tear osmolarity and ocular surface staining) [4]. Nonetheless, the report acknowledgedthat no single gold standard test has yet been established, and that there is a need for new, reliable diagnostic biomarkers.  
In recent years, a great number of imaging techniques and devices for the examination of the ocular surface have been developed and placed on the market (Table 1). These devices offer the advantage of providing automated results of the examined tests, thus avoiding observer bias; moreover, since most of these examinations are noninvasive, they do not alter the results of subsequent tests, representing useful screening tools for discriminating healthy subjects from patients affected by or at risk for DED. Finally, combining different techniques in a comprehensive ocular surface workup may increase sensitivity and specificity to diagnose the disease and monitor its course after specific treatments [5; 6; 7].  
In this review, we summarize the current research available about the development and use of novel noninvasive diagnostic techniques for the diagnosis and follow-up of DED.