Proposed Article Structure
This topic is best organized around clinical interpretation rather than a generic trial template. A logical structure is: clinical background and unmet need; study overview; major findings; mechanistic and translational interpretation; implications for diagnosis and management; limitations and research priorities; and a concise practice-focused conclusion. That structure is followed below.
Highlights
First, a pain-predominant phenotype was identified in 6.9% of patients carrying a diagnosis of dry eye disease. Second, these patients had disproportionately severe symptoms despite relatively limited objective ocular surface findings, reinforcing the familiar but often clinically frustrating signs-symptoms mismatch in dry eye practice. Third, migraine and psychiatric disorders were strongly associated with this phenotype, whereas autoimmune disease was less common, suggesting that at least some cases labeled as “dry eye” may be better understood through a pain-processing framework than a purely tear-film or inflammatory model.
Background: When “Dry Eye” Is Not Just Dryness
Dry eye disease is one of the most common conditions seen in eye care and general medical practice. It is classically defined as a multifactorial disease of the ocular surface characterized by tear film instability, hyperosmolarity, inflammation, and neurosensory abnormalities. That last element, neurosensory abnormality, has become increasingly important. In routine practice, clinicians regularly encounter patients with severe burning, stinging, photophobia, or “grittiness” that appears out of proportion to staining, Schirmer testing, tear breakup time, or meibomian gland findings.
This discrepancy has major consequences. Patients may cycle through lubricants, anti-inflammatory drops, punctal occlusion, lid therapies, and environmental modifications with incomplete relief. Clinicians may interpret the lack of visible corneal damage as evidence that symptoms are exaggerated, while patients may feel dismissed because the pain is real even when slit-lamp findings are modest. Over the last decade, this gap has led to growing interest in neuropathic ocular pain and in a subset of dry eye presentations driven less by tear deficiency alone and more by altered peripheral and central pain processing.
The report by Mejía-Salgado, Galor, and de-la-Torre is clinically important because it attempts to identify how often a pain-predominant dry eye phenotype occurs and what characteristics distinguish it from other forms of dry eye disease. If a recognizable phenotype exists, it could improve diagnostic accuracy, reduce therapeutic delay, and encourage more appropriate multidisciplinary care.
Study Overview
According to the published abstract in Ophthalmology, the investigators identified a pain-predominant phenotype among patients diagnosed with dry eye disease. The key result was frequency: 6.9% of the dry eye cohort met criteria for this phenotype. The phenotype was defined by severe symptoms in the setting of minimal signs, an approach that aligns with the clinical concept of ocular pain out of proportion to ocular surface disease.
The abstract indicates a phenotypic comparison rather than an interventional trial. Publicly available details at the citation level do not provide a full methods section, so variables such as exact recruitment setting, sample size, phenotype definition thresholds, symptom instruments, sign-based cutoffs, and statistical modeling cannot be fully reproduced here without access to the complete article. Nonetheless, the broad design is clear enough to support clinical interpretation: this was a characterization study asking who these patients are, how often they appear, and what comorbidities cluster with them.
Key Findings
Frequency of the pain phenotype
The most immediately useful finding is that 6.9% of patients diagnosed with dry eye disease exhibited a pain-predominant phenotype. This is not the majority of dry eye, but it is far from trivial. In a high-volume ophthalmology or optometry clinic, a prevalence near 7% implies that such patients are encountered regularly. For specialists working in tertiary ocular surface or pain clinics, the proportion may be even higher.
Clinically, this frequency supports the idea that pain-predominant dry eye is not a rare curiosity. Rather, it is a meaningful subgroup that deserves deliberate recognition, much as clinicians now distinguish evaporative dry eye from aqueous-deficient disease or identify meibomian gland dysfunction as a major contributor to symptoms.
Severe symptoms despite minimal signs
The defining characteristic was a mismatch between symptom burden and objective findings. This matters because traditional dry eye management is often driven by visible ocular surface pathology. Yet symptoms such as burning, wind sensitivity, allodynia, or severe irritation can emerge from abnormal corneal nerve function, peripheral sensitization, or central sensitization even when fluorescein staining and tear metrics are relatively unimpressive.
This is also where terminology becomes important. Calling these cases “refractory dry eye” may be imprecise if the primary driver is pain dysregulation rather than persistent tear film failure alone. The study’s framing encourages clinicians to ask whether the diagnosis should be broadened from dry eye disease to dry eye with a pain phenotype, or in selected cases to ocular surface pain with overlapping dry eye features.
Association with migraine
The reported strong association with migraine is especially informative. Migraine is a prototypical sensory processing disorder characterized by trigeminal activation, central sensitization, photophobia, and overlap with other chronic pain syndromes. The eye is densely innervated by trigeminal afferents, making biologic overlap plausible. Patients with migraine may be more likely to interpret ocular surface stimuli as painful, to have lowered sensory thresholds, or to develop persistent discomfort following transient peripheral insults.
For clinicians, this means a migraine history should not be treated as incidental in the dry eye interview. A patient with severe “dryness,” light sensitivity, fluctuating pain, and normal-to-mild surface findings may in fact sit closer to the migraine-neuropathic pain spectrum than to classic inflammatory dry eye alone.
Association with psychiatric disorders
The phenotype was also strongly associated with psychiatric disorders. This observation should be handled carefully and clinically. It does not imply that symptoms are psychogenic or not biologically based. Rather, anxiety, depression, trauma-related conditions, and somatic symptom amplification commonly coexist with chronic pain states and can influence pain perception, coping, sleep, treatment adherence, and quality of life. The relationship is likely bidirectional: persistent ocular pain can worsen mood, and mood disorders can intensify pain experience.
From a practice standpoint, these comorbidities can help identify patients at risk for persistent symptoms and poor response to standard ocular surface treatment alone. They also support a biopsychosocial model of care in which ophthalmologists, primary care clinicians, neurologists, and mental health professionals may all have a role.
Lower prevalence of autoimmune disease
Interestingly, autoimmune conditions were less prevalent in the pain-predominant group. This finding is clinically useful because autoimmune disease, particularly Sjogren disease and related connective tissue disorders, is strongly linked to aqueous-deficient dry eye with objective ocular surface compromise. A lower autoimmune burden in the pain phenotype suggests that the mechanisms may differ from more classic inflammatory or glandular dry eye subsets.
This does not exclude autoimmune disease in symptomatic patients with pain out of proportion to signs, but it does caution against assuming that all severe symptom presentations reflect systemic inflammatory dryness. In other words, a highly symptomatic patient without major staining or tear deficiency may merit a pain-focused evaluation before reflexively escalating immune-directed treatment.
Mechanistic Interpretation
The findings fit well with current thinking about neuropathic ocular pain. Corneal nerves can become hyperresponsive after surgery, infection, inflammation, contact lens wear, environmental stress, or chronic surface disease. Over time, pain may persist after the original trigger has lessened. Patients then report spontaneous burning, dysesthesia, hyperalgesia, or allodynia, often triggered by wind, light, or temperature change. In some, central sensitization develops, making symptoms less tightly linked to peripheral tissue injury.
The migraine association supports trigeminal system involvement. The psychiatric association supports the broader chronic pain framework. The limited ocular findings support the idea that visible epithelial injury is not required for severe symptom generation. Together, these observations strengthen the concept that “dry eye” can sometimes serve as a clinical entry point into a neurosensory disorder.
This interpretation is also consistent with the TFOS DEWS II definition of dry eye disease, which explicitly includes neurosensory abnormalities. The present report helps operationalize that concept by identifying a phenotype clinicians may recognize in day-to-day practice.
Clinical Implications for Assessment
History should be expanded beyond dryness
When patients report severe discomfort but demonstrate limited staining or tear abnormalities, the interview should probe for pain quality and sensory triggers. Important features include burning, shooting pain, aching, photophobia, pain to wind or air conditioning, pain with light touch around the eyes, and symptoms that persist despite frequent lubrication. Asking about migraine, fibromyalgia, temporomandibular disorder, chronic headache, anxiety, depression, sleep disturbance, and prior ocular procedures may uncover a pain-centered phenotype.
Signs-symptoms discordance is diagnostically meaningful
The common clinical reflex is to search harder for occult meibomian gland disease or subtle aqueous deficiency when symptoms seem extreme. That remains appropriate, but the current study suggests that discordance itself is an important clue, not merely a nuisance. Severe symptoms with modest signs should trigger consideration of neuropathic ocular pain, especially when accompanied by migraine or psychiatric comorbidity.
Testing may need to go beyond the standard dry eye workup
Not every clinic has access to advanced corneal esthesiometry, in vivo confocal microscopy, or specialized pain questionnaires, but even simple office-based phenotyping may help. A topical anesthetic challenge, while imperfect, can sometimes distinguish predominantly peripheral from more centralized pain if symptoms persist despite anesthetic instillation. Standardized questionnaires for dry eye symptoms, photophobia, and pain catastrophizing may also prove useful in future phenotype-guided care pathways.
Clinical Implications for Management
The study does not test treatment, so it should not be overinterpreted as establishing a therapeutic algorithm. Still, its implications are clear. Patients with a pain-predominant phenotype are unlikely to improve with lubrication alone. Ocular surface optimization remains necessary, since even mild evaporative or tear-film abnormalities can amplify nociception, but management may need to expand to include pain-informed strategies.
These may include treatment of coexisting migraine, attention to sleep and mood disorders, environmental trigger reduction, and in selected cases systemic neuromodulatory therapy directed by clinicians familiar with chronic pain. Some patients benefit from a combined approach involving ophthalmology, neurology, pain medicine, psychiatry, or primary care. The key practice change is conceptual: persistent severe symptoms should not automatically be labeled treatment failure if the chosen treatment only targets tear film biology.
The lower prevalence of autoimmune disease in this phenotype may also help avoid unnecessary escalation toward systemic inflammatory explanations when the broader clinical picture points elsewhere. Precision in phenotyping could therefore improve both outcomes and resource use.
Strengths, Limitations, and Generalizability
The main strength of this work is phenotypic clarification. Dry eye is frequently discussed as if it were a single disorder, but clinicians know it is heterogeneous. Identifying a discrete pain-predominant subgroup with recognizable comorbidity patterns is highly relevant for practice.
The main limitation, based on currently accessible information, is that full methodological detail is not available in the abstract alone. Without the complete article, it is difficult to evaluate the exact phenotype definition, potential referral bias, confounder adjustment, symptom instrument performance, and whether the cohort came from primary eye care, tertiary centers, or a mixed population. Those details affect generalizability. Specialty centers, for example, may enrich for complex pain presentations. In addition, phenotyping studies can be influenced by how “minimal signs” and “severe symptoms” are operationalized.
Another limitation is the usual challenge of cross-sectional interpretation. Associations with migraine and psychiatric disorders are clinically compelling, but they do not prove causality. The pain phenotype may share mechanisms with these conditions, be amplified by them, or simply cluster in susceptible individuals. Prospective studies are needed to determine whether these comorbidities predict treatment response, symptom persistence, or transition from ocular surface disease to chronic ocular pain.
How This Fits With Existing Literature
The study aligns with a growing body of literature arguing that at least some dry eye symptoms arise from neuropathic mechanisms. Prior work from Galor and colleagues has shown that dry eye symptoms can resemble non-ocular chronic pain syndromes and are associated with depression, post-traumatic stress symptoms, and migraine-like features. Reviews on neuropathic ocular pain have similarly emphasized that corneal nerve dysfunction and central sensitization can produce severe symptoms despite a relatively quiet ocular surface.
What is useful about the current report is that it moves from concept to phenotype frequency and characterization. That is a practical advance. Clinicians need more than theory; they need to know how often this pattern occurs and which clues should trigger a broader diagnostic frame.
Conclusion
The central message of this report is straightforward and important: not all patients labeled with dry eye disease are suffering primarily from tear deficiency or ocular surface inflammation. In about 6.9% of cases, the dominant clinical picture is pain. These patients show severe symptoms with limited signs and are enriched for migraine and psychiatric comorbidity, while autoimmune disease is less common.
For clinicians, the implication is not to abandon standard dry eye evaluation, but to recognize when it is insufficient. A pain-predominant phenotype should be suspected when symptoms are intense, conventional signs are modest, and the history includes migraine, sensory hypersensitivity, or psychiatric comorbidity. This phenotype may require a broader, multidisciplinary approach and may explain why some patients remain highly symptomatic despite apparently appropriate ocular surface therapy. As dry eye classification continues to evolve, pain phenotyping may become one of the most clinically useful steps toward personalized care.
Funding and ClinicalTrials.gov
Funding information and any ClinicalTrials.gov registration were not reported in the citation-level materials provided here. Readers should consult the full Ophthalmology article for complete disclosure and study administration details.
References
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