While it is an exceptionally uncommon condition, some patients may present post-LASIK with refractory dry eye symptoms characteristic of NCP. Our study identified 18 patients seen by a single surgeon over the course of 26 years presenting with persistent and severe symptoms of DES out of proportion to their clinical examination. Treatment for these patients consisted of a combination of dry eye therapies, anti-inflammatory medications, pain control, anticonvulsants, and management of comorbid neuropsychiatric conditions. Of the 18, ten patients reported alleviation of their symptoms, two did not, and six were lost to follow-up. There is a paucity of data regarding the incidence of NCP post-LASIK treatment. From this case series, the prevalence of NCP post-LASIK is approximately 1 in every 900 cases, making it an extremely rare condition following LASIK surgery.
Risk factors associated with the development of DES could also play a role in the development of NCP . Multiple studies have shown that women are at an increased risk of developing DES post-LASIK [5, 12, 13], and this was consistent with what we observed in our case series. Asian ethnicity has also been associated with increased risk of developing DES after LASIK [5, 14]. Interestingly, only one patient in our case series was of Asian ethnicity, and we observed that 83.3% of individuals who developed NCP post-LASIK identified as Caucasian. The population demographics of the region in which these individuals were diagnosed and treated are primarily Caucasian (72.8%), with only 5.4% Asian . This difference could explain why we observed that most individuals who developed NCP following LASIK were Caucasian.
Neuropsychiatric conditions such as depression, anxiety, and post-traumatic stress disorder (PTSD) have also been associated with an increased risk of developing DES [10, 16,17,18,19]. We noted that 50.0% of the patients in our case series had a history of neuropsychiatric conditions. Studies have also found worsening of neuropsychiatric conditions as a result of NCP [2, 20], and another study has also reported rare cases of suicide following laser refractive surgery . Although worsening of symptoms of neuropsychiatric conditions was not measured in our patients, one individual (case 3) with a history of depression committed suicide within 1 year of onset of symptoms of NCP post-LASIK. Previous studies in patients with NCP post-LASIK have not documented the prevalence of neuropsychiatric disease in their studies. However, a study of 181 patients diagnosed with neuropathic ocular pain showed that 43.6% were on an antidepressant and 40.9% were taking an anxiolytic . Another study of 59 patients with NCP documented that 16.7% of their patients had depression and 10% had anxiety . The US Centers for Disease Control (CDC) reports that the percentage of adults above 18 years of age that report feelings of depression in the US population is 4.7% and the percentage that reports frequent feelings of anxiety is 11.2% . Our study results, in conjunction with existing literature, further support the hypothesis that the presence of neuropsychiatric conditions can predispose individuals to the development of NCP. Understanding that underlying neuropsychiatric conditions may predispose the patient to NCP should prompt physicians who diagnose or suspect this condition to ask additional questions. The physician should inquire about a past medical history of neuropsychiatric disorders, confirm that these patients have a provider who is actively managing these conditions, and refer the patient to the appropriate psychologist or psychiatrist if they are indeed not being actively managed.
Fibromyalgia, other functional pain syndromes, autoimmune diseases, and thyroid diseases are some of the other systemic diseases shown to be linked to NCP . Of the patients in our study, 22.2% had a diagnosis of functional pain syndrome, 33.3% had an autoimmune condition, and 27.8% had hypothyroidism. Other studies have shown the occurrence of autoimmune diseases in patients with NCP at 16.7%, hypothyroid disease at 16.7%, and fibromyalgia at 6.7% . Of the patients with hypothyroid disease, two were known to have Hashimoto’s thyroiditis. In the United States, fibromyalgia affects about 2% of the adult population , hypothyroidism is seen in 4.6% of the population 12 years and older , and autoimmune disease is present in 5–8% of the population . There is no consensus in the literature regarding the prevalence of comorbidities in individuals with NCP, but the occurrence here is higher than the prevalence of the general US population.
The symptoms of NCP are nonspecific and can be similar to those seen with DES . The literature reveals that those individuals with NCP report symptoms such as ocular pain, irritation, itchiness, dryness, grittiness, burning, aching, light sensitivity, soreness, and foreign body sensation [9, 13, 24, 27, 28]. Our case series is consistent with previous literature regarding symptoms associated with NCP. Ocular pain is the only consistent symptom we observed among our patients. Additionally, the literature shows that SLE of the cornea in individuals with NCP post-LASIK tends to be normal and will occasionally show dryness [13, 24, 27]. In our study, 15 (83.3%) individuals had evidence of MGD and three (16.7%) individuals had tear breakup time test results indicative of DES on clinical evaluation. Although most individuals in our study did have some evidence of minimal DES on clinical evaluation, the severity of the symptoms reported was out of proportion to what was seen on examination.
IVCM of the cornea may also be helpful in the diagnosis of NCP [9, 10, 13, 24, 27]. Studies have reported that this test tends to demonstrate the presence of MNs, increased nerve tortuosity and beading, decreased nerve fiber density, and a larger dendritic cell population in individuals with NCP [9, 24, 27]. IVCM of the cornea obtained on one of the patients (case 18) in our study at the time of diagnosis also showed decreased nerve density, increased nerve beading, and presence of MNs. However, it is worth noting that a recent study published demonstrated that only 16 out of 63 individuals with features of neuropathic pain had MNs on IVCM. Additionally, 10 out of 55 individuals with no features of neuropathic pain also had MNs on IVCM. Finally, the same study also found that the presence of MNs on IVCM among individuals with and without dry eye symptoms was not statistically significant . This indicates that although the presence of MNs on IVCM may be helpful in the diagnosis of NCP, their absence does not rule out this condition.
Studies have previously shown that testing the changes in pain level after applying a topical anesthetic on the cornea can be used to differentiate between peripheral and central sensitization of pain in individuals with NCP [10, 13, 24, 27]. The application of a topical anesthetic should reduce the transmission of peripheral pain. Therefore, patients who experience complete or partial resolution of pain suffer from peripheral pain or mixed peripheral and central pain, respectively. Individuals who do not notice any improvement in their symptoms suffer, at least in part, from central pain [13, 24]. In our study, eight patients were evaluated with a topical tetracaine challenge test. Of these patients, five reported no improvement in their symptoms and three had complete but transient resolution of pain post-anesthetic application. This indicates that of those eight patients, five had a component of central sensitization of pain and three had either peripheral or mixed sensitization of pain. Utilizing this test to determine the etiology of NCP, central versus peripheral, can help guide treatment decisions [13, 24].
Variability in symptoms, along with a benign clinical examination, makes NCP a difficult condition to diagnose. It should be included in the differential diagnosis for any individual who reports severe ocular pain, burning, irritation, light and air sensitivity, and foreign body sensation with minimal or no evidence of ocular surface disease post-LASIK. Although symptoms of NCP overlap with those of DES, the severity reported by patients can point towards a diagnosis of NCP. In addition, the risk factors listed above may help raise clinical suspicion for the disease if other corneal diseases have been ruled out.
Literature suggests that the treatment approach of this condition should be multimodal . Studies have reported successful management of NCP with artificial tears, ABS, anti-inflammatory agents (topical steroids, cyclosporine, anakinra, tacrolimus), antidepressants (TCAs, selective serotonin reuptake inhibitors [SSRIs], and serotonin–norepinephrine reuptake inhibitors [SNRIs]), anticonvulsants (gabapentin, carbamazepine, and pregabalin), pain medications (naltrexone or tramadol), contact lenses (scleral or soft bandage), vitamins (B12 and D), omega-3 fatty acids, exercise, and even electrical stimulation of the trigeminal ganglion [13, 24, 27, 30,31,32,33,34,35]. Each patient in our study had a unique multimodal treatment plan involving many of the treatments listed. Since all patients reviewed here were managed with more than one therapy, the relative contribution of each modality in improving the symptoms of ocular pain cannot be assessed. We believe that there is no single treatment approach, and most patients will require several modalities to achieve significant improvement of symptoms. Of the patients who were assessed, 83.3% had improvement in their pain symptoms following multimodal treatment. Although these symptoms can be extraordinarily debilitating, especially when left untreated, most patients have significant improvement with regular follow-up. It is critical to recognize the validity of these patients’ symptoms, despite there being limited or no evidence of corneal pathology related to dry eye, and begin treatment with regular follow-up. The majority of the patients presented with debilitating symptoms but were then able to return to normal activities of daily living following treatment.
While the data presented here today represents one physician’s experience over a 26-year career performing LASIK, our study has some limitations. As with all retrospective analyses, there are limits in standardization. As the knowledge of best practices for treatment and diagnosis evolved, so did the diagnosis and treatment for the patients in this study. For this reason, and due to the rarity of the condition and the multimodal treatment approach for the disease, the treatment regimen could not be standardized amongst the patients. This lack of standardization included the lack of a pain scale such as the visual analog scale (VAS) or ocular pain assessment survey (OPAS). Because of the rarity of this disease, we suggest that future studies, especially any prospective studies, include a standardized pain scale in the assessment of ocular pain in the workup or diagnosis of NCP. The tetracaine challenge was performed on some patients for somatosensory assessment, but we realize that there are additional assessments of this nature available. Corneal esthesiometry measured with a device such as the Cochet–Bonnet contact esthesiometer was not done but would be suggested for future studies. As with other retrospective studies, we did not have controls. Additionally, there was incomplete data in some of the patients’ charts and not all the data gathered was comparable between the cases. We attempted to estimate the prevalence of post-LASIK NCP over the 26 years, but this is based on the assumption that patients with NCP returned for follow-up outside the immediate postoperative period. The mean onset of symptoms in our patient population was 9.6 months, with the lower limit being 2 months; thus, the delay in onset could have led to increased loss of follow-up. Despite these limitations, the knowledge presented helps to elucidate general statistics regarding NCP in the post-LASIK population that have otherwise not been documented.