Refractive features and amblyopia in Duane's Retraction Syndrome: A review of the 582 patients / Características refractivas y ambliopía en el síndrome de retracción de Duane: una revisión de los 582 pacientes

Purpose: To report the visual and refractive characteristics and the prevalence of amblyopia in patients with different types of Duane's Retraction Syndrome (DRS). Method: This retrospective study was performed on hospital records of 582 DRS patients at Farabi Hospital, Iran, from 2012 to March 2022. Results: The mean age of patients was 19.4 ± 11.9 (range, 3–70) years [335 (57.6 %) females and 247 (42.4 %) males (P < .001)]. DRS type I, II, III, and IV were presented in 347 (59.6 %), 148 (25.4 %), 82 (14.1 %), and 5 (0.9 %) patients, respectively. There were 530 (91.1 %) patients with unilateral and 52 (8.9 %) with bilateral involvement. In the unilateral patients, the DRS eyes' corrected distance visual acuity (CDVA) and astigmatism were significantly worse than the Non-DRS Eyes (P < .001). The mean amount of all refractive and visual parameters in bilateral patients' right or left eyes was significantly lower than in unilateral patients' non-DRS eyes (all P < .05). Anisometropia was observed in 75(12.9 %) of the patients. Amblyopia was observed in 18.5 % (98 patients) and 36.5 % (19 patients) of unilateral and bilateral DRS patients, respectively (P < .001). In unilateral patients, amblyopia was found in 57 (16.4 %) patients with Type I, 22 (14.9 %) patients with Type II, 16 (19.5 %) patients with Type III, and 3 (60 %) patients with Type IV. Forty-four (37.6 %) of patients with amblyopia had anisometropia. Conclusion: This large-scale study indicates that DRS types differ in terms of refractive error, visual acuity, and the prevalence of amblyopia and anisometropia. Clinicians should be aware of the clinical features associated with different types of DRS.(AU)

Internuclear Ophthalmoplegia Following COVID-19 with Abnormal Findings on Neuroimaging; A Case Report.

COVID-19 had been reported to be associated with neuro-ophthalmic complications. However, there is a shortage of evidence regarding internuclear ophthalmoplegia (INO) presentation after COVID-19 infection with related brain magnetic resonance imaging (MRI). Herein, we report a case of INO in a 69-year-old woman with presentation of diplopia following COVID-19 infection, along with her neuroimaging. We concluded that it is important to recognize the possibility of INO in patients with diplopia after COVID-19 and to consider brain MRI as an informative tool in these patients.

Acute bilateral nodular scleritis following strabismus surgery in a patient with Down syndrome.

Scleritis is a rare complication of strabismus surgery. We present the case of an 11-year-old girl with Down syndrome who underwent strabismus surgery and developed bilateral symmetric nodular scleritis 3 weeks after surgery. Anterior segment optical coherence tomography revealed localized hyporeflective thickening of the sclera at the primary site of muscle insertion in both eyes. Treatment with topical and oral corticosteroids led to resolution of her condition.

Clinical characteristics and surgical outcomes in patients with superior oblique muscle palsy: a retrospective study on 1057 patients.

BACKGROUND: To evaluate the clinical findings of patients with SOP who underwent surgery. METHODS: This historical cohort study was performed on 1057 SOP patients managed with surgery in Farabi Hospital, Iran, from 2011 to 2022. RESULTS: There were 990 (93.7%) patients with unilateral SOP with the mean age of 21.8 ± 14.8 years. Of these, 715 patients (72.2%) were diagnosed with congenital SOP, and 275 patients (27.8%) had acquired SOP (P < 0.001). In contrast, 67 (6.3%) patients were diagnosed with bilateral SOP, with the mean age of 19.4 ± 15.6 years. Among these, 18 cases exhibited the masked type. The mean angle of vertical deviation in primary position at far in unilateral and bilateral cases was 15.6 ± 8.3 and 13.3 ± 9.1 △, respectively (P < 0.001). In unilateral cases, abnormal head posture (AHP) was detected in 847 (85.5%) patients and 12 (1.2%) had paradoxical AHP. Amblyopia was found in 89 (9.9%) unilateral and 7 (10.3%) bilateral cases. Solitary inferior oblique myectomy, was the most common surgery in both unilateral (n = 756, 77.1%) and bilateral (n = 35, 52.2%) patients. The second surgery was performed for 84 (8.6%) unilateral and 33 (49.3%) bilateral cases (P < 0.001). The prevalence of amblyopia and the mean angle of horizontal deviation were significantly higher in patients who needed more than one surgery (all P < 0.05). CONCLUSION: Congenital SOP was more than twice as frequent as acquired SOP and about 90% of unilateral and 50% of bilateral cases were managed with one surgery. Amblyopia and significant horizontal deviation were the most important factors for reoperation. TRIAL REGISTRATION: The Institutional Review Board approval was obtained from the Tehran University of Medical Sciences (IR.TUMS.FNM.REC.1400.012) and this study adhered to the tenets of the Declaration of Helsinki and HIPAA.

Refractive features and amblyopia in Duane's Retraction Syndrome: A review of the 582 patients.

PURPOSE: To report the visual and refractive characteristics and the prevalence of amblyopia in patients with different types of Duane's Retraction Syndrome (DRS). METHOD: This retrospective study was performed on hospital records of 582 DRS patients at Farabi Hospital, Iran, from 2012 to March 2022. RESULTS: The mean age of patients was 19.4 ± 11.9 (range, 3-70) years [335 (57.6 %) females and 247 (42.4 %) males (P < .001)]. DRS type I, II, III, and IV were presented in 347 (59.6 %), 148 (25.4 %), 82 (14.1 %), and 5 (0.9 %) patients, respectively. There were 530 (91.1 %) patients with unilateral and 52 (8.9 %) with bilateral involvement. In the unilateral patients, the DRS eyes' corrected distance visual acuity (CDVA) and astigmatism were significantly worse than the Non-DRS Eyes (P < .001). The mean amount of all refractive and visual parameters in bilateral patients' right or left eyes was significantly lower than in unilateral patients' non-DRS eyes (all P < .05). Anisometropia was observed in 75(12.9 %) of the patients. Amblyopia was observed in 18.5 % (98 patients) and 36.5 % (19 patients) of unilateral and bilateral DRS patients, respectively (P < .001). In unilateral patients, amblyopia was found in 57 (16.4 %) patients with Type I, 22 (14.9 %) patients with Type II, 16 (19.5 %) patients with Type III, and 3 (60 %) patients with Type IV. Forty-four (37.6 %) of patients with amblyopia had anisometropia. CONCLUSION: This large-scale study indicates that DRS types differ in terms of refractive error, visual acuity, and the prevalence of amblyopia and anisometropia. Clinicians should be aware of the clinical features associated with different types of DRS.

Computed tomography scan to diagnose abducens nerve palsy cases with superior-compartment atrophy.

PURPOSE: To use orbital computed tomography (CT) to explore the proportion of superior-compartment lateral rectus muscle atrophy in abducens nerve palsy and its relationship with clinical findings. METHODS: Twenty-two patients with isolated unilateral abducens nerve palsy were enrolled. Orbital CT scans of all patients were acquired. All measurements were performed in two ways for normal and paretic lateral rectus muscles: posterior volume (mm3) and maximal cross-section area (mm2). These variables were also measured separately in the superior and inferior 40% of the muscle. Primary position esotropia and amount of abduction limitation was also recorded. RESULTS: The mean deviation was 23.4Δ ± 12.1Δ (range, 0Δ-50Δ); the mean limitation of abduction, -2.7 ± 1.3 (range, -1 to -5). Seven cases (31.8%) showed the gross morphologic characteristics of superior-compartment atrophy. In these 7 cases, the mean percentage of atrophy in posterior volume and in maximal cross-section was significantly greater in the superior compartment than the inferior compartment (P = 0.02 for both). The mean limitation of abduction in these 7 cases (-1.7 ± 0.9; range, -1 to -3) was significantly lower than in other cases (-3.1 ± 1.3, range, -1 to -5 [P = 0.02]). CONCLUSIONS: In our study cohort, a subgroup of abducens nerve palsy cases demonstrated evidence of superior portion lateral rectus atrophy on orbital CT. The superior-compartment-atrophy group had both a smaller primary gaze esotropia and a smaller abduction deficit, providing evidence that compartmental atrophy should be considered in patients with partially retained lateral rectus function.

No-split, no-tenotomy transposition of only the superior rectus muscle combined with medial rectus recession in patients with complete abducens nerve palsy.

PURPOSE: To evaluate the outcomes of no-split, no-tenotomy transposition of only the superior rectus muscle combined with medial rectus recession in patients with complete abducens nerve palsy. METHODS: In this procedure, the temporal margin of the superior rectus muscle, 10 mm posterior to the insertion, was secured with a nonabsorbable suture and sutured to the sclera at a distance of 12 mm from the limbus in the superotemporal quadrant, halfway between the superior rectus and lateral rectus. Success was defined as distance and near alignment of ≤8Δ and no diplopia in primary position 6 months after surgery. RESULTS: A total of 8 patients with abducens nerve palsy underwent the procedure. At the last follow-up, the mean postoperative change in primary position deviation was 42.6Δ ± 8.1Δ (range, 34Δ-57Δ) for distance and 42.1Δ ± 7.5Δ (35Δ -57Δ) for near, a significant reduction (P = 0.012). Abduction deficit also improved significantly (P = 0.010). Postoperatively, no vertical deviation or torsional diplopia was induced. At the 6 months' follow-up, compared with the first postoperative visit, an esodrift at near developed in 1 patient. Of the 8 cases, 6 fulfilled the criteria for success. CONCLUSIONS: In our small study cohort, no-split, no-tenotomy superior rectus transposition and medial rectus recession improved esotropia and abduction limitation without inducing significant vertical deviations or torsional diplopia.

Concomitant Unilateral Duane Retraction Syndrome and Contralateral Brown's Syndrome.

A 10-year-old boy was introduced with a chief complaint of ocular misalignment from birth. Ocular examination indicated right Brown and left Duane retraction syndrome in a non-familial pattern. We suspect that a teratogenic damage or genetic mutation may be responsible for this combination.

Modified transposition using silicone band for multiple rectus muscle palsies.

Purpose: To report the results of partial vertical rectus muscle transposition using a silicone band. Observations: We retrospectively gathered data on two patients with multiple vertical and horizontal extraocular muscle paresis and diplopia who had been treated with vertical rectus muscle transposition with the aid of a silicone band. Both patients had acceptable results on follow-up. Conclusion: Using the silicone band, we tried to effectively transpose the target muscles to obtain acceptable results.

Superior Rectus Transposition Surgery: Safety, Efficacy, and Place in Therapy.

Abduction limitation in esotropic Duane retraction syndrome (DRS), esotropic Mobius syndrome, and sixth nerve palsy is one of the difficult-to-manage problems in strabismus surgery. The procedure of superior rectus transposition (SRT) was introduced by Johnston et al. In this procedure, the superior rectus (SR) muscle is disinserted and sutured adjacent to the insertion of lateral rectus (LR) muscle. The purpose of this review is to explore literature about efficacy and safety of SRT and its usage in strabismus surgery.

Retinal misregistration and effect of surgery on its improvement in patients with epiretinal membrane.

PURPOSE: To evaluate the prevalence of retinal misregistration, that is, misalignment of retinal elements that affect central and peripheral fusion, and the effect of surgery in patients with epiretinal membrane (ERM). METHODS: This prospective interventional case-series was performed on 32 patients with symptomatic ERM with the complaint of binocular diplopia or decreased visual acuity. After the diagnosis of ERM, optotype frame, synoptophore, and lights on-off tests were used to evaluate retinal misregistration. Patients with severe symptoms underwent surgery and were followed for 3 months. RESULTS: Of the 32 patients, 6 (19%) had preoperative diplopia. Optotype frame, synoptophore, and lights on-off tests had positive results in 20 (63%), 19 (63%), and 11 (34%) cases, respectively. Of the 6 diplopia cases, 5 showed positive results in all 3 tests and 1 was positive on optotype frame and synoptophore testing. Of the 26 cases without diplopia, 15 (58%) showed positive results in at least one test, including 6 (23%) in all three tests, 6 (23%) in two tests, and 3 (12%) in only one test. Ten patients underwent surgery. Postoperatively, all patients had negative lights on-off test, but optotype frame and synoptophore tests were negative in eight patients (80%). Two cases (20%) had postoperative diplopia, including 1 case with postoperative new-onset diplopia. CONCLUSIONS: The prevalence of retinal misregistration was higher than the rate of diplopia. Surgery improved diplopia and results of tests of retinal misregistration.

Anaglyphic Three-Dimensional Movie: A Simple Binocular Method to Treat Anisometropic or Strabismic Amblyopia in Adults.

Purpose: To evaluate the efficacy of anaglyphic three-dimensional movies to treat adults with anisometropic or strabismic amblyopia. Methods: This is an interventional case series. The seven cases were put on a trial frame containing subjective refraction, fogging plus lenses for the dominant eye, correcting prism, and anaglyphic red-cyan plastic spectacles. Patients participated in 20 sessions of 1.5 h of anaglyphic three-dimensional animated movie watching in the office. Significant visual acuity (VA) improvement was defined as improvement ≥0.2 in logMAR values. Change in octaves of stereopsis was defined as halving the arcsec or 0.3 change in log arcsec. Results: The average age was 26.9 ± 10.0 (16-42) years. The mean VA in amblyopic eye improved significantly from 0.42 ± 0.19 (0.15-0.7) logMAR to 0.25 ± 0.15 (0.1-0.5) logMAR after completion of sessions (P = 0.02), and four cases showed significant VA improvement. The mean stereoacuity improved significantly from 2.6 ± 0.3 (2.1-2.9) log arcsec to 2.1 ± 0.5 (1.7-2.9) log arcsec (P = 0.04). Four cases showed ≥2 octaves improvements in stereopsis. Conclusion: A simple and readily available method of amblyopia treatment can be effective in some adult cases.

Non-absorbable versus Absorbable Sutures for Medial Rectus Advancement in Consecutive Exotropia, a Pilot Randomized Clinical Trial.

PURPOSE: To compare non-absorbable and absorbable sutures for medial rectus advancement in consecutive exotropia. METHODS: In a pilot randomized clinical trial, 40 subjects with consecutive exotropia >15 PD that underwent unilateral medial rectus advancement with or without resection were randomly assigned to two groups: using non-absorbable (polyester) suture in the non-absorbable group and absorbable (vicryl) suture in the absorbable group. The success rate was defined as the final postoperative angle of deviation <10 PD. RESULTS: Thirty-three patients (18 in the non-absorbable and 15 in the absorbable group) had completed the study. At last follow-up, the distance deviation improved from 29.2 ± 15.5 to 7.6 ± 7.9 in the non-absorbable group and from 25.9 ± 8.4 to 8.1 ± 10.7 in the absorbable group. The near deviation improved from 31.4 ± 15.9 to 7.2 ± 8.0 in the non-absorbable and from 29.0 ± 7.6 to 6.8 ± 11.9 in the absorbable group. The amount of the final correction of the distance and near deviation was not statistically different between the groups (P = .80 and P = .99, respectively). At the final examination, the exoshifts for distance and near were not statistically different between 2 groups (p = .61 and 0.54, respectively). At the final examination, the success was obtained in 12 patients (66.7%) and 8 patients (53.3%) in the non-absorbable and absorbable group, respectively (p = .73). CONCLUSION: In our study, there was no statistical difference in success rate or exoshift between non-absorbable and absorbable sutures. So, considering local inflammation induced by non-absorbable sutures in some cases, the absorbable sutures can be an appropriate option for the treatment of consecutive exotropia.

Comparison of the Accuracy of Anterior Segment Optical Coherence Tomography and Ultrasound Biomicroscopy in Localizing Rectus Muscle Insertions.

PURPOSE: To compare the accuracy of anterior segment optical coherence tomography (AS-OCT) and ultrasound biomicroscopy (UBM) in localizing rectus muscle insertions. METHODS: The study was performed on 27 patients (39 rectus muscles) who required primary or secondary surgery. Using caliper function in the AS-OCT and UBM software, the distance from the insertion site to the anterior chamber angle was measured. The actual muscle insertion distance from limbus was considered as the measured distance plus 1 mm. The measurements by UBM and AS-OCT were compared with intraoperative measurements and with each other. RESULTS: AS-OCT and UBM were performed on 13 medial rectus, 24 lateral rectus, and 2 superior rectus muscles. Ninety two percent of UBM measurements (36 muscles) were within 1 mm, one was within 1-1.5 mm, and 2 were within 1.5-2 mm of surgery measurements. Eighty five percent of AS-OCT measurements (33 muscles) were within 1 mm, 5 were within 1-1.5 mm, and one was within 1.5-2 mm of surgery measurements. In all cases, the mean absolute error of the UBM (0.54 ± 0.44) and AS-OCT (0.51 ± 0.36) showed no significant difference (p = .76). CONCLUSION: AS-OCT and UBM can be used interchangeably to localize rectus muscle insertions and showed good agreement with intraoperative measurements.

A Review of Transposition Techniques for Treatment of Complete Abducens Nerve Palsy.

PURPOSE: To review various types of extraocular muscle transposition procedures for management of strabismus in sixth cranial nerve palsy with little lateral rectus (LR) muscle function, along with their pros and cons. METHODS: We performed a comprehensive review of transposition procedures in sixth cranial nerve palsy, based on literature published anytime up to March 2021. A thorough search through PubMed and Cochrane databases was performed. All types of clinical studies on different transposition procedures in LR palsy, were included. RESULTS: Eighty-six original articles in English, with full text or abstracts available, were included in the review, among which 16 are prospective studies, 48 retrospective, 3 review articles, 1 randomized clinical trial, 17 case reports, and 1 letter. Vertical rectus transposition has demonstrated promising results, especially in abduction improvement and expansion of binocular diplopia-free visual field, albeit the possible adverse effects such as anterior segment ischemia, especially in the presence of medial rectus contracture, and induced vertical deviation may become troublesome. Partial muscle transposition, single muscle transposition, and also transposition without tenotomy have all been introduced to reduce the risk of multiple muscle manipulation and ischemia. On the other hand, different adjustable transpositions are being utilized to manage concomitant or induced vertical deviations. CONCLUSION: Transposition procedures are highly effective in the treatment of esotropia caused by complete LR palsy. Various techniques for vertical muscle transposition have been proposed, with each of them having certain advantages and disadvantages.

Retinal displacement following pars plana vitrectomy with silicone oil tamponade for rhegmatogenous retinal detachment.

PURPOSE: To evaluate the frequency of retinal displacement after pars plana vitrectomy (PPV) using silicone oil tamponade in patients with rhegmatogenous retinal detachment (RRD). METHODS: Patients with fresh RRD were enrolled in this prospective interventional case series. A standard 3-port PPV with silicone oil tamponade was performed in all cases. A complete ocular examination, optical coherence tomography and fundus autofluorescence (FAF) imaging were performed at 1 and 3 months follow-up. Orthoptic examinations including synoptophore and light on-off tests were also performed at 3 months. RESULTS: Twenty-three eyes from 23 patients with mean age of 56.6 ± 11 (range: 38-82) years were included. All patients were pseudophakic. Downward retinal displacement was found in 2 eyes (8.7%) showing hyperautofluorescent lines parallel to retinal vessels in FAF image. The patients with retinal displacement did not complain of metamorphopsia and did not show abnormality in orthoptic tests. CONCLUSION: Unintentional retinal shift following PPV with silicone oil tamponade for RRD is uncommon and might have little clinical significance.

Superior Rectus Transposition and Medial Rectus Recession for Treatment of Duane Retraction Syndrome and Sixth Nerve Palsy.

Purpose: To evaluate the outcome of augmented superior rectus transposition (SRT) with medial rectus (MR) recession in patients with Duane Retraction Syndrome (DRS) and sixth nerve palsy.Methods: Twenty four patients (16 DRS and 8 sixth nerve palsy) that underwent the procedure were included. The superior rectus muscle was secured, detached, and re-attached to the sclera along the spiral of Tilaux, adjacent to lateral rectus insertion. A non-absorbable augmentation suture was passed through the sclera, 8 mm posterior to the insertion of the lateral rectus.Results: At the last follow-up, the effect of surgery in decreasing esotropia in both groups was significant (P = .001 for DRS group, P = .002 for sixth nerve palsy). In both groups, abduction deficit improved significantly (P < .001 for DRS and P = .008 for sixth nerve palsy). After the surgery, small, asymptomatic vertical deviation in primary position was induced in five patients (20.8%). Post-operatively, none of the patients complained of torsional diplopia. In the 6-month follow-up, compared with the first postoperative visit, an eso-drift at distance or near developed in 11 patients (45.8%). Of the 11 patients with eso-drift, overcorrection (exotropia of 3-14 PD) was present at the first post-operative visit in 5 cases. Four cases showed an exo-drift (2-5 PD) at distance or near over time.Conclusion: SRT with medial rectus recession improves esotropia and abduction limitation without inducing significant vertical deviations and torsional diplopia. Some of the cases that underwent SRT with MR recession may show an eso-drift. The eso-drift can correct initial exotropia in some cases.

Bupivacaine Injection without Electromyographic Guide for Correction of Residual Esotropia and Exotropia after Strabismus Surgery.

Purpose: To evaluate the effect of bupivacaine injection without electromyographic guide for correcting residual esotropia and exotropia after strabismus surgery. Methods: Thirty patients with residual esotropia or exotropia after strabismus surgery were included in the study. Three milliliters of bupivacaine 0.5% were injected into medial or lateral rectus muscle without electromyographic guide. Results: The mean pre-injection misalignments were 14.8 ± 3.4 (8-20) PD at distance and 14.7 ± 4.4 (6-25) PD at near. The 1 month post-injection alignment changes were 5.2 ± 2.6 (2-13) PD at distance and 6.5 ± 3.1 (2-18) PD at near. The 6 months post-injection alignment changes were 5.8 ± 2.6 (2-13) PD at distance and 7.0 ± 3.6 (2-18) PD at near. LogMAR of the worst eye had strong correlations with 6 months far alignment change (ρ = 0.39, p = .04), 6 months near alignment change (ρ = 0.41, p = .03), and 12 months near alignment change (ρ = 0.69, p = .01). Conclusion: The effect of bupivacaine injection without electromyographic guide for correcting residual esotropia or exotropia after strabismus surgery was between 2 and 18 PD, comparable with other studies on unoperated cases. The effect of bupivacaine may increase with decreasing visual acuity.

The influence of alternate part-time patching on control of intermittent exotropia: a randomized clinical trial.

PURPOSE: To evaluate the effect of alternate part-time patching on deviation control in patients with intermittent exotropia in comparison to observation. METHODS: In a randomized clinical trial, untreated 3-8-year-old children with intermittent exotropia were randomly divided into patching group who treated with alternate part-time patching and observation group. Deviation control was assessed with 3-point and 6-point scales. Stereoacuity and suppression were evaluated with Titmus and Worth-4-dot tests respectively. All exams were repeated 3 and 6 months after beginning of treatment. RESULTS: Seventy-six patients (35 in patching and 41 in observation group) with a mean age of 4.99 ± 1.33 years completed the 6-month course of study. Based on 3-point scale, deviation control was significantly better in patching group after 3 and 6 months at near and after 3 months at far (p = 0.011, 0.011, and 0.03, respectively) but non-significant after 6 months at far (p = 0.16). According to 6-point scale, deviation control was also significantly better in patching group after 3 months (p = 0.03 at far, 0.003 at near) and 6 months (p = 0.03 at far, 0.003 at near). Three and 6 months stereoacuity was not significantly different between groups (p = 0.86 for both). However, there was greater stereoacuity changes among patching group in comparison with observation group from baseline to 3 and 6 months (p = 0.006 for both). CONCLUSION: Patching seems effective in improving deviation control of 3-8-year-old children with intermittent exotropia in comparison with observation based on two common office control scales. TRIAL REGISTRATION NUMBER AND DATE: NCT03700632 (10/9/2018).

Extraocular Muscle Palsy in Patients with Chronic Orbital Myositis.

BACKGROUND: Orbital myositis (OM) is a subgroup of idiopathic orbital inflammation. It can involve single or multiple extraocular muscles and result in restriction or paresis of extraocular muscles. METHOD: We reported two unusual cases of extraocular muscle paresis in the fibrotic stage of chronic OM and reviewed the literature related to this finding. RESULTS: The first case was of a 38-year-old woman with chronic OM with large-angle right eye exotropia and right medial rectus paresis. She received a botulinum A toxin injection into the right lateral rectus muscle as a first treatment, but it was unsuccessful in correcting her deviation. Subsequently, she underwent two strabismus surgeries, which successfully resolved her diplopia in primary gaze. The second case was of a 35-year-old woman with chronic OM and left lateral rectus palsy, which was managed with a botulinum A toxin injection. CONCLUSION: OM can cause extraocular muscle palsy in the chronic fibrotic stage of the disease.