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Surgical outcomes of phototherapeutic keratectomy on Epithelial basement membrane dystrophy, and the characterisation of Bowman´s Layer
Linköping University, Department of Clinical and Experimental Medicine, Division of Neuroscience. Linköping University, Faculty of Health Sciences.
2014 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

Background. Epithelial basement membrane dystrophy (EBMD) is a common disease of the anterior cornea that can lead to problems with vision and/or painful recurrent erosions of the corneal epithelium. Several treatment options have been used, but recurrence of EBMD after treatment is a problem. Excimer laser phototherapeutic keratectomy (PTK) has become an increasingly popular surgical option in recent years due to its accuracy, reproducibility, and good clinical outcomes. When treating EBMD with PTK, the anterior corneal structures including the epithelium, Bowman´s layer (BL), and subbasal nerves are disrupted or removed completely. Little is known about how BL, nerves, and the stroma recover after PTK treatment, or how they could influence recurrence of EBMD symptoms. Additionally, very little is known about the properties and actual thickness of BL in-vivo.

Aims. To improve the understanding and management of EBMD by investigating the clinical diagnosis and treatment of EBMD and its relationship to Bowman´s layer.

Method. An excimer laser was used to treat EBMD patients at the Department of Ophthalmology during the period 2001-2010. IVCM was used to perform pre- and postoperative examinations. In particular, images of anterior corneal structures, cells, and nerves in high-resolution were obtained. Additionally, a group of over 100 healthy volunteers underwent a full ophthalmic examination including IVCM. Other subjects examined in this work included a group of 17 patients who underwent full-thickness transplantation of the cornea.

Results and conclusions. Clinical follow-up revealed that PTK is an effective method of alleviating the clinical symptoms of EBMD, but the dystrophy can recur with time. Recurrence can be divided into clinical and morphologic types, and may depend upon treatment parameters including the type and depth of ablation. IVCM was found to be a useful screening tool pre- and postoperatively, and could prevent patients with symptoms, but no visible signs of EBMD on slit lamp examination, to go undiagnosed and untreated. BL was found to play a role in regenerative wound healing after PTK, and was also found to be important regarding the treatment and recurrence of EBMD. BL may present a physical barrier that protects the subepithelial nerve plexus thereby facilitating sensory recovery, and BL may also serve as a barrier that prevents direct traumatic contact with the corneal stroma, avoiding a stromal wound healing response. To aid in accurate assessment of BL in patients, an in vivo method for determining BL thickness was developed. This method could be an important tool to aid in clinical assessment and planned treatments of the anterior cornea. Using this tool, a large inter-individual variability in BL thickness and a strong negative correlation of BL thickness with age were found in a healthy population. Using IVCM, it was also found that subbasal nerves are pathologically reduced in EBMD compared to a healthy population, and that this nerve deficit does not improve in the long term after PTK treatment.

Place, publisher, year, edition, pages
Linköping: Linköping University Electronic Press, 2014. , 69 p.
Series
Linköping University Medical Dissertations, ISSN 0345-0082 ; 1397
National Category
Medical and Health Sciences
Identifiers
URN: urn:nbn:se:liu:diva-106248DOI: 10.3384/diss.diva-106248ISBN: 978-91-7519-391-5 (print)OAI: oai:DiVA.org:liu-106248DiVA: diva2:714972
Public defence
2014-05-23, Nils-Holgersalen, Campus US, Linköpings universitet, Linköping, 13:00 (Swedish)
Opponent
Supervisors
Available from: 2014-04-30 Created: 2014-04-30 Last updated: 2014-05-16Bibliographically approved
List of papers
1. The Role of Bowmans Layer in Corneal Regeneration after Phototherapeutic Keratectomy: A Prospective Study Using In Vivo Confocal Microscopy
Open this publication in new window or tab >>The Role of Bowmans Layer in Corneal Regeneration after Phototherapeutic Keratectomy: A Prospective Study Using In Vivo Confocal Microscopy
2009 (English)In: INVESTIGATIVE OPHTHALMOLOGY and VISUAL SCIENCE, ISSN 0146-0404, Vol. 50, no 9, 4192-4198 p.Article in journal (Refereed) Published
Abstract [en]

PURPOSE. To examine the role of Bowmans layer (BL) on the nature of anterior corneal regeneration after excimer laser phototherapeutic keratectomy (PTK). METHODS. A cohort of 13 patients underwent PTK to remove either 7 mu m of BL for treatment of primary recurrent corneal erosions (RCE; six patients) or complete BL removal (15-mu m ablation) to treat RCE or poor vision secondary to map-dot-fingerprint (MDF) dystrophy (seven patients). Clinical examinations and laser-scanning in vivo confocal microscopy (IVCM) were conducted before surgery and at a mean of 4 and 8 months after surgery. RESULTS. Total BL removal resulted in a significant decline in subbasal nerve density at 4 months (P = 0.007) that barely recovered to preoperative levels at 8 months (P = 0.055). With BL partially present, subbasal nerve density did not significantly change from preoperative levels. Superficial, wing, and basal epithelial cell density recovered to preoperative levels within 4 months after PTK, regardless of the presence of BL. Subepithelial keratocytes, however, were more densely distributed in corneas without BL relative to those with a partial BL present (P = 0.005), and increased anterior keratocyte reflectivity was noted in all eyes without BL and in no eye with a partial BL present. CONCLUSIONS. Subbasal nerve regeneration is delayed and subepithelial keratocyte density and reflectivity remain elevated up to 10 months after total BL removal by PTK. The results provide initial evidence for a possible role of BL in facilitating rapid stromal wound healing and an associated recovery of anterior corneal transparency and the restoration of epithelial innervation after epithelial trauma.

National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:liu:diva-20753 (URN)10.1167/iovs.09-3781 (DOI)
Note
Original Publication: Neil Lagali, Johan Germundsson and Per Fagerholm, The Role of Bowmans Layer in Corneal Regeneration after Phototherapeutic Keratectomy: A Prospective Study Using In Vivo Confocal Microscopy, 2009, INVESTIGATIVE OPHTHALMOLOGY and VISUAL SCIENCE, (50), 9, 4192-4198. http://dx.doi.org/10.1167/iovs.09-3781 Copyright: Research in Vision and Opthalmology http://www.arvo.org/ Available from: 2009-09-19 Created: 2009-09-18 Last updated: 2014-04-30
2. Clinical Outcome and Recurrence of Epithelial Basement Membrane Dystrophy after Phototherapeutic Keratectomy A Cross-sectional Study
Open this publication in new window or tab >>Clinical Outcome and Recurrence of Epithelial Basement Membrane Dystrophy after Phototherapeutic Keratectomy A Cross-sectional Study
2011 (English)In: OPHTHALMOLOGY, ISSN 0161-6420, Vol. 118, no 3, 515-522 p.Article in journal (Refereed) Published
Abstract [en]

Objective: To evaluate the outcome of phototherapeutic keratectomy (PTK) treatment of epithelial basement membrane dystrophy (EBMD) patients and to examine clinical and morphologic signs of recurrent dystrophy. Design: Cross-sectional, clinic-based study. Participants: Fifty-two eyes of 39 patients diagnosed with EBMD who underwent PTK between 2001 and 2008. Methods: Preoperative symptoms, best spectacle-corrected visual acuity (BSCVA), and refraction data were collected. At follow-up, refraction and BSCVA were measured, symptoms were noted, and slit-lamp biomicroscopy and in vivo confocal microscopy (IVCM) were performed. Main Outcome Measures: Best spectacle-corrected visual acuity and signs of recurrent EBMD based on symptoms and morphologic features. An assessment of EBMD severity after PTK additionally was considered. Results: Mean follow-up time was 43 months (range, 7-100 months). After PTK, BSCVA remained unchanged or improved in 49 (98%) of 51 eyes. Twenty-four (46%) of 52 eyes had recurrence of some form, and recurrence was correlated positively with postoperative time (P andlt; 0.001). Symptomatic recurrence occurred in 7 eyes (13%), whereas morphologic recurrence occurred in 21 eyes (40%). Symptoms were coupled with positive IVCM findings in 3 (43%) of 7 cases and with slit-lamp findings in 1 (14%) of 7 cases. Of 17 eyes with morphologic recurrence by IVCM, 9 eyes (53%) were classified as having grade 1 recurrence, 8 eyes (47%) were classified as having grade 2 recurrence, and none were classified as having grade 3 recurrence. Morphologic recurrence was associated with epithelial removal by laser ablation before PTK. Conclusions: Although PTK is an effective method of alleviating the clinical symptoms of EBMD, the dystrophy can recur with time. The relationship between the postoperative development of clinical symptoms and the corneal morphologic features is complex and requires further investigation.

Place, publisher, year, edition, pages
Elsevier Science B.V., Amsterdam., 2011
National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:liu:diva-66860 (URN)10.1016/j.ophtha.2010.07.003 (DOI)000287964400015 ()
Note
Original Publication: Johan Germundsson, Per Fagerholm and Neil Lagali, Clinical Outcome and Recurrence of Epithelial Basement Membrane Dystrophy after Phototherapeutic Keratectomy A Cross-sectional Study, 2011, OPHTHALMOLOGY, (118), 3, 515-522. http://dx.doi.org/10.1016/j.ophtha.2010.07.003 Copyright: Elsevier Science B.V., Amsterdam. http://www.elsevier.com/Available from: 2011-03-22 Created: 2011-03-21 Last updated: 2014-04-30
3. An Accurate Method to Determine Bowmans Layer Thickness In Vivo in the Human Cornea
Open this publication in new window or tab >>An Accurate Method to Determine Bowmans Layer Thickness In Vivo in the Human Cornea
2012 (English)In: Investigative Ophthalmology and Visual Science, ISSN 0146-0404, E-ISSN 1552-5783, Vol. 53, no 4, 2354-2359 p.Article in journal (Refereed) Published
Abstract [en]

PURPOSE. To determine an accurate value for Bowmans layer (BL) thickness in vivo in humans. less thanbrgreater than less thanbrgreater thanMETHODS. Seventeen corneal transplant patients were examined preoperatively by laser-scanning in vivo confocal microscopy (IVCM), and corneal buttons were removed post-operatively and sectioned for light microscopy (LM). Nine corneas with uniformly thick BL by LM were used for thickness measurement. In the uniformly thick samples, probable overestimation of BL thickness in vivo by a first in vivo method (Method 1) led to the development of a revised in vivo method (Method 2). Method 2 was used to measure BL thickness in 20 healthy volunteers. less thanbrgreater than less thanbrgreater thanRESULTS. In nine patients, mean BL thickness prior to transplantation was 13.7 +/- 1.6 mu m by IVCM (Method 1) while BL thickness of the removed corneal button was 9.7 +/- 1.7 mu m by LM (P andlt; 0.001). The correlation of BL thickness between IVCM (Method 1) and LM was poor (P = 0.226). In 20 right eyes of 20 normal corneas, both in vivo methods were used to determine BL thickness. Mean BL thickness by Method 1 was 13.2 +/- 1.6 mu m and by Method 2 was 9.1 +/- 1.4 mu m (P andlt; 0.001). BL thickness measurements by both in vivo methods were highly correlated (P andlt; 0.001). less thanbrgreater than less thanbrgreater thanCONCLUSION. BL thickness by a revised in vivo method was close to LM values in this study and to values reported in fixed tissue in other studies. The authors believe this revised method provides the most accurate estimates of BL thickness in vivo to date.

Place, publisher, year, edition, pages
Association for Research in Vision and Ophthalmology (ARVO), 2012
National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:liu:diva-78278 (URN)10.1167/iovs.11-8565 (DOI)000303669400076 ()
Note

Funding Agencies|European Union||

Available from: 2012-06-08 Created: 2012-06-08 Last updated: 2017-12-07
4. Age-Related Thinning of Bowman's Layer in the Human Cornea In Vivo
Open this publication in new window or tab >>Age-Related Thinning of Bowman's Layer in the Human Cornea In Vivo
2013 (English)In: Investigative Ophthalmology and Visual Science, ISSN 0146-0404, E-ISSN 1552-5783, Vol. 54, no 9, 6143-6149 p.Article in journal (Refereed) Published
Abstract [en]

Purpose. To determine the thickness of Bowman's layer (BL) in vivo in a healthy population and to determine its variation with age.

Methods. Eighty-two subjects aged 15 to 88 years with clear, healthy corneas were examined bilaterally with laser scanning in vivo confocal microscopy (IVCM). Bowman's layer thickness was determined from IVCM images of anterior and posterior BL boundaries. For a given eye, BL thickness was averaged across four central locations by two independent observers. In addition, central corneal thickness was measured by time-domain optical coherence tomography.

Results. A significant negative correlation of BL thickness with age was found in right eyes (Pearson r = −0.579, P < 0.0001) and in left eyes (r = −0.558, P < 0.0001). Linear regression analysis yielded a decline in BL thickness of 0.06 μm per year. In 41 older subjects (mean age, 64.4 years), BL thickness was significantly thinner (mean ± SD, 8.6 ± 1.7 μm in right eyes) than that in 41 younger subjects (mean age, 31.6 years) (mean ± SD, 10.7 ± 1.6 μm in right eyes) (P < 0.001). No correlation of corneal thickness with age or of BL thickness with corneal thickness was observed. Strong intereye correlations in BL thickness (r = 0.771, P < 0.0001) and corneal thickness (r = 0.969, P < 0.001) were found.

Conclusions. Bowman's layer thins with age in the normal cornea, losing one-third of its thickness between the ages of 20 and 80 years. In vivo measurement of BL thickness by IVCM could aid in clinical assessment and planned treatments of the anterior cornea.

Place, publisher, year, edition, pages
Association for Research in Vision and Ophthalmology (ARVO), 2013
Keyword
Bowmans layer, in vivo confocal microscopy, image analysis, aging, collagen
National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:liu:diva-100037 (URN)10.1167/iovs.13-12535 (DOI)000325169500028 ()
Note

Funding Agencies|Swedish Research Council||Konung Gustav V and Drottning Viktorias Frimurarestiftelse||County Council of Ostergotland||Cronqvist Foundation||

Available from: 2013-10-25 Created: 2013-10-25 Last updated: 2017-12-06Bibliographically approved
5. Pathologically reduced subbasal nerve density in epithelial basement membrane dystrophy is unaltered by phototherapeutic keratectomy treatment
Open this publication in new window or tab >>Pathologically reduced subbasal nerve density in epithelial basement membrane dystrophy is unaltered by phototherapeutic keratectomy treatment
2014 (English)In: Investigative Ophthalmology and Visual Science, ISSN 0146-0404, E-ISSN 1552-5783, Vol. 55, no 3, 1835-1841 p.Article in journal (Refereed) Published
Abstract [en]

PURPOSE: To investigate the effect of phototherapeutic keratectomy (PTK) treatment on corneal epithelial wing cell and corneal subbasal nerve density in epithelial basement membrane dystrophy (EBMD).

METHODS: A total of 39 patients with EBMD who underwent PTK treatment, 40 healthy volunteers, and 24 untreated eyes with EBMD were examined with laser-scanning in vivo confocal microscopy (IVCM). Corneal subbasal nerves and epithelial wing cells were manually quantified from IVCM images by two observers, while epithelial wing cells were additionally quantified by a fully automated method.

RESULTS: Subbasal nerve density was significantly reduced in untreated (10,164 ± 4139 μm/mm(2); n = 24) and PTK-treated (10,624 ± 4479 μm/mm(2); n = 39) EBMD eyes, relative to healthy controls (18,241 ± 4479 μm/mm(2); n = 40) (P < 0.001). Subbasal nerve density in PTK-treated and untreated eyes did not differ (P > 0.05). Epithelial wing cell density did not differ between PTK-treated and untreated EBMD eyes, by either manual or automated analysis; however, epithelial wing cell density in PTK-treated EBMD corneas was significantly reduced (P = 0.008) relative to healthy corneas, by automated cell counting.

CONCLUSIONS: Subbasal nerve density in EBMD is reduced by 45% and recovers only to the reduced level in the long term after PTK treatment, whereas epithelial wing cell density in EBMD is not affected by PTK in the long term. Fully automated cell analysis from IVCM images could provide an objective, standardized means to quantify and compare corneal cell densities in future studies.

National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:liu:diva-106246 (URN)10.1167/iovs.13-12533 (DOI)000333645900016 ()24569577 (PubMedID)
Available from: 2014-04-30 Created: 2014-04-30 Last updated: 2017-12-05Bibliographically approved

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