We read with interest the recent publication by Bertolin et al. (“In vitro establishment, validation and characterisation of conjunctival epithelium outgrowth using tissue fragments and amniotic membrane”). Their validated conjunctival analogue of the simple limbal epithelial transplantation does represent a promising advance in the field. It is, however, interesting to note that the established tissue application was mainly validated on its growth potential and not specifically on its ability to reinstate a healthy ocular mucosal surface.
Functional validation is of utmost importance, especially as the glued fragments are directly transplanted. This approach circumvents the need for expensive cell culture but also bypasses the stringent release criteria for cell therapies or tissue-engineered transplantation products. We would suggest that before this technique can be considered fully validated, it should be demonstrated that the obtained conjunctival cells contribute to the first line of mucosal defence, i.e. barrier formation. Several conjunctival barriers can be identified, such as intercellular junction complexes, glycocalyx and secreted mucins. Bertolin et al. demonstrated the presence of tight junctions (cfr. ZO-1 protein) and a glycocalyx (cfr. membrane-associated mucin-1), but failed to address the presence of goblet cells. As goblet cells are responsible for the secretion of mucin 5AC, which is the most abundant mucin in the mucin la...
We read with interest the recent publication by Bertolin et al. (“In vitro establishment, validation and characterisation of conjunctival epithelium outgrowth using tissue fragments and amniotic membrane”). Their validated conjunctival analogue of the simple limbal epithelial transplantation does represent a promising advance in the field. It is, however, interesting to note that the established tissue application was mainly validated on its growth potential and not specifically on its ability to reinstate a healthy ocular mucosal surface.
Functional validation is of utmost importance, especially as the glued fragments are directly transplanted. This approach circumvents the need for expensive cell culture but also bypasses the stringent release criteria for cell therapies or tissue-engineered transplantation products. We would suggest that before this technique can be considered fully validated, it should be demonstrated that the obtained conjunctival cells contribute to the first line of mucosal defence, i.e. barrier formation. Several conjunctival barriers can be identified, such as intercellular junction complexes, glycocalyx and secreted mucins. Bertolin et al. demonstrated the presence of tight junctions (cfr. ZO-1 protein) and a glycocalyx (cfr. membrane-associated mucin-1), but failed to address the presence of goblet cells. As goblet cells are responsible for the secretion of mucin 5AC, which is the most abundant mucin in the mucin layer of the tear film, its presence is crucial to obtain a normal, hydrated ocular surface. Presence of mucin-producing goblet cells is so characteristic of the conjunctiva that it is a cardinal feature of impression cytology techniques in the diagnosis of corneal limbal stem cell deficiency. We therefore consider goblet cells (and their associated mucin production) in 2D and 3D cultures the “sine qua non” for conjunctival epithelium and propose that it should be a core element of the validated characterization process.
As functional goblet cells are difficult to maintain in culture, it could be debated that the absence of goblet cells in the outgrowth does not implicate their absence during in vivo expansion. If conjunctival stem cells in the outgrowth could be shown to have bipotent properties, it is reasonable to assume that conjunctival goblet cells can differentiate from these bipotent stem cells and that they can be preserved once they are placed in their natural tightly regulated environment, including the conjunctival innervation of the epithelium. Do the authors have any experience with goblet cell maturation? In any case, these properties would have to be well proven before this technique can be relied on in the clinic.
We like to congratulate Mullany et al. for their paper on normal-tension glaucoma is associated with cognitive impairment.1 To link normal-tension glaucoma (NTG) to cognitive impairment and therefore to a neurodegenerative process opens a new vista and research approach for glaucoma research. NTG indeed is an intriguing optic neuropathy that presents with a glaucomatous optic disc appearance and visual field loss similar to that seen in primary open angle glaucoma. The main risk factor for glaucoma however, increased intraocular pressure is missing.
Unlike other cranial nerves the optic nerve is a white matter tract of the brain, enveloped in the meninges (dura, arachnoid and pia mater) and surrounded by cerebrospinal fluid (CSF) on its entire length. And CSF indeed may be the link that connects the neurodegenerative process leading to cognitive impairment and the glaucomatous optic neuropathy in NTG. Recent research demonstrated a relationship between decreased CSF flow, measured in the ventricles and the spinal cord, and cognitive deficit in the elderly.2 In NTG, impaired CSF dynamics was demonstrated with computer assisted cisternography in the subarachnoid space of the intraorbital optic nerve most pronounced in the bulbar region behind the eye globe.3 In a recent publication we found an elevated L-PGDS concentration in the subarachnoid space of the optic nerve in NTG patients with optic nerve sheath compartment syndrome that results in a reduced CSF turnover.4...
We like to congratulate Mullany et al. for their paper on normal-tension glaucoma is associated with cognitive impairment.1 To link normal-tension glaucoma (NTG) to cognitive impairment and therefore to a neurodegenerative process opens a new vista and research approach for glaucoma research. NTG indeed is an intriguing optic neuropathy that presents with a glaucomatous optic disc appearance and visual field loss similar to that seen in primary open angle glaucoma. The main risk factor for glaucoma however, increased intraocular pressure is missing.
Unlike other cranial nerves the optic nerve is a white matter tract of the brain, enveloped in the meninges (dura, arachnoid and pia mater) and surrounded by cerebrospinal fluid (CSF) on its entire length. And CSF indeed may be the link that connects the neurodegenerative process leading to cognitive impairment and the glaucomatous optic neuropathy in NTG. Recent research demonstrated a relationship between decreased CSF flow, measured in the ventricles and the spinal cord, and cognitive deficit in the elderly.2 In NTG, impaired CSF dynamics was demonstrated with computer assisted cisternography in the subarachnoid space of the intraorbital optic nerve most pronounced in the bulbar region behind the eye globe.3 In a recent publication we found an elevated L-PGDS concentration in the subarachnoid space of the optic nerve in NTG patients with optic nerve sheath compartment syndrome that results in a reduced CSF turnover.4 Reduced CSF turnover is thought to result in malnutrition of axons, neurons and glial cells as well as in accumulation of toxic waste products on the other hand. An experimental induced optic nerve sheath compartment in an animal model demonstrated the most impressive damage to axons and glial cells not on the site where the compartment was created (close to optic canal), but behind the lamina cribrosa in an area densely packed with mitochondria.5 A toxic damage following the CSF compartmentation seems to be the most likely explanation.
We encourage to focus in further studies on CSF dynamics in both, dementia and NTG.
References:
1. Mullany S, Xiao L, Qassim A, Marshall H, Gharahkhani P, MacGregor S, Hassall MM, Siggs OM, Souzeau E, Craig JE. Normal-tension glaucoma is associated with cognitive impairment. Br J Ophthalmol. 2021 Mar 29:bjophthalmol-2020-317461. doi: 10.1136/bjophthalmol-2020-317461. Epub ahead of print. PMID: 33781990.
2. Attier-Zmudka J, Sérot JM, Valluy J, Saffarini M, Macaret AS, Diouf M, Dao S, Douadi Y, Malinowski KP, Balédent O. Decreased Cerebrospinal Fluid Flow Is Associated With Cognitive Deficit in Elderly Patients. Front Aging Neurosci. 2019 Apr 30;11:87. doi: 10.3389/fnagi.2019.00087. PMID: 31114494; PMCID: PMC6502902.
3. Pircher A, Montali M, Wostyn P, Pircher J, Berberat J, Remonda L, Killer HE. Impaired cerebrospinal fluid dynamics along the entire optic nerve in normal-tension glaucoma. Acta Ophthalmol. 2018 Aug;96(5):e562-e569. doi: 10.1111/aos.13647. Epub 2018 Mar 12. PMID: 29532640.
4. Pircher A, Neutzner A, Montali M, Huber A, Scholl HPN, Berberat J, Remonda L, Killer HE. Lipocalin-type Prostaglandin D Synthase Concentration Gradients in the Cerebrospinal Fluid in Normal-tension Glaucoma Patients with Optic Nerve Sheath Compartmentation. Eye Brain. 2021 Apr 14;13:89-97. doi: 10.2147/EB.S297274. PMID: 33883963; PMCID: PMC8053785.
5. Jaggi GP, Harlev M, Ziegler U, Dotan S, Miller NR, Killer HE. Cerebrospinal fluid segregation optic neuropathy: an experimental model and a hypothesis. Br J Ophthalmol. 2010 Aug;94(8):1088-93. doi: 10.1136/bjo.2009.171660. Epub 2010 May 27. PMID: 20508039
We would like to congratulate Uwaydat et al. on their large series of spontaneously closed macular holes (MH), which adds new information to the literature.(1) It reinforces the observation that traumatic MH can spontaneously close and that a period of observation in these eyes, where the results of surgery are not clear, is a worthwhile option. However, we disagree with their conclusion that eyes with recent onset small primary MHs should also be observed. The authors don’t suggest a time period for observation but found that the median time for closure for these small holes was 4.4 months.
The report by Uwaydat et al. has 40 authors and the 60 cases of idiopathic MH were collected over at least a two-year period. Assuming a conservative number of 25 MH cases seen per surgeon per annum, this would give a spontaneous closure rate of ~3%, which is similar to the published literature as the authors review in their article.
MH are known to enlarge with time, even in the short term. Madi et al, reported that 83% enlarged, by a median of 105 microns in 8 weeks. (2) Similarly, Berton et al recently estimated that holes less than 250 microns enlarge by a mean of 1.67 microns per day, resulting in a similar 100-micron increase in 2 months.(3)
The anatomical and visual outcomes of surgery are dependent on MH diameter and duration. Holes greater than 300 microns, and with a duration more than four months are less likely to regain 0.3 logMAR or better.(4)...
We would like to congratulate Uwaydat et al. on their large series of spontaneously closed macular holes (MH), which adds new information to the literature.(1) It reinforces the observation that traumatic MH can spontaneously close and that a period of observation in these eyes, where the results of surgery are not clear, is a worthwhile option. However, we disagree with their conclusion that eyes with recent onset small primary MHs should also be observed. The authors don’t suggest a time period for observation but found that the median time for closure for these small holes was 4.4 months.
The report by Uwaydat et al. has 40 authors and the 60 cases of idiopathic MH were collected over at least a two-year period. Assuming a conservative number of 25 MH cases seen per surgeon per annum, this would give a spontaneous closure rate of ~3%, which is similar to the published literature as the authors review in their article.
MH are known to enlarge with time, even in the short term. Madi et al, reported that 83% enlarged, by a median of 105 microns in 8 weeks. (2) Similarly, Berton et al recently estimated that holes less than 250 microns enlarge by a mean of 1.67 microns per day, resulting in a similar 100-micron increase in 2 months.(3)
The anatomical and visual outcomes of surgery are dependent on MH diameter and duration. Holes greater than 300 microns, and with a duration more than four months are less likely to regain 0.3 logMAR or better.(4)
Surgery achieves closure rates of over 98% for small and medium sized holes, and a risk of a worse visual outcome than preoperatively is very low.(4)
Taking this information together, observing a 200 micron hole with a 2-month duration, for even 2 months would likely result in a 100-micron size increase, and a four-fold reduction in the chances of achieving 0.3logMAR or better, set against a 5% chance of observing spontaneous closure.
The spontaneous closure rate in smaller holes is likely to be higher than previously stated however, it is not a common observation, and delaying surgery carries real risks for the patient. Although the options should be discussed with the patient, we advocate prompt surgery for all primary macular holes, including small ones, as the best means of achieving good functional results.
1. Uwaydat, S. H. et al. Clinical characteristics of full thickness macular holes that closed without surgery. Br. J. Ophthalmol. (2021) doi:10.1136/bjophthalmol-2021-319001.
2. Madi, H. A., Dinah, C., Rees, J. & Steel, D. H. W. The Case Mix of Patients Presenting with Full-Thickness Macular Holes and Progression before Surgery: Implications for Optimum Management. Ophthalmol. J. Int. d’ophtalmologie. Int. J. Ophthalmol. Zeitschrift fur Augenheilkd. 233, 216–221 (2015).
3. Berton, M., Robins, J., Frigo, A. C. & Wong, R. Rate of progression of idiopathic full-thickness macular holes before surgery. Eye (Lond). 34, 1386–1391 (2020).
4. Steel, D. H. et al. Factors affecting anatomical and visual outcome after macular hole surgery: findings from a large prospective UK cohort. Eye (Lond). 35, 316–325 (2021).
Atik et al (BJOhttps://bjo.bmj.com/content/105/5/602) have done an excellent job of summarizing the current state of the art for conducting health economic evaluations in ophthalmology. Not surprisingly, however, such tools and techniques were originally designed to address broader questions of healthcare funding and resource allocation across many disparate clinical areas. As such, the general use case was very far removed from ophthalmology. This is relevant as a central component is the calculation of the utility parameters used, particularly in cost-effectiveness calculations (1). At present, the standard default utility measure remains the EQ5D, which does not prima facie include a vision specific domain (2). Rather, a “Vision Bolt-On” to the EQ5D which asks patients whether they “Have no problems seeing”; “Have some problem seeing”; or “Have extreme problems seeing” is proposed for increasing the precision of the utility score derived from patients for ophthalmic interventions (3). Unfortunately, the “Vision Bolt On” while theoretically increasing the discriminating power of the EQ-5D has not been widely adopted in economic evaluations conducted in ophthalmology (3-4). Moreover, as currently configured, the “Vision Bolt On” questions fail to adequately account for the clinical differences, say between central or fine reading vision which may be more relevant in patients with age-related macular degeneration, versus...
Atik et al (BJOhttps://bjo.bmj.com/content/105/5/602) have done an excellent job of summarizing the current state of the art for conducting health economic evaluations in ophthalmology. Not surprisingly, however, such tools and techniques were originally designed to address broader questions of healthcare funding and resource allocation across many disparate clinical areas. As such, the general use case was very far removed from ophthalmology. This is relevant as a central component is the calculation of the utility parameters used, particularly in cost-effectiveness calculations (1). At present, the standard default utility measure remains the EQ5D, which does not prima facie include a vision specific domain (2). Rather, a “Vision Bolt-On” to the EQ5D which asks patients whether they “Have no problems seeing”; “Have some problem seeing”; or “Have extreme problems seeing” is proposed for increasing the precision of the utility score derived from patients for ophthalmic interventions (3). Unfortunately, the “Vision Bolt On” while theoretically increasing the discriminating power of the EQ-5D has not been widely adopted in economic evaluations conducted in ophthalmology (3-4). Moreover, as currently configured, the “Vision Bolt On” questions fail to adequately account for the clinical differences, say between central or fine reading vision which may be more relevant in patients with age-related macular degeneration, versus the loss of peripheral retinal photoreceptors on a patient’s navigation vision such as in glaucoma. Additional attempts designed to extend the “Vision Bolt On” including the Glaucoma Utility Index (GUI) to increase such discriminating abilities, however, have concluded that more research on the link between utility measures and precise clinical parameters is needed to better capture the subtle components of a patient’s vision on their overall global utility score (5). The time is, therefore, ripe for a concerted research effort to develop and validate such a truly relevant utility measure tailored to ophthalmic interventions.
Word Count: 300
References:
1. Smith AF, Brown GC. Understanding cost-effectiveness: a detailed review, Brit-J-Ophthalmol, 2000; 84: 794-798
3. Yang Y, Rowen D, Brazier J, et al. An exploratory study to test the impact on three "bolt-on" items to the EQ-5D. Value Health 2015 Jan;18(1):52-60.
4. Luo N, Wang X, Ang M, et al. A Vision "Bolt-On" Item Could Increase the Discriminatory Power of the EQ-5D Index Score. Value Health 2015;18(8):1037‐1042
5. Burr JM, Kilonzo M, Vale L, et al. Developing a preference-based Glaucoma Utility Index using a discrete choice experiment. Optom Vis Sci. 2007;84(8):797‐808
Martel et al. report the prevalence, features and risk factors of visual hallucinations following eye removal (1). The findings indicate that visual hallucinations may be a significant and prevalent association of eye amputation, occurring in around one-third of cases. Throughout the paper, visual hallucinations are referred to as phantom visions, and categorised under the broad catchment of the phantom eye syndrome that includes pain and tactile sensations as well as visual hallucinations. Although the authors speculate phantom visions could be considered a subtype of Charles Bonnet syndrome (CBS) they are reluctant to refer to them as CBS, perhaps because of the longstanding debate as to whether CBS should be used to refer to a specific type of visual hallucination or a specific underlying cause (2,3). Where CBS is used to refer to a specific hallucination type, it is typically reserved for complex hallucinations and excludes the simple, ‘elementary’ hallucinations described as the most common experiences following enucleation. The consequence is that a range of terms have evolved to describe symptoms that have the same cause, adding confusion to the literature and hindering research and extensive efforts to raise awareness and establish appropriate patient management pathways for people with visual hallucinations (4-6).
It is our opinion that both the simple and complex visual hallucinations described in the study should be referred to as Charles Bonnet syndrome....
Martel et al. report the prevalence, features and risk factors of visual hallucinations following eye removal (1). The findings indicate that visual hallucinations may be a significant and prevalent association of eye amputation, occurring in around one-third of cases. Throughout the paper, visual hallucinations are referred to as phantom visions, and categorised under the broad catchment of the phantom eye syndrome that includes pain and tactile sensations as well as visual hallucinations. Although the authors speculate phantom visions could be considered a subtype of Charles Bonnet syndrome (CBS) they are reluctant to refer to them as CBS, perhaps because of the longstanding debate as to whether CBS should be used to refer to a specific type of visual hallucination or a specific underlying cause (2,3). Where CBS is used to refer to a specific hallucination type, it is typically reserved for complex hallucinations and excludes the simple, ‘elementary’ hallucinations described as the most common experiences following enucleation. The consequence is that a range of terms have evolved to describe symptoms that have the same cause, adding confusion to the literature and hindering research and extensive efforts to raise awareness and establish appropriate patient management pathways for people with visual hallucinations (4-6).
It is our opinion that both the simple and complex visual hallucinations described in the study should be referred to as Charles Bonnet syndrome. In fact, irrespective of eye condition or visual pathway disease, surveys that include both simple and complex hallucinations find a similar ratio of simple to complex as that described by the authors following eye removal (see for example 7,8) and it has been argued previously that restriction of the use of CBS to denote complex hallucinations only should be revisited (3). Broadening the term to include simple and complex phenomena reflects current practice (9,10) and has become particularly pressing as the International Classification of Diseases (ICD-11) now includes CBS for the first time, using it to refer to the specific causal mechanism of visual release.
Inconsistent terminology in the visual hallucination literature threatens to widen the gap between patients and appropriate referral to support services. This problem is particularly acute in CBS due to low awareness of the condition among physicians (7, 11). There is need for unity to ensure all patients receive accurate and clear messaging about visual hallucinations and can be signposted to relevant organisations, such as Esme’s Umbrella, for advice and support.
References
1. Martel A, Baillif S, Thomas P, et al. Phantom vision after eye removal: prevalence, features and related risk factors. British Journal of Ophthalmology, Published Online First: 12 May 2021. doi: 10.1136/bjophthalmol-2021-319091
2. ffytche DH. Visual hallucinatory syndromes: past, present, and future. Dialogues in Clinical Neuroscience. 2007;9(2):173-189.
3. ffytche DH. Visual hallucinations and the Charles Bonnet syndrome. Current Psychiatry Reports. 2005;7(3): 168-79.
4. O'Brien J, Taylor JP, Ballard C, Barker RA, Bradley C, Burns A, Collerton D, Dave S, Dudley R, Francis P, Gibbons A. Visual hallucinations in neurological and ophthalmological disease: pathophysiology and management. Journal of Neurology, Neurosurgery & Psychiatry, 2020; 91(5): 512-519.
5. Carpenter K, Jolly JK, Bridge H. The elephant in the room: understanding the pathogenesis of Charles Bonnet syndrome. Ophthalmic and Physiological Optics, 2019; 39(6): 414-421.
6. Best J, Liu PY, ffytche D, Potts J, Moosajee M. Think sight loss, think Charles Bonnet syndrome. Therapeutic Advances in Ophthalmology, 2019. doi:10.1177/2515841419895909
7. Cox TM, ffytche DH. Negative outcome Charles Bonnet Syndrome, British Journal of Ophthalmology, 2014; 98: 1236-9.
8. Santhouse AM, Howard RJ, ffytche DH. Visual hallucinatory syndromes and the anatomy of the visual brain. Brain. 2000;123: 2055-64
9. Jones L, Moosajee M. Visual hallucinations and sight loss in children and young adults: a retrospective case series of Charles Bonnet syndrome. British Journal of Ophthalmology, Published Online First: 15 September 2020. doi: 10.1136/bjophthalmol-2020-317237
10. Jones L, Ditzel-Finn L, Potts J, Moosajee M. Exacerbation of visual hallucinations in Charles Bonnet syndrome due to the social implications of COVID-19. BMJ Open Ophthalmology, 2021; 6(1), p.e000670.
11. Gordon KD, Felfeli T. Family physician awareness of Charles Bonnet syndrome, Family Practice, 2018; 35(5): 595-8.
Corneal graft rejection following vaccination was first reported in 1988 by T L Steinemann, B H Koffler and C D Jennings [1]. This article is missing from Table 1, “Summary of reported cases of corneal graft rejection”. As it is the first published study to describe this temporal association, it merits mention.
In regards to preventative measures, we recommend thoroughly counseling patients with grafts. They should be educated on the salient warning signs of rejection including pain, redness, blurred vision, and irritation. Patients should also be informed that COVID-19 vaccination may pose a risk to the viability of their corneal grafts. We recommend prophylactically increasing topical steroids for 3-4 weeks around the time of each vaccination.
References
1. Steinemann TL, Koffler BH, Jennings CD. Corneal allograft rejection following immunization. Am J Ophthalmol. 1988 Nov 15;106(5):575-8. doi: 10.1016/0002-9394(88)90588-0. PMID: 3056015.
Dear Editor,
With great excitement, we read the original article titled “Short-term real-world outcomes following intravitreal brolucizumab for neovascular AMD: SHIFT study” by Bulirsch et al.1 We congratulate the authors on their detailed analysis and on adding another important real world data related to brolucizumab usage. As we are still trying to understand the pathogenesis of brolucizumab related immunogenicity and the population at risk,2-4 it would be very helpful for the readers if the authors could share the following information.
1. Were the 7 eyes in which IOI was recorded have history of any other autoimmune systemic diseases such as arthritis, thyroid abnormalities etc ?
2. It would be helpful if the authors could clarify if the 4 eyes that had intermediate uveitis and vitreous cells underwent fluorescein angigraphy or wide filed imaging to rule out the possibility of peripheral retinal vasulilits.
3. It would be helpful for the readers if we could know the indication of using subconjunctival dexamethasone in four cases?
4. After treatment, were all the patients who had vitritis completely free of cells/inflammation on clinical examination or were they asymptomatic?
Ashish Sharma, Nilesh Kumar, Nikulaa Parachuri
Lotus Eye Hospital and Institute, Coimbatore, TN, India
References
1. Bulirsch LM, Saßmannshausen M, Nadal J, et al Short-term real-world outcomes following intravitreal brolucizumab for neovas...
Dear Editor,
With great excitement, we read the original article titled “Short-term real-world outcomes following intravitreal brolucizumab for neovascular AMD: SHIFT study” by Bulirsch et al.1 We congratulate the authors on their detailed analysis and on adding another important real world data related to brolucizumab usage. As we are still trying to understand the pathogenesis of brolucizumab related immunogenicity and the population at risk,2-4 it would be very helpful for the readers if the authors could share the following information.
1. Were the 7 eyes in which IOI was recorded have history of any other autoimmune systemic diseases such as arthritis, thyroid abnormalities etc ?
2. It would be helpful if the authors could clarify if the 4 eyes that had intermediate uveitis and vitreous cells underwent fluorescein angigraphy or wide filed imaging to rule out the possibility of peripheral retinal vasulilits.
3. It would be helpful for the readers if we could know the indication of using subconjunctival dexamethasone in four cases?
4. After treatment, were all the patients who had vitritis completely free of cells/inflammation on clinical examination or were they asymptomatic?
Ashish Sharma, Nilesh Kumar, Nikulaa Parachuri
Lotus Eye Hospital and Institute, Coimbatore, TN, India
References
1. Bulirsch LM, Saßmannshausen M, Nadal J, et al Short-term real-world outcomes following intravitreal brolucizumab for neovascular AMD: SHIFT study British Journal of Ophthalmology Published Online First: 12 April 2021. doi: 10.1136/bjophthalmol-2020-318672
2. Sharma A, Kumar N, Parachuri N, Singh S, Bandello F, Regillo CD, Boyer D, Nguyen QD. Understanding Retinal Vasculitis Associated with Brolucizumab: Complex Pathophysiology or Occam's Razor? Ocul Immunol Inflamm. 2021 May 20:1-3. doi: 10.1080/09273948.2021.1897628.
3. Singer M, Albini TA, Seres A, Baumal CR, Parikh S, Gale R, Kaiser PK, Lobach I, Feltgen N, Joshi MR, Ziemssen F, Bodaghi B. Clinical Characteristics and Outcomes of Eyes with Intraocular Inflammation after Brolucizumab: Post Hoc Analysis of HAWK and HARRIER. Ophthalmol Retina. 2021 May 7:S2468-6530(21)00162-7. doi: 10.1016/j.oret.2021.05.003.
4. Sharma A, Kumar N, Parachuri N, Kuppermann BD, Bandello F, Regillo CD, Boyer D, Nguyen QD. Brolucizumab-foreseeable workflow in the current scenario. Eye (Lond). 2021 Feb 2. doi: 10.1038/s41433-020-01324-w.
We welcome the recent meta-analysis by Hedengran and co-workers in the British Journal of Ophthalmology (BJO).1 This study compared the efficacy and safety of benzalkonium chloride (BAK)-preserved eye drops with alternatively preserved (AP) and preservative-free (PF) eye drops. The meta-analysis was conducted on 16 studies that range from 15 days to 6 months of study duration. Change in IOP in BAK vs AP and PF groups was meta-analysed as the primary outcome. Conjunctival hyperaemia, ocular hyperaemia, total ocular adverse effects (AE), and TBUT were also meta-analysed. The authors found no evidence of significant change in IOP and conjunctival hyperaemia between BAK vs AP and PF treatment groups. The authors concluded that the main reason for detecting no clinical differences between the groups was related to the lack of long-term clinical studies on the safety of BAK vs AP and PF eye drops. We are in consensus with Kontas AG et al., comments on the deficiencies of this meta-analysis.
We do not agree to the conclusion, “BAK-containing and PF medications do not differ with respect to tolerability and therapy outcome”. We would like to direct the authors and readers to our recently published study in the journal, Clinical and Experimental Ophthalmology (CEO), which involved the randomised evaluation of the inflammatory effects of PF vs BAK and PF vs polyquad (PQ)-preserved eye drops in naïve glaucomatous patients over the period of 24 months.2 We p...
We welcome the recent meta-analysis by Hedengran and co-workers in the British Journal of Ophthalmology (BJO).1 This study compared the efficacy and safety of benzalkonium chloride (BAK)-preserved eye drops with alternatively preserved (AP) and preservative-free (PF) eye drops. The meta-analysis was conducted on 16 studies that range from 15 days to 6 months of study duration. Change in IOP in BAK vs AP and PF groups was meta-analysed as the primary outcome. Conjunctival hyperaemia, ocular hyperaemia, total ocular adverse effects (AE), and TBUT were also meta-analysed. The authors found no evidence of significant change in IOP and conjunctival hyperaemia between BAK vs AP and PF treatment groups. The authors concluded that the main reason for detecting no clinical differences between the groups was related to the lack of long-term clinical studies on the safety of BAK vs AP and PF eye drops. We are in consensus with Kontas AG et al., comments on the deficiencies of this meta-analysis.
We do not agree to the conclusion, “BAK-containing and PF medications do not differ with respect to tolerability and therapy outcome”. We would like to direct the authors and readers to our recently published study in the journal, Clinical and Experimental Ophthalmology (CEO), which involved the randomised evaluation of the inflammatory effects of PF vs BAK and PF vs polyquad (PQ)-preserved eye drops in naïve glaucomatous patients over the period of 24 months.2 We profiled the inflammatory cytokines and analysed the ocular AE (via OSDI questionnaire) at baseline and then at 1, 3, 6, 12 and 24 months, respectively. Our results showed that the pro-inflammatory cytokines such as IL-6, IL-8, and IL-1beta were significantly increased in a time-dependent fashion in BAK group compared to PF and PQ groups. Notably, the increased levels of these cytokines significantly correlated to the OSDI in BAK group. Our results conformed with previously published in-vivo and in-vitro studies.3 4
Although our study has demonstrated that PF and PQ-preserved eye drops do not elicit ocular AE, the increased levels of IL-1beta in PQ group starting 12-month onwards indicated that PQ preserved eye drops may produce delayed ocular surface discomfort. As the main aim of our study was to compare the BAK vs PF and PQ-preserved eye drops, there is a likelihood that bimatoprost could elicit ocular hyperaemia even when used as a PF formulation. A previous study has reported that bimatoprost causes vasodilation mediated via nitric oxide synthase but not through the induction of pro-inflammatory cytokines.5
We agree to author’s views, “Longer clinical studies with standardised safety measurements and grading methods are highly advisable to fully identify any potential differences between preservation methods.” We recommend that a longitudinal study comparing the PF-bimatoprost with BAK-preserved bimatoprost should be conducted to validate the ocular responses. Additionally, to comprehensively ascertain the effect of other analogues, it is essential to study the ocular effects of PF-latanoprost vs BAK-latanoprost and PF-travoprost vs BAK-travoprost.
Imran Mohammed
Harminder S. Dua
Anthony J. King
Academic Ophthalmology, School of Medicine, The University of Nottingham, UK
References:
1. Hedengran A, Steensberg AT, Virgili G, et al. Efficacy and safety evaluation of benzalkonium chloride preserved eye-drops compared with alternatively preserved and preservative-free eye-drops in the treatment of glaucoma: a systematic review and meta-analysis. Br J Ophthalmol 2020;104(11):1512-18. doi: 10.1136/bjophthalmol-2019-315623 [published Online First: 2020/02/14]
2. Mohammed I, Kulkarni B, Faraj LA, et al. Profiling ocular surface responses to preserved and non-preserved topical glaucoma medications: A 2-year randomized evaluation study. Clin Exp Ophthalmol 2020;48(7):973-82. doi: 10.1111/ceo.13814 [published Online First: 2020/06/22]
3. Baudouin C, Denoyer A, Desbenoit N, et al. In vitro and in vivo experimental studies on trabecular meshwork degeneration induced by benzalkonium chloride (an American Ophthalmological Society thesis). Trans Am Ophthalmol Soc 2012;110:40-63. [published Online First: 2013/07/03]
4. Baudouin C, Pisella PJ, Fillacier K, et al. Ocular surface inflammatory changes induced by topical antiglaucoma drugs: human and animal studies. Ophthalmology 1999;106(3):556-63. doi: 10.1016/S0161-6420(99)90116-1 [published Online First: 1999/03/18]
5. Impagnatiello F, Bastia E, Almirante N, et al. Prostaglandin analogues and nitric oxide contribution in the treatment of ocular hypertension and glaucoma. Br J Pharmacol 2019;176(8):1079-89. doi: 10.1111/bph.14328 [published Online First: 2018/04/19]
Recently, Lam et al. [1] concluded that patients with macular pucker and foveoschisis had a higher risk of postoperative macular oedema. Since only 5/17 cases had baseline fluorescein angiography it is unclear how they distinguished foveoschisis due to tangential traction, versus cystoid macular edema (CME). Is it possible that postoperative CME was recurrent and not new? In our experience, resolution of foveoschisis takes much longer than the relatively swift resolution in 25% and partial resolution in 68.8% of cases at 1 month, so perhaps CME was a confounding factor. Indeed, Figure 3 appears more like exudative cyst than ‘foveoschisis’.
Previous studies [2] found that nearly half of patients with macular pucker had multiple centers of retinal contraction which were associated with a higher prevalence of intraretinal cysts and greater macular thickening. Was en face OCT performed to determine the number of contraction centers and its relationship to foveoschisis as well as outcomes of surgery? Additionally, anomalous PVD with vitreoschisis [3] and vitreo-papillary adhesion [4] may be important in the pathogenesis of macular pucker. Did the authors correlate these with foveoschisis and postoperative outcomes?
There was no significant difference in postoperative visual acuity (VA) between the foveoschisis and control groups, but this may not be the best outcome measure in macular pucker surgery. Studies [5] have shown that quantifying contrast sensitivity fu...
Recently, Lam et al. [1] concluded that patients with macular pucker and foveoschisis had a higher risk of postoperative macular oedema. Since only 5/17 cases had baseline fluorescein angiography it is unclear how they distinguished foveoschisis due to tangential traction, versus cystoid macular edema (CME). Is it possible that postoperative CME was recurrent and not new? In our experience, resolution of foveoschisis takes much longer than the relatively swift resolution in 25% and partial resolution in 68.8% of cases at 1 month, so perhaps CME was a confounding factor. Indeed, Figure 3 appears more like exudative cyst than ‘foveoschisis’.
Previous studies [2] found that nearly half of patients with macular pucker had multiple centers of retinal contraction which were associated with a higher prevalence of intraretinal cysts and greater macular thickening. Was en face OCT performed to determine the number of contraction centers and its relationship to foveoschisis as well as outcomes of surgery? Additionally, anomalous PVD with vitreoschisis [3] and vitreo-papillary adhesion [4] may be important in the pathogenesis of macular pucker. Did the authors correlate these with foveoschisis and postoperative outcomes?
There was no significant difference in postoperative visual acuity (VA) between the foveoschisis and control groups, but this may not be the best outcome measure in macular pucker surgery. Studies [5] have shown that quantifying contrast sensitivity function (CSF), distortions (3-D Threshold Amsler Grid), and 3-D macular volume (as opposed to 2-D central thickness) more completely characterizes the benefits of surgery. Specifically, VA, CSF, and macular thickness all improved (34%, 35%, 33%, respectively; P<0.001 for each) postoperatively, but did not normalize relative to control (fellow) eyes. [5] In fact, only the Distortions Index (92% improved, P<0.01) and macular volume normalized, demonstrating the discriminating power and sensitivity of these outcome measures of surgical success. What is not known, however, is the relationship to ‘foveoschisis’.
References
1. Lam M, Philippakis E, Gaudric A, Tadayoni R, Couturier A. Postoperative outcomes of idiopathic epiretinal membrane associated with foveoschisis. Br J Ophthalmol. 2021 Feb 17:bjophthalmol-2020-317982. doi: 10.1136/bjophthalmol-2020-317982. Epub ahead of print. PMID: 33597194.
2. Gupta P, Sadun AA, Sebag J. Multifocal retinal contraction in macular pucker analyzed by combined optical coherence tomography/scanning laser ophthalmoscopy. Retina. 2008 Mar;28(3):447-52.
3. Gupta P, Yee KM, Garcia P, Rosen RB, Parikh J, Hageman GS, Sadun AA, Sebag J. Vitreoschisis in macular diseases. Br J Ophthalmol. 2011 Mar;95(3):376-80.
4. Wang MY, Nguyen D, Hindoyan N, Sadun AA, Sebag J. Vitreo-papillary adhesion in macular hole and macular pucker. Retina. 2009 May;29(5):644-50.
5. Nguyen JH, Yee KM, Sadun AA, Sebag J. Quantifying Visual Dysfunction and the Response to Surgery in Macular Pucker. Ophthalmology. 2016 Jul;123(7):1500-10.
In their review and meta-analysis, Hedengran and coworkers1 report no relative therapeutic benefit of preservative-free (PF) therapies over benzalkonium chloride (BAK)-preserved ones. Should the costlier PF medications therefore be abandoned, or should we question this conclusion?
Ten of the 16 comparative trials analysed were of short duration, (between 15 and 90 days), the longest taking 6 months. Once-a-day medication was used in each trial, yet the dose response curve for BAK toxicity shows that each additional drop of BAK-containing medication doubles the likelihood of lissamine green corneal staining2 and increases the risk of early failure of glaucoma surgery.3 BAK toxicity is slow in onset increasing over time, due to its continual accumulation within ocular tissues.3 Thus, inconsistencies between experimental studies, which document the harmful effects of BAK and clinical trials, which do not, likely relate to the timing, dosing and duration of glaucoma therapy.4 Two to 12 week trials comparing BAK with alternatively preserved eyedrops, or PF formulations have shown no convincing differences in ocular tolerability, yet the benefits from switching from once-a-day preserved to PF therapy, accrue several months later.4 Longer term transition to alternatively preserved, or PF formulations improves tolerability, and there is good evidence that substituting PF tafluprost for BAK-containing latanoprost significantly improves tolerability.3 So sh...
In their review and meta-analysis, Hedengran and coworkers1 report no relative therapeutic benefit of preservative-free (PF) therapies over benzalkonium chloride (BAK)-preserved ones. Should the costlier PF medications therefore be abandoned, or should we question this conclusion?
Ten of the 16 comparative trials analysed were of short duration, (between 15 and 90 days), the longest taking 6 months. Once-a-day medication was used in each trial, yet the dose response curve for BAK toxicity shows that each additional drop of BAK-containing medication doubles the likelihood of lissamine green corneal staining2 and increases the risk of early failure of glaucoma surgery.3 BAK toxicity is slow in onset increasing over time, due to its continual accumulation within ocular tissues.3 Thus, inconsistencies between experimental studies, which document the harmful effects of BAK and clinical trials, which do not, likely relate to the timing, dosing and duration of glaucoma therapy.4 Two to 12 week trials comparing BAK with alternatively preserved eyedrops, or PF formulations have shown no convincing differences in ocular tolerability, yet the benefits from switching from once-a-day preserved to PF therapy, accrue several months later.4 Longer term transition to alternatively preserved, or PF formulations improves tolerability, and there is good evidence that substituting PF tafluprost for BAK-containing latanoprost significantly improves tolerability.3 So short duration studies are unlikely to reveal substantive differences.4
Several methodological issues within this systematic review merit consideration. First, there is no protocol registration, which questions its transparency. Such protocols safeguard against biased post hoc decisions in review methods, such as selective outcome reporting. Second, there is no flow diagram presenting the process of report selection. Third, cross-over trials were considered as parallel in this meta-analysis, leading to a unit-of-analysis error, which should be avoided. Appropriate unbiased methodology does exist to impute within-patient differences to incorporate cross-over trials into a meta-analysis.5 Fourth, there was no risk-of-bias assessment across studies, such as a funnel plot and an asymmetry test, to elicit evidence of publication bias. A risk-of-bias in individual studies’ evaluation was performed utilizing an old Cochrane tool. Recently, a revised Cochrane risk-of-bias tool (the RoB 2.0) for randomized trials has been introduced, and is now the preferred option.6 Last but not least every meta-analysis should include the GRADE approach for grading the strength and quality of evidence.
Unfortunately, this review and most published literature focus on mild glaucoma therapy-related ocular surface disease (GTR-OSD). The dosing and number of IOP-lowering medications needed for glaucoma control increase with disease duration so studies to determine the optimal formulations needed to avert longer term moderate/severe GTR-OSD are sorely needed.3 We agree with the authors’ statement that the “study lengths are short, especially in the context of BAK-preserved eyedrop use often being lifelong”, but are unable to accept the conclusion that BAK-containing and PF medications do not differ with respect to tolerability and therapy outcome.
Anastasios G. Konstas1, Gábor Holló2, Andreas Katsanos3, Konstadinos G. Boboridis1, Anna-Bettina Haidich4, Gordon N. Dutton5.
1: 1st and 3rd University Departments of Ophthalmology, Aristotle University of Thessaloniki, Thessaloniki, Greece;
2: Tutkimusz Ltd and Eye Center, Prima Medica Health Centers, Budapest, Hungary;
3: Ophthalmology Department, University of Ioannina, Ioannina, Greece;
4: Department of Hygiene, Social-Preventive Medicine & Medical Statistics, School of Medicine, Faculty of Health Sciences, Aristotle University of Thessaloniki, Thessaloniki, Greece;
5: Department of Ophthalmology, Caledonian University, Glasgow, UK.
Correspondence to: Anastasios G. Konstas, 1st and 3rd University Departments of Ophthalmology, Aristotle University of Thessaloniki, Thessaloniki, Greece; email: agkonstas@gmail.com
References
1. Hedengran A, Steensberg AT, Virgili G, Azuara-Blanco A, Kolko M. Efficacy and safety evaluation of benzalkonium chloride preserved eye-drops compared with alternatively preserved and preservative-free eye-drops in the treatment of glaucoma: a systematic review and meta-analysis. Br J Ophthalmol 2020;104:1512-18.
2. Leung EW, Medeiros FA, Weinreb RN. Prevalence of ocular surface disease in glaucoma patients. J Glaucoma 2008;17:350–5.
3. Konstas AGP, Labbe A, Katsanos A et al. The treatment of glaucoma using topical preservative-free agents: an evaluation of safety and tolerability. Expert Opin Drug Saf 2021;20:453-66.
4. Rasmussen CA, Kaufman PL, Kiland JA. Benzalkonium chloride and glaucoma. J Ocul Pharmacol Ther 2014;30:163–9.
5. Elbourne DR, Altman DG, Higgins JP et al. Meta-analyses involving cross-over trials: methodological issues. Int J Epidemiol 2002;31:140-9.
6. Sterne JAC, Savović J, Page MJ et al. RoB 2: a revised tool for assessing risk of bias in randomised trials. BMJ 2019;366:l4898.
To the editor,
We read with interest the recent publication by Bertolin et al. (“In vitro establishment, validation and characterisation of conjunctival epithelium outgrowth using tissue fragments and amniotic membrane”). Their validated conjunctival analogue of the simple limbal epithelial transplantation does represent a promising advance in the field. It is, however, interesting to note that the established tissue application was mainly validated on its growth potential and not specifically on its ability to reinstate a healthy ocular mucosal surface.
Functional validation is of utmost importance, especially as the glued fragments are directly transplanted. This approach circumvents the need for expensive cell culture but also bypasses the stringent release criteria for cell therapies or tissue-engineered transplantation products. We would suggest that before this technique can be considered fully validated, it should be demonstrated that the obtained conjunctival cells contribute to the first line of mucosal defence, i.e. barrier formation. Several conjunctival barriers can be identified, such as intercellular junction complexes, glycocalyx and secreted mucins. Bertolin et al. demonstrated the presence of tight junctions (cfr. ZO-1 protein) and a glycocalyx (cfr. membrane-associated mucin-1), but failed to address the presence of goblet cells. As goblet cells are responsible for the secretion of mucin 5AC, which is the most abundant mucin in the mucin la...
Show MoreWe like to congratulate Mullany et al. for their paper on normal-tension glaucoma is associated with cognitive impairment.1 To link normal-tension glaucoma (NTG) to cognitive impairment and therefore to a neurodegenerative process opens a new vista and research approach for glaucoma research. NTG indeed is an intriguing optic neuropathy that presents with a glaucomatous optic disc appearance and visual field loss similar to that seen in primary open angle glaucoma. The main risk factor for glaucoma however, increased intraocular pressure is missing.
Unlike other cranial nerves the optic nerve is a white matter tract of the brain, enveloped in the meninges (dura, arachnoid and pia mater) and surrounded by cerebrospinal fluid (CSF) on its entire length. And CSF indeed may be the link that connects the neurodegenerative process leading to cognitive impairment and the glaucomatous optic neuropathy in NTG. Recent research demonstrated a relationship between decreased CSF flow, measured in the ventricles and the spinal cord, and cognitive deficit in the elderly.2 In NTG, impaired CSF dynamics was demonstrated with computer assisted cisternography in the subarachnoid space of the intraorbital optic nerve most pronounced in the bulbar region behind the eye globe.3 In a recent publication we found an elevated L-PGDS concentration in the subarachnoid space of the optic nerve in NTG patients with optic nerve sheath compartment syndrome that results in a reduced CSF turnover.4...
Show MoreWe would like to congratulate Uwaydat et al. on their large series of spontaneously closed macular holes (MH), which adds new information to the literature.(1) It reinforces the observation that traumatic MH can spontaneously close and that a period of observation in these eyes, where the results of surgery are not clear, is a worthwhile option. However, we disagree with their conclusion that eyes with recent onset small primary MHs should also be observed. The authors don’t suggest a time period for observation but found that the median time for closure for these small holes was 4.4 months.
The report by Uwaydat et al. has 40 authors and the 60 cases of idiopathic MH were collected over at least a two-year period. Assuming a conservative number of 25 MH cases seen per surgeon per annum, this would give a spontaneous closure rate of ~3%, which is similar to the published literature as the authors review in their article.
MH are known to enlarge with time, even in the short term. Madi et al, reported that 83% enlarged, by a median of 105 microns in 8 weeks. (2) Similarly, Berton et al recently estimated that holes less than 250 microns enlarge by a mean of 1.67 microns per day, resulting in a similar 100-micron increase in 2 months.(3)
The anatomical and visual outcomes of surgery are dependent on MH diameter and duration. Holes greater than 300 microns, and with a duration more than four months are less likely to regain 0.3 logMAR or better.(4)...
Show MoreAtik et al (BJOhttps://bjo.bmj.com/content/105/5/602) have done an excellent job of summarizing the current state of the art for conducting health economic evaluations in ophthalmology. Not surprisingly, however, such tools and techniques were originally designed to address broader questions of healthcare funding and resource allocation across many disparate clinical areas. As such, the general use case was very far removed from ophthalmology. This is relevant as a central component is the calculation of the utility parameters used, particularly in cost-effectiveness calculations (1). At present, the standard default utility measure remains the EQ5D, which does not prima facie include a vision specific domain (2). Rather, a “Vision Bolt-On” to the EQ5D which asks patients whether they “Have no problems seeing”; “Have some problem seeing”; or “Have extreme problems seeing” is proposed for increasing the precision of the utility score derived from patients for ophthalmic interventions (3). Unfortunately, the “Vision Bolt On” while theoretically increasing the discriminating power of the EQ-5D has not been widely adopted in economic evaluations conducted in ophthalmology (3-4). Moreover, as currently configured, the “Vision Bolt On” questions fail to adequately account for the clinical differences, say between central or fine reading vision which may be more relevant in patients with age-related macular degeneration, versus...
Show MoreMartel et al. report the prevalence, features and risk factors of visual hallucinations following eye removal (1). The findings indicate that visual hallucinations may be a significant and prevalent association of eye amputation, occurring in around one-third of cases. Throughout the paper, visual hallucinations are referred to as phantom visions, and categorised under the broad catchment of the phantom eye syndrome that includes pain and tactile sensations as well as visual hallucinations. Although the authors speculate phantom visions could be considered a subtype of Charles Bonnet syndrome (CBS) they are reluctant to refer to them as CBS, perhaps because of the longstanding debate as to whether CBS should be used to refer to a specific type of visual hallucination or a specific underlying cause (2,3). Where CBS is used to refer to a specific hallucination type, it is typically reserved for complex hallucinations and excludes the simple, ‘elementary’ hallucinations described as the most common experiences following enucleation. The consequence is that a range of terms have evolved to describe symptoms that have the same cause, adding confusion to the literature and hindering research and extensive efforts to raise awareness and establish appropriate patient management pathways for people with visual hallucinations (4-6).
It is our opinion that both the simple and complex visual hallucinations described in the study should be referred to as Charles Bonnet syndrome....
Show MoreDear Editor,
Corneal graft rejection following vaccination was first reported in 1988 by T L Steinemann, B H Koffler and C D Jennings [1]. This article is missing from Table 1, “Summary of reported cases of corneal graft rejection”. As it is the first published study to describe this temporal association, it merits mention.
In regards to preventative measures, we recommend thoroughly counseling patients with grafts. They should be educated on the salient warning signs of rejection including pain, redness, blurred vision, and irritation. Patients should also be informed that COVID-19 vaccination may pose a risk to the viability of their corneal grafts. We recommend prophylactically increasing topical steroids for 3-4 weeks around the time of each vaccination.
References
1. Steinemann TL, Koffler BH, Jennings CD. Corneal allograft rejection following immunization. Am J Ophthalmol. 1988 Nov 15;106(5):575-8. doi: 10.1016/0002-9394(88)90588-0. PMID: 3056015.
Dear Editor,
With great excitement, we read the original article titled “Short-term real-world outcomes following intravitreal brolucizumab for neovascular AMD: SHIFT study” by Bulirsch et al.1 We congratulate the authors on their detailed analysis and on adding another important real world data related to brolucizumab usage. As we are still trying to understand the pathogenesis of brolucizumab related immunogenicity and the population at risk,2-4 it would be very helpful for the readers if the authors could share the following information.
1. Were the 7 eyes in which IOI was recorded have history of any other autoimmune systemic diseases such as arthritis, thyroid abnormalities etc ?
2. It would be helpful if the authors could clarify if the 4 eyes that had intermediate uveitis and vitreous cells underwent fluorescein angigraphy or wide filed imaging to rule out the possibility of peripheral retinal vasulilits.
3. It would be helpful for the readers if we could know the indication of using subconjunctival dexamethasone in four cases?
4. After treatment, were all the patients who had vitritis completely free of cells/inflammation on clinical examination or were they asymptomatic?
Ashish Sharma, Nilesh Kumar, Nikulaa Parachuri
Lotus Eye Hospital and Institute, Coimbatore, TN, India
References
Show More1. Bulirsch LM, Saßmannshausen M, Nadal J, et al Short-term real-world outcomes following intravitreal brolucizumab for neovas...
Dear Editor:
We welcome the recent meta-analysis by Hedengran and co-workers in the British Journal of Ophthalmology (BJO).1 This study compared the efficacy and safety of benzalkonium chloride (BAK)-preserved eye drops with alternatively preserved (AP) and preservative-free (PF) eye drops. The meta-analysis was conducted on 16 studies that range from 15 days to 6 months of study duration. Change in IOP in BAK vs AP and PF groups was meta-analysed as the primary outcome. Conjunctival hyperaemia, ocular hyperaemia, total ocular adverse effects (AE), and TBUT were also meta-analysed. The authors found no evidence of significant change in IOP and conjunctival hyperaemia between BAK vs AP and PF treatment groups. The authors concluded that the main reason for detecting no clinical differences between the groups was related to the lack of long-term clinical studies on the safety of BAK vs AP and PF eye drops. We are in consensus with Kontas AG et al., comments on the deficiencies of this meta-analysis.
We do not agree to the conclusion, “BAK-containing and PF medications do not differ with respect to tolerability and therapy outcome”. We would like to direct the authors and readers to our recently published study in the journal, Clinical and Experimental Ophthalmology (CEO), which involved the randomised evaluation of the inflammatory effects of PF vs BAK and PF vs polyquad (PQ)-preserved eye drops in naïve glaucomatous patients over the period of 24 months.2 We p...
Show MoreRecently, Lam et al. [1] concluded that patients with macular pucker and foveoschisis had a higher risk of postoperative macular oedema. Since only 5/17 cases had baseline fluorescein angiography it is unclear how they distinguished foveoschisis due to tangential traction, versus cystoid macular edema (CME). Is it possible that postoperative CME was recurrent and not new? In our experience, resolution of foveoschisis takes much longer than the relatively swift resolution in 25% and partial resolution in 68.8% of cases at 1 month, so perhaps CME was a confounding factor. Indeed, Figure 3 appears more like exudative cyst than ‘foveoschisis’.
Previous studies [2] found that nearly half of patients with macular pucker had multiple centers of retinal contraction which were associated with a higher prevalence of intraretinal cysts and greater macular thickening. Was en face OCT performed to determine the number of contraction centers and its relationship to foveoschisis as well as outcomes of surgery? Additionally, anomalous PVD with vitreoschisis [3] and vitreo-papillary adhesion [4] may be important in the pathogenesis of macular pucker. Did the authors correlate these with foveoschisis and postoperative outcomes?
There was no significant difference in postoperative visual acuity (VA) between the foveoschisis and control groups, but this may not be the best outcome measure in macular pucker surgery. Studies [5] have shown that quantifying contrast sensitivity fu...
Show MoreDear Editor,
In their review and meta-analysis, Hedengran and coworkers1 report no relative therapeutic benefit of preservative-free (PF) therapies over benzalkonium chloride (BAK)-preserved ones. Should the costlier PF medications therefore be abandoned, or should we question this conclusion?
Show MoreTen of the 16 comparative trials analysed were of short duration, (between 15 and 90 days), the longest taking 6 months. Once-a-day medication was used in each trial, yet the dose response curve for BAK toxicity shows that each additional drop of BAK-containing medication doubles the likelihood of lissamine green corneal staining2 and increases the risk of early failure of glaucoma surgery.3 BAK toxicity is slow in onset increasing over time, due to its continual accumulation within ocular tissues.3 Thus, inconsistencies between experimental studies, which document the harmful effects of BAK and clinical trials, which do not, likely relate to the timing, dosing and duration of glaucoma therapy.4 Two to 12 week trials comparing BAK with alternatively preserved eyedrops, or PF formulations have shown no convincing differences in ocular tolerability, yet the benefits from switching from once-a-day preserved to PF therapy, accrue several months later.4 Longer term transition to alternatively preserved, or PF formulations improves tolerability, and there is good evidence that substituting PF tafluprost for BAK-containing latanoprost significantly improves tolerability.3 So sh...
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