Dear Editor

Regarding the editorial by Khaw et al.[1] we are surprised that after quite a few years now non- penetrating filtering surgery (NPFS) remains only partly understood by many ophthalmologists. There are at present two main NPFS: viscocanalostomy as described by Stegmann, in which outflow filtration is at least in theory not subconjunctival, and deep sclerectomy with or without an implant or even with viscoelastics, the success of which depends on several outflow routes - an important one being subconjunctival. Careful postoperative follow up becomes therefore mandatory and is at least as important as the procedure itself. If needed subconjunctival injection of antimetabolites, needling or use of lasers for goniopuncture, iris desincarceration and attempts of possible bleb reduction or closure of possible seidel may be required. It also becomes evident that antimetabolites play an important role in high risk cases for filtration failure undergoing NPFS (apart from viscocanolostomy as describd by Stegmann). Furthermore in our hospital we have been using antimetabolites also in cases requiring low postoperative IOP such as normal tension glaucoma since 1994. We do not understand the comment made stating that greater care should be taken with antimetabolites used during NPFS, since we intraoperatively use these agents before the deeper scleral flap is being excised or even created. Thus at this stage this does not differ with trabeculectomy. Later on the anterior chamber is not entered and furthermore the deep scleral flap which has been exposed to antimetabolites is being excised making the danger of intraoperative intraocular penetration considerably less than with trabeculectomy (even with unintended macroperforation during NPFS).

Additional sutures are added in cases of accidental macroperforaton so that the incidence of early significant hypotony in the hands of experienced surgeons with NPFS is not high. Moreover postoperative suturelysis may then be required in these cases if the sutures have been made too tight or too numerous.

References are being made to the article by Brart et al. However how reliable is it to compare the efficacy of two procedures without giving the same chances of success to both? Intraoperative antimetabolites were used for all trabeculectomies and yet never with NPFS. Yet strangely enough, postoperative antimetabolites as well as needling with an attempt to lift the scleral flap in some, were used in both groups. The author also writes in the discussion that patients with successful drainage at 6 and 12 months following viscocanalostomy had evidence of subconjunctival drainage of aqueous as opposed to eyes without successful drainage. Later on he further states that 'with our viscocanalostomy technique, the subconjunctival route is the main pathway' and 'observation of the disappearance of subconjunctival blebs in our patients with drainage failure after viscocanalostomy appears to suggest that subconjunctival fibrosis is responsible'. Clearly, if antimetabolites are being used in trabeculectomies, it should be used in NPFS before any reliable conclusions can be drawn. Goniopunture was also only done after 18 months which of course will not be of great help if the outflow route after the trabeculodescemet's membrane has scarred down. Thus to promote good filtration in addition to intraoperative and postoperative use of antimetabolites, goniopuncture can help in enhancing and thus in maintaining a flow under the scleral flap. Using lasers for suturelysis in trabeculectomies or for goniopuncture in NPFS is part of the armementarium we have in glaucoma surgery. The final aim for the patient is not to know whether the procedure is penetrating or not, but rather how effective it is so that the discussion on whether or not to use goniopunture is futile.

For ophthalmologists performing NPFS, the later is compared to trabeculectomy what phacoemulsification was to extracapsular cataract extraction. They will never go back to it unless obliged to do so. However it is clear that there is a learning curve to this surgery and that it is not as forgiveful as is trabeculectomy.

E. Ravinet, MD
A. Mermoud, MD

Reference

(1) Khaw PT, Wells AP, Lim KS. Surgery for glaucoma in the 21st century. Br J Ophthalmol 2002;86: 710-711.

We thank the authors for their prompt reply and do want to thank them for this wonderful paper which definitely serves as an excellent continuing professional development(CPD) module for us and will also be used by many CPD providers immediately after its publication

But another CPD module one engages in, is the GRADE system. And that has set me thinking trying to fill my learning gaps and the following is just my reflection in an attempt to improve my own understanding and I add that I realise that I could be completely wrong

The GRADE system can be used to grade the quality of evidence and strength of recommendations for diagnostic tests or strategies. (BMJ 2008;336:1106) which entails that "Inferring from data on accuracy that a diagnostic test or strategy improves patient-important outcomes will require the availability of effective treatment, reduction of test related adverse effects or anxiety, or improvement of patients' wellbeing from prognostic information"

Vascular malformations may be single vessel form ( arterial, capillary, lymphatic or veinous) or combined. Their flow characteristics may give a clue as to whether there is going to be an involution or not. The clinical characteristics are also important and Orbital LMs are reported to cause proptosis in 85%, ptosis in 73%, and restrictive eye movements in 46% of patients (Tunc M, Sadri E, Char DH. Orbital lymphangioma: an analysis of 26 patients. Br J Ophthalmol 1999; 83:76 - 80.). There is also a real risk of bleeding in such cases .Hence a diagnostic modality to be used may include one which gives maximum information in terms of whether vision can be potentially lost, extra ocular muscles are involved or not and if one needs to intervene surgically , then what are the planes involved; in addition to the fact whether bleeding is already present and in presence of bleeding an angiography hardly gives any information . One definitely doesn't want to make the patient spend money over multiple imaging modalities and would want the modality to be safe and repeatable and the repeat imaging comparable to look for changes in size ,homogeneity and other issues like evidence of inflammation, post procedure bleeding or infection and inflammation.So one tends to do an MRI in my opinion and I agree that it is open to interpretation since as an ophthalmologist I would love to look at extra ocular muscle involvement and possibility of amblyopia and would want to institute therapy based on prognosis which in turn is based on imaging.. A digital subtraction angiography thus becomes a secondary investigation which needs to be carefully selected keeping in mind risks both present and future besides economic considerations of a second test which is invasive and needs radiation which may potentially cause cancers

We do know that even after meticulous extensive surgical ligation of feeder , we do get recurrences and also have complications like perioperative haemorrhage(1) . Both these conditions do need follow up imaging at times . We have been following the reports of success with transarterial embolisation and do realise that some authors do a repeat digital subtraction angiography to check for resolution (2)

We realise that it may not be possible to scientifically conclude that a modality is a gold standard or the preferred treatment modality unless we evaluate the resolution of lesions by follow up imaging to prove that the same imaging shows complete resolution of malformation in the long term and that would be risky with a digital subtraction angiography since even the first imaging or treatment is associated with radiation risks which in itself is under investigation for leukaemia and head cancers which are projected even for CT scan in childhood

It has been suggested that " Use of CT scans in children to deliver cumulative doses of about 50 mGy might almost triple the risk of leukaemia and doses of about 60 mGy might triple the risk of brain cancer" and so ", radiation doses from CT scans ought to be kept as low as possible and alternative procedures, which do not involve ionising radiation, should be considered if appropriate." (3)

The risk of leukemia is reported highest from head scans for children younger than 5 years of age at a rate of 1.9 cases per 10,000 CT scans (4)

The dose for digital subtraction angiography can be high (5)

For the imaging of cerebral vessels, the effective dose according to some authors is calculated as 0.67 mSv for CTAngiography(CTA) and 2.71 mSv for Digital subtraction angiography(DSA) . For the imaging of cervicocerebral vessels, the effective dose is 4.85 mSv for CTA and 3.60 mSv for DSA. The maximum absorbed dose (milligray) for skin, brain, salivary glands, and eyes is 166.2, 73.5, 35.6, and 21.8 mGy for DSA and 19.0, 16.9, 20.4, and 14.8 mGy for CTA, respectively.

Various authors have studied risks and projected risks of head cancer and leukaemia with CT radiation (6) (7) (8)

As early as 2009 it has been estimated that 29000 cancers in future may be caused due to CT Scan with 4000 cancers due to head CT with this being more for radiation in children (9)

And so we wonder what would the strategy be, for reimaging , in case some of these kids do come back with recurrent swelling which may be inflammatory /infection /haemorrhage or simply recurrence because inflammation may stimulate lymphatic memory and regrowth (10)

Some authors have looked at the utility of 4 D imaging instead of repeat DSA even for small recurrences with small flow in brain AVMs (11) and found that the " diagnostic accuracy of 4D MRA for residual brain AVM compared with DSA, reached a sensitivity of 73.7%, specificity 100%, positive predictive value 100%, and negative predictive value 78.3%" (11) and so I wonder if this can be used to study the residual effects scientifically over a long term in case repeated imaging is necessary. I wonder if the GRADES approach is justified herein.

As far as the issue of anemia is concerned ,we know that inequalities exist in all human societies, even so-called "egalitarian" ones and I quote an American report that "An estimated 20 percent of American children will have anemia at some point in their childhood"(12) and another that states "Most children with mild anemia have no signs or symptoms" and even the BMJ best practices reports that "It is estimated that 3% of men and 8% of women in the UK have iron deficiency anaemia" and that Infants and adolescents have an increased risk as a result of high demand related to growth spurts besides the fact that " Microangiopathic hemolytic anemia (MAHA), has also been described with large capillary hemangiomas of the periocular region'wherein the erythrocytes are destroyed from coagulation, or are sheared or fragmented by high pressure forcing them through the abnormally small vessels of the hemangioma" (13) and unless an imaging is done one doesn't know whether the mass is a hemangioma or a lymphatic mass and some patients may benefit from ruling out an anemia at the outset without much damage done in the process

Besides it was long assumed anthropologically that iron deficiency anemia has marked effects on the flat bones of the cranium of infants and young children and that as the body attempts to compensate for low iron levels by increasing red blood cell production in the young, sieve-like lesions develop in the cranial vaults (termed porotic hyperostosis) and/or the orbits (termed cribia orbitalia)(14) and so if one does detect anemia there may be some reason though not strong enough to keep intracranial extensions in mind

I guess routine haemoglobin may fit into GRADES considering the low costs and relative safety in comparison to possible utility , but considering the issue of cancers with radiation in childhood routine digital subtraction angiography in every case may still need evaluation and we are still far away from a sweeping conclusion that sclerotherapy with digital subtraction angiography in all Paediatric cases should be the first line of treatment of orbital lymphatic malformations because we never do repeat angiography to prove resolution and neither are we sure whether the use of digital subtraction angiography is safe In terms of projected head and neck cancers and leukaemia which any radiation has the potential to cause in a child population ,where this condition is predominant

We agree to the wonderful results presented , but object to the conclusion of stating that sclerotherapy should be a first line of treatment of orbital malformations without long term efficacy scientifically proven by repeat imaging and long term risk of cancers with radiation associated with this being evaluated and discussed because sclerotherapy as is mutually agreed is dangerous without a digital subtraction angiography which being a radiation based modality carries with it the risks of cancers

References :- 1) Warrier S, Prabhakaran VC, Valenzuela A, Sullivan TJ, Davis G, Selva D.Orbital arteriovenous malformations. Arch Ophthalmol. 2008 Dec;126(12):1669-75.doi: 10.1001/archophthalmol.2008.501. 2) Sato K, Matsumoto Y, Kondo R, Tominaga T. Intraorbital arteriovenousmalformation treated by transarterial embolization: technical case report.Neurosurgery. 2011 Jun;68(2 Suppl Operative):383-7; discussion 387. doi:10.1227/NEU.0b013e31821522ec. 3) Radiation exposure from CT scans in childhood and subsequent risk of leukaemia and brain tumours: a retrospective cohort study.Pearce, Mark S et al.The Lancet , Volume 380 , Issue 9840 , 499 - 505) 4) Miglioretti DL, Johnson E, Williams A, Greenlee RT, Weinmann S, Solberg LI, Feigelson HS, Roblin D, Flynn MJ, Vanneman N, Smith-Bindman R. The use ofcomputed tomography in pediatrics and the associated radiation exposure andestimated cancer risk. JAMA Pediatr. 2013 Aug 1;167(8):700-7. doi:10.1001/jamapediatrics.2013.311. 5) Manninen AL, Isokangas JM, Karttunen A, Siniluoto T, Nieminen MT. A comparisonof radiation exposure between diagnostic CTA and DSA examinations of cerebral and cervicocerebral vessels. AJNR Am J Neuroradiol. 2012Dec;33(11):2038-42. doi:10.3174/ajnr.A3123. 6) Mathews John D, Forsythe Anna V, Brady Zoe, Butler Martin W, Goergen Stacy K, Byrnes Graham B et al. Cancer risk in 680?000 people exposed to computed tomography scans in childhood or adolescence: data linkage study of 11 million Australians 2013; 346 :f2360) 7) Huang WY, Muo CH, Lin CY, Jen YM, Yang MH, Lin JC, Sung FC, Kao CH (2014) Paediatric head CT scan and subsequent risk of malignancy and benign brain tumour: a nation-wide population-based cohort study. Br J Cancer 110(9): 2354-2360. 8) Meulepas JM, Ronckers CM, Smets AM, Nievelstein RA, Jahnen A, Lee C, Kieft M, Lameris JS, van Herk M, Greuter MJ, Jeukens CR, van Straten M, Visser O, van Leeuwen FE, Hauptmann M (2014) Leukemia and brain tumors among children after radiation exposure from CT scans: design and methodological opportunities of the Dutch Pediatric CT Study. Eur J Epidemiol 29(4): 293-301 9) Berrington de Gonz?lez A, Mahesh M, Kim KP, Bhargavan M, Lewis R, Mettler F, Land C. Projected cancer risks from computed tomographic scans performed in the United States in 2007. Arch Intern Med. 2009 Dec 14;169(22):2071-7. doi: 10.1001/archinternmed.2009.440. 10) Kelley PM, Connor AL, Tempero RM. Lymphatic vessel memory stimulated by recurrent inflammation. Am J Pathol. 2013 Jun;182(6):2418-28. doi: 10.1016/j.ajpath.2013.02.025. 11) Soize S, Bouquigny F, Kadziolka K, Portefaix C, Pierot L. Value of 4D MR angiography at 3T compared with DSA for the follow-up of treated brain arteriovenous malformation. AJNR Am J Neuroradiol. 2014 Oct;35(10):1903-9. doi: 10.3174/ajnr.A3982. 12) Irwin JJ, Kirchner JT. Anemia in children. Am Fam Physician. 2001;64(8):1379-1386. 13) Haik BG, Karcioglu ZA, Gordon RA, Pechous BP. Capillary hemangioma (infantile periocular hemangioma) Surv Ophthalmol. 1994;38(5):399-426. 14) Walker et al. 2009 "The Causes of Porotic Hyperostosis and Cribra Orbitalia: A Reappraisal of the Iron-Deficiency-Anemia Hypothesis" American Journal of Physical Anthropology.

Conflict of Interest:

None declared

Dear Editor,

We read with interest the paper by Cazabon et al.[1] on the important emerging problem of sudden visual loss after removal of silicone oil. We have seen a similar pattern of visual loss in our own patients typically seen in macula on detachments associated with giant retinal tears. We have identified 12 cases between 2 units (St Thomas’, London and Sunderland Eye Infirmary), but 5 of these clearly describe onset of visual loss before oil removal (onset between 1 month and 5 months after oil insertion).[2] Results of investigations were very similar to those reported by Cazabon et al. In 4 of 5 pattern ERG was suggestive of macular dysfunction. The timing of onset of visual loss obviously alters the potential aetiology, which as stated is unknown.

In their paper, information on acuity for cases 2 and 3, between 1 week after oil insertion and oil removal is not provided. Did these cases have visual loss preceding oil removal? Developing cataract can obviously hinder interpretation of acuity measurements. In our cases the symptoms described did not fit with cataract (scotoma, red desaturation) and persisted if any cataract was removed.

We have seen a further case since this report, a 46 year old female with a giant retinal tear and macula-on retinal detachment affecting the right eye. Acuity reduced during period of tamponade from 6/6 2 weeks after oil insertion to 6/36+1, which did not recover after oil removal. She reported a central negative scotoma. Electrophysiology suggested macular dysfunction.

We have speculated that photo-toxicity may play a role, as oil transmits light more in the blue spectrum than aqueous.[3] The fat soluble macula pigments, lutein and zeaxanthin, are thought to protect the macula from photo-oxidative damage. Silicone oil has previously been reported to dissolve fat soluble elements from the retina.[4]

We measured the macular pigment optical density (MPOD) in this case using a modified confocal scanning laser ophthalmoscope and 2-wavelength autofluorescence technique 3 weeks after oil removal. The results showed a substantially reduced MPOD in the eye which had silicone oil compared to the fellow eye. Although the peak MPOD, at the foveal centre, of both eyes was similar (0.47 Right vs. 0.52 Left), the MPOD at half-degree, one-degree and 2-degrees eccentricity from the foveal centre was markedly lower in the eye which had silicone oil (0.12, 0.06, 0.02 respectively vs. 0.40, 0.22, 0.07).

Although MPOD varies greatly between individuals, there is usually high inter-ocular symmetry in normal eyes.[5] Further work is required to determine whether or not this relates to the visual loss and whether therapeutic supplementation, may reduce the risk of visual loss.

References

1. Cazabon S, Groenewald C, Pearce IA, Wong D. Visual loss following removal of intraocular silicone oil. Br J Ophthalmol 2005;89:799-802.

2. Herbert EN, Habib M, Steel D, Williamson TH. Central scotoma associated with intraocular silicone oil tamponade develops before oil removal. Graefe’s Arch Clin Exp Ophthalmol. DOI 10.1007/s00417-005-0076-6.

3. Azzolini C, Docchio F, Brancato R Trabucchi G. Interactions between light and vitreous fluid substitutes. Arch Ophthalmol. 1992;110:1468-1471.

4. Refojo MF, Leong FL, Chung H et al. Extraction of retinol and cholesterol by intraocular silicone oils. Ophthalmology 1998;95:614-8.

5. Bone RA, Sparrock JM.. Comparison of macular pigment densities in human eyes. Vision Res. 1971;11:1057-1064.

Dear Editor,

We read the article 'Bevacizumab and ranibizumab tachyphylaxis in the treatment of choroidal neovascularisation' with interest. We congratulate the authors for trying to establish the efficacy of a promising treatment strategy for Tachyphylaxis to Anti-VEGF drugs in Exudative AMD. We agree with the authors that this could be a useful option in patients who develop tachyphylaxis. However, there are some unanswered questions .

Firstly,the total number of Exudative ARMD patients treated with Lucentis or Avastin in the study period was not provided in the article. This would be useful for calculating the incidence of tachyphylaxis, thus providing information on the magnitude of the problem.

Secondly,although 80-81% subjects responded to switching to the alternate Anti-VEGF group, most of these required multiple injections post intervention. Also, at the end of the study period 11 of the 26 treated eyes had persistent exudation and continued to need therapy. Could this be attributed to tachyphylaxis to the second drug after switching? This may be due to either these subjects being predisposed to developing tachyphylaxis or ill sustained effect of the second anti VEGF drug as a response to chronic blockade of signaling mediated by VEGF. All these issues lead us to question the efficiency and feasibility of switching a patient from one anti-VEGF to another.

We also noted a difference in the response to the two anti-VEGFs. The group switched from bevacizumab to ranibizumab therapy subsequently required a higher number of ranibizumab injections with a mean of 7(1-16) versus 2.75 (1-6) bevacizumab injections in the other group. Though this difference may not be significant due to the relatively small size in each group, it is contrary to expectations since ranibizumab has a much higher binding efficacy to VEGF?.

The long term sustenance of positive effect of switching needs to be studied prospectively before recommending it.

References

1.Gasperini JL, Fawzi AA, Khondkaryan A, Lam L, Chong LP, Eliott D, Walsh AC, Hwang J, Sadda SR. Bevacizumab and ranibizumab tachyphylaxis in the treatment of choroidal neovascularisation. Br J Ophthalmol. 2012 Jan:96(1):14-20.

2.Ferrara N, Damico L, Shams N, Lowman H, Kim R. Development of Ranibizumab, An Anti-vascular endothelial growth actor antigen binding fragment, as therapy for neovascular age-related macular degeneration. Retina2006;26 (8):859-870

Conflict of Interest:

None declared