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Authors’ Response

The origin of spontaneous venous pulsations is controversial. Although classically thought to arise from fluctuations in intraocular pressure during the cardiac cycle, recent evidence suggests that fluctuations in intracranial pressure may be the proximate cause. A recent report found spontaneous retinal venous pulsations to be present in 89.3% of normal adults. In our study, only 25% of children with pseudopapilloedema had spontaneous retinal venous pulsations versus 75% of children in our control group (p1⁄40.0055), demonstrating that the presence or absence of spontaneous retinal venous pulsations is not useful in distinguishing pseudopapilloedema from papilloedema. A potential weakness of this study was that neuroimaging was not performed in all patients with pseudopapilloedema. However, all patients were examined sequentially with photographs used to document the stability of the optic disc appearance. Pseudopapilloedema has been attributed to a tight scleral canal producing axonal crowding and impaired axonal transport. A likely explanation for the lack of spontaneous venous pulsations in pseudopapilloedema is that prelaminar axonal distension can focally impede retinal venous drainage and elevate retinal venous pressure in a similar manner to the increased perioptic cerebrospinal fluid pressure of papilloedema. We have found mild venous distension to be present in almost all children with pseudopapilledema, as shown in figure 1. In further support of this mechanism, it has been reported that optic disc oedema due to anterior ischaemic optic neuropathy or optic neuritis may similarly extinguish spontaneous retinal venous pulsations in the absence of elevated intracranial pressure. Indeed, a recent case report has documented spontaneous retinal venous pulsations confined to the normal optic disc in a patient with unilateral pseudopapilloedema. As pseudopapilloedema is characterised by a diffuse degeneration of optic nerve axons over the patient’s lifetime, this mechanism would predict that spontaneous retinal venous pulsations may reappear in older adults with optic disc drusen. We conclude that the absence of spontaneous venous pulsations should not raise suspicion for the diagnosis of papilloedema in the asymptomatic child with elevated optic discs.

The origin of spontaneous venous pulsations is controversial. Although classically thought to arise from fluctuations in intraocular pressure during the cardiac cycle, 3 recent evidence suggests that fluctuations in intracranial pressure may be the proximate cause. 4 A recent report found spontaneous retinal venous pulsations to be present in 89.3% of normal adults. 5 In our study, only 25% of children with pseudopapilloedema had spontaneous retinal venous pulsations versus 75% of children in our control group (p¼0.0055), demonstrating that the presence or absence of spontaneous retinal venous pulsations is not useful in distinguishing pseudopapilloedema from papilloedema. A potential weakness of this study was that neuroimaging was not performed in all patients with pseudopapilloedema. However, all patients were examined sequentially with photographs used to document the stability of the optic disc appearance.
Pseudopapilloedema has been attributed to a tight scleral canal producing axonal crowding and impaired axonal transport. 6 A likely explanation for the lack of spontaneous venous pulsations in pseudopapilloedema is that prelaminar axonal distension can focally impede retinal venous drainage and elevate retinal venous pressure in a similar manner to the increased perioptic cerebrospinal fluid pressure of papilloedema. We have found mild venous distension to be present in almost all children with pseudopapilledema, as shown in figure 1. In further support of this mechanism, it has been reported that optic disc oedema due to anterior ischaemic optic neuropathy or optic neuritis may similarly extinguish spontaneous retinal venous pulsations in the absence of elevated intracranial pressure. 7 Indeed, a recent case report has documented spontaneous retinal venous pulsations confined to the normal optic disc in a patient with unilateral pseudopapilloedema. 8 As pseudopapilloedema is characterised by a diffuse degeneration of optic nerve axons over the patient's lifetime, 1 this mechanism would predict that spontaneous retinal venous pulsations may reappear in older adults with optic disc drusen.
We conclude that the absence of spontaneous venous pulsations should not raise suspicion for the diagnosis of papilloedema in the asymptomatic child with elevated optic discs.
Incorrect study design and analysis: the effect of genetic variants in SERPING1 on the risk of neovascular age-related macular degeneration The recently published study by Lee et al 1 is described as a retrospective cohort study; however, this is incorrect. The study subjects were selected on the basis of having neovascular age-related macular degeneration (AMD) or not, and the two groups being matched with respect to ethnicity. The frequency of individual genotypes was then compared between the groups. This is not a retrospective cohort study; rather, it is a matched case-control study. Unfortunately, this is not merely a semantic issue as the statistical analysis is also incorrect. The authors' use of t and c 2 tests when comparing demographic and clinical variables between the cases and controls fails to account for the matched nature of the study design; paired t and McNemar's tests should have been used. Additionally, the authors state 'Evaluation of the effects of individual genotypes on the risk of AMD was performed by logistic regression with the normal haplotype dummy coded as reference.' There are two issues of concern here. The first is that conditional logistic regression should have been used in order to account for the matched nature of the study design. The second is that given the casecontrol study design, estimation of AMD risk is not possible. While it is possible to interpret ORs in a case-control study as risk ratios, this is only appropriate when specific conditions are met and it is not clear whether this is the case in the current study. The authors are strongly urged to conduct a reanalysis of their study data and provide readers with the appropriate measures of association and p values, amending their interpretations as warranted.

Authors' response
We would like to take this opportunity to respond to Dr Gerald McGwin's comments regarding our article on the association of SERPING1 polymorphisms with neovascular age-related macular degeneration. 1 2 It appears that a few editorial errors led to the confusion regarding our study design. First, the abstract inappropriately states that our participants were ethnically matched. In the Methods section, we explained that all participants were Caucasian, and no variable was used for matching. Because our study was not of a matched nature, the use of logistic regressions, t tests and c 2 tests in our statistical analysis was appropriate. Second, this caseecontrol study was mistakenly described as a retrospective cohort study in the Methods section. Finally, our use of the term 'risk' in reference to the odds risk ratio may have been misleading. A more accurate description of our findings would be that SERPING1 has a modest effect on the likelihood of neovascular age-related macular degeneration. We would like to apologise for any misunderstanding our wording may have caused as well as to affirm the appropriateness of our data analysis.

Bleeding statistics
I read with interest the recent work by Chandra et al and commend them for collecting such a group of patients, but I wish for clarification on a few points. 1 They described the present work as a retrospective caseecontrol study; I feel that this is incorrect. The patients studied were selected on the basis of an exposure of interest, in this case to warfarin pharmacotherapy and matched with respect to age, sex and presenting complaint. The participants were followed (retrospectively) to record outcomes of pars plana vitrectomy as well as presenting features. Therefore, this study describes a retrospective (or historical) matched cohort study, not a retrospective caseecontrol study. When performing the matching was there a reason that other patient-specific variables, both systemic (blood pressure, liver disease, clotting disorders, medication) and ocular, which could potentially influence the outcome were not controlled for? Could the authors also explain their reasoning for dividing the international normalised ratio (INR) ranges as they have? Most indications for warfarinisation recommend a target range of between 2 and 3; for those with recurrent venous thrombus embolism while on warfarin, mechanical heart prostheses or antiphospholipid antibodies, a higher range of 3e4 may be set. A quarter of patients operated on in this series had INRs that were below the lower suggested range (and therefore at an additional risk of thrombic complications due to underanticoagulation). Were any adverse events relating to subtherapeutic INRs looked for or recorded? Similarly, it may be clinically more relevant to know in the subgroup labelled 'high therapeutic' how many of the 41.3% patients were 'supratherapeutic' (INR>4 or better still outside their personal target range). I can readily accept the authors' conclusion that risk of stopping warfarin treatment probably outweighs any theoretical benefit but that may not be the case should the actual INR lie well above the target. Similar to our Royal College guidelines for cataract surgery, a current safe approach may be one that encourages surgery when the INR is within the therapeutic range for that condition. Further prospective studies may be needed to assess whether there is any additional risk as the INR increases; however, this is likely to show high interpersonal variability as both clinical (age, sex, body surface area, comorbidity, ethnicity and polypharmacy) and genetic (CYP2C9 and VKORC1 polymorphisms) factors have thus far been implicated. 2 Rather than a 'one size fits all' approach, in an era where we are aiming for 'personalised medicine', our best strategy may be to identify those patients at the highest risk of warfarin-related ocular morbidity and weigh this against their individualised risk of thromboembolic disease should the INR be reduced. This would allow for a more informed discussion during the preoperative consent process.
Treatment of non-arteritic anterior ischaemic optic neuropathy I was interested to read the paper by Modarres and colleagues 1 entitled "Intravitreal erythropoietin injection for the treatment of non-arteritic anterior ischaemic optic neuropathy" (NA-AION). The authors have made several misleading statements that require comment.
In my prospective study 2 of visual outcome in 312 patients with NA-AION treated with corticosteroid therapy versus 301 untreated cases, there was a significantly higher visual acuity (p¼0.001) and visual field (p¼0.005) improvement in the treated than the untreated group. Modarres and colleagues commented that the claims of that study are not justified because of "lack of randomization, the retrospective nature of the study and the lack of corroboration via other studies". None of these statements is correct: it was indeed a 'prospective study'; as discussed in detail elsewhere, 2 3 it definitely fulfilled all the scientific criteria of randomisation, and it 2 confirmed the beneficial effect of corticosteroid therapy of two previous preliminary studies. 2 They made two common mythical statements: (a) "The exact etiology and pathogenesis of NAION are not known." and (b) "NAION may have similarities to ischaemic brain diseases". Both statements are not valid. They are perpetuated by clinicians who lack in-depth knowledge of the basic scientific facts about NA-AION. I have discussed the invalidity of both these issues at length elsewhere, 4 based on basic, experimental and clinical (from more than 1000 cases of NA-AION) scientific research about NA-AION. I concluded that "The pathogenesis of NA-AION is complex but not, as often stated, unknown." Pathogenetically, NA-AION and stroke are totally different clinical entities. As discussed elsewhere, 4 stroke is a 'thromboembolic disorder' with occlusion of the involved artery, whereas NA-AION is NOT thromboembolic but a 'hypotensive' disorder. In NA-AION, my fluorescein angiographic studies almost never showed any actual occlusion of arteries to the optic nerve head in more than a thousand fresh NA-AION eyes but simply transient hypoperfusion or non-perfusion of its circulation (except for a rare case where embolism might be responsible for NA-AION). Thus, the two