Dear Editor, we thank West et al. for their interest in our paper. Firstly, we wish to point out that as stated in our paper's conclusion, we fully endorse early surgery in all cases of paediatric & adolescent blowout fracture. We are committed to educating referrers and colleagues in other specialities to recognize & refer these patients as soon as possible. Secondly, West et al claim that we did not adequately highlight patients with white-eyed blowout fractures who they presume have muscle ischaemia and poorer outcomes. Jordan et al's paper on white-eyed blowout fractures postulated that perimuscular soft tissue entrapment causes muscle ischaemia due to a "compartment-type syndrome"1. This remains unproven. Iliff et al's clinical and experimental animal study could not confirm the existence of orbital compartment syndromes in blowout fractures2. They identified direct muscle damage, nerve contusion and incarceration of the muscular fascial network as more likely causes of postoperative diplopia. If muscle ischaemia was present, urgent surgery (within hours) to prevent muscle necrosis would be indicated. Other causes of muscle damage may not require the same degree of urgency. Further information on the causes of diplopia and prospective randomized trials comparing outcomes after various intervals to surgery are required. Until more is known, our stance on white-eyed blowout fractures is not dogmatic: each case is considered individually and surgery is performed as soon as practicable. This approach does not preclude urgent surgery if it is required.

West et al. also stated that our results may have been better if our patients with white-eyed blowout fractures had undergone earlier surgery. They compared our results with three studies 3-5. Unfortunately, each study presents its results differently. We described diplopia on extreme gaze as self-reported or elicited on examination. We consider these children did not have significant diplopia. Ethanadan et al describe a similar group with diplopia as not "relevant" for day to day activites3. Gerbino et al describe three motility outcomes: full extraocular muscle recovery, diplopia in supraduction & vertical diplopia4. They did not state if postoperative diplopia in their cases was functionally significant or elicited on examination only. Bansagi et al used a numerical scale for comparing supraductions before and after surgery instead of reporting on diplopia5. Comparison of our results and those of other studies is difficult. We do not accept that our results are necessarily inferior to other studies' results when consensus on describing motility outcomes is lacking.

1. Jordan DR, Allen LH, White J et al: Intervention within days for some orbital floor fractures: The white-eyed blowout. Ophthal Plast Reconstr Surg 1998;14(6):379-390.

2. Iliff N, Manson PN, Katz J et al. Mechanisms of extraocular muscle injury in orbital fractures. Plast Reconstr Surg 1999;103:787-99

3. Ethunandan M, Evans BT. Linear trapdoor or "white-eye" blowout fracture of the orbit: not restricted to children Br J Oral Maxillofac Surg. 2010 May 12 [Epub ahead of print]

4. Gerbino G et al. Surgical Management of Orbital Trapdoor Fracture in Pediatric Population. J Oral Maxillofac Surg 2010; 68: 1310-1316.

5. Bansagi ZC, Meyer DR. Internal orbital fractures in the pediatric age group: characterization and management. Ophthalmology 2000; 107(5): 829-836.

Conflict of Interest:

None declared

Authors' Reply to Sandberg et al. letter entitled "Lack of scientific rationale for use of valproic acid for retinitis pigmentosa"

Radouil Tzekov 1, Carol Bigelow2, Christine Clemson1, Jenna Checchi1, Mark Krebs3, Shalesh Kaushal1

Author Affiliations

1 Department of Ophthalmology University of Massachusetts Medical School Worcester, MA, USA

2 Division of Biostatistics and Epidemiology/Department of Public Health University of Massachusetts School of Public Health and Health Sciences, Amherst, MA, USA

3 Department of Molecular Genetics and Microbiology, University of Florida Gainesville, FL, USA

Correspondence to: Dr. Shalesh Kaushal Shalesh.Kaushal@umassmemorial.org

Dear Editor, We appreciate the concerns raised by Sandberg et al. in their recent letter1 pertaining to the design and statistical methods of our analysis described in our recent article,2 and we welcome the opportunity to respond to each point raised.

Study Design. We agree that ideally the best, "gold standard" study design would involve the use of matched controls, with matching on eye function at baseline, as we plan to do in our upcoming clinical trial. For preliminary pilot studies, however, other study designs, including methodologies that do not have controls, can also be meaningful, especially when the objectives are to assess treatment potential and establish the equipoise necessary for further investigation in a randomized control study. An example that is relevant to our work is presented by an article from one of the authors of the letter (Rosner et al., 2006; Section 4.1),3 in which the investigators assessed the potential benefit of treatment and concluded that their findings were suggestive of a lack of effect due to treatment. These researchers did not have a control group, yet they felt comfortable with the conclusions based on this design. Our analytical design and findings are consistent with this example. Our focus was an exploration of potential therapeutic value, and our detailed description of visual function in 14 eyes establishes a possible treatment benefit that merits a randomized control trial.

Statistical analysis. We believe that the exploration of treatment potential in a sample size of seven is best addressed with detailed descriptions rather than formal tests of statistical significance. Given that significance levels were reported, however, we agree with Sandberg et al. that the unit of analysis should have taken into account the correlation structure of the data. We thank Dr. Rosner for pointing out the modification of the Wilcoxon Signed Rank Test for use with paired data. We expect to use this modification in future studies that have formal tests of significance as their goal. With respect to our pilot analysis, with this correction, calculated by Dr. Rosner, the statistical significance of the improvements in visual field and visual acuity (p= 0.14 and p=0.06, respectively) no longer meets widely used thresholds (such as p < 0.05), as the Sandberg et al. letter points out. We reason that these p-values, as they pertain to a small sample size setting, do not provide conclusive evidence of the null hypothesis, as the associated confidence intervals of the differences are wide. Accordingly, while we could calculate a corrected analysis of statistical significance, we believe the relevance of our findings to the advancement of treatment for retinitis pigmentosa would be the same. We would also like to note that the calculated p-values for improvement in visual acuity and visual field have been compared to a hypothesis for no change in function. We would expect a comparison to historical controls that experience on average some deterioration in function to have associated p-values that are closer to p <0.05. We observed a potential for treatment benefit that was accompanied by at most modest and tolerable side effects. This is of public health importance as our data contribute to a growing body of literature that collectively suggests the appropriateness of a larger scale study of valproic acid therapy that utilizes randomization and comparisons with controls.

Floor effects. We appreciate the issue of floor effects. In this regard, we wish to note that in our sample, only 1 of the 14 eyes studied exhibited visual acuity of less than 20/200 (logMAR = 1.0). Importantly, even in this case, the visual acuity is only questionably "floor". Visual acuity below 20/200 is routinely measured in clinical settings and when converted to logMAR values, it can be recorded reproducibly to a logMAR of 2.6. Additionally, only 1 out of 14 eyes had a visual field area at baseline, which was < 10% of normal. Thus, only this one eye could be considered for some presence of floor effect. However, even in this case, the increase in visual field area from baseline to follow-up was relatively large (from ~4% to ~10% of normal), so it is unlikely that such an increase happened by chance only. In summary, we feel that floor effect concerns are unjustified in this particular data set.

Comparison with historical data. We understand that one of the goals of relatively large observational studies like the ones cited in our work4,5 is to serve as benchmarks against which subsequent (often much smaller in size) studies can be compared. Of note, testing of the visual field in our work was done exactly the same way as in the two cited works. Also, the population can be regarded as very similar, as in all three cases the patients were referred to a large tertiary center. In this regard, the criticism that we used "different methods" is unjustified. Again, we wish to reiterate that ours was an exploratory analysis that included a comparison of our findings with those of other, independent studies. The utility of our analysis, as with other small-scale studies, is to inform the appropriateness and design of future, large-scale studies. Indeed, we fully support the concept that large-scale clinical trials that enroll a broad diversity of patients are the best tools for inference to a "whole" population.

Relevance to a clinical trial. Retinitis pigmentosa is a very serious disease, there is currently no treatment, and it is devastating for its sufferers. In our opinion, our detailed description of the seven patients' longitudinal data regarding their responses to valproic acid administration is essential to the understanding of its therapeutic potential. Eleven of the 14 eyes (79%) presented in our analysis experienced gains in retinal function, and the probability of this happening by chance is small, even when corrected for clustering, etc. Our conclusion is that these results, together with the findings of similarly conducted independent studies, make a clear case for further study using randomized control trial methodology. We would like to also point out that regarding the lack of a large sample size in our pilot analysis, we are in a similar situation as Dr. Berson and his group faced before the initiation of their clinical trial testing the effects of vitamin A in retinitis pigmentosa in 1984, when the preliminary clinical data were limited to the finding that ERG was lower in 2 out of 18 patients on Vitamin A (11%, no statistical significance presented),6 yet the trial proceeded and established no effect on visual field or visual acuity, but confirmed a small positive effect on ERG (which was the primary endpoint) due to treatment.

Valproic acid side effects. First, our article included the side effects that were reported to us by the patients whose charts we analyzed, as is essential in an exploratory pilot analysis. Second, the Sandberg et al. letter introduces isolated anecdotal evidence regarding valproic acid treatment side effects. Virtually every drug is associated with a myriad of mostly rare side effects that are bound to occur when administered to the general population. However, the correct approach would be to place potential side effects into the context of the drug's potential therapeutic benefits. With respect to valproic acid, this drug was in clinical use in Europe since the mid-1960s, was approved in the United States in 1978 and has met the test of decades of use in the general population. Thus, its side effects are well known. Specifically, it has been clearly established that the frequency and severity of most of the side effects of valproic acid are dose-dependent. The maximum recommended dose in the US is 60 mg/kg/day? (which translates to 4500 mg/day for a 75 kg patient), and this is the dose range where the most (and most severe) side effects appear. In the present analysis, the maximum dose used was ~10 mg/kg/day, which is six times less than the maximum recommended dose. It has been demonstrated that the lower dosing level used in our work is associated with very low frequency and low-grade severity of side effects. Examining the literature reveals that in a study summarizing results of 16 trials and 1140 patients treated with different doses of valproate, side effects were observed in 26% of the patients, but discontinuation of the therapy was required in only 2%.7 Furthermore, in 48 children dosed with 30 mg/kg/day or more of sodium valproate for 22 months, a change in therapy was required in five patients (average dose = ~47 mg/kg/day) and withdrawal was required in two patients (average dose = ~43 mg/kg /day).8 Similarly, in a study that followed up 118 patients for an average period of 18 months on valproate monotherapy on a mean dosage of ~19.4 mg/kg/day, only four patients (3.4%) elected to discontinue treatment.9 Side effects in this last study were observed in 16% of the patients at the time of the first follow-up visit, but only in 2% (excluding weight gain that had stabilized) by the last analyzed follow-up visit.9 Neither hearing loss nor deterioration in vision function was reported in any of the three studies cited above (a combined population of 1306 patients) and, therefore, if associated with the drug intake, should be a very rare occurrence. As mentioned in our article and in our recent letter to the journal,10 we saw very few side effects with the low dose employed in our analysis, and only one patient elected to discontinue treatment. We agree with a recent review that summarized the 30 years of clinical experience with the drug, which stated "Valproate also possesses an impressive safety profile, being well-tolerated in most patients".11

Summary. Although valproic acid has been used for several indications during the past 30+ years, its possible therapeutic effect in retinal degenerative diseases is currently unknown. We believe that the state of knowledge regarding the treatment of retinitis pigmentosa at the inception of our analysis warranted a "pilot analysis" approach to the exploration of valproic acid and a detailed description of individual eyes. We would like to emphasize that the goal of our pilot data analysis was to examine the potential benefit of valproic acid; this analysis provided preliminary data that we believe warrants further investigation in a randomized control study. The initial impression of a therapeutic benefit presented in our analysis can be best clarified in such a clinical trial.12

Sincerely, R. Tzekov C. Bigelow C. Clemson J. Checchi M. Krebs S. Kaushal

References

1. Sandberg MA, Rosner B, Weigel-DiFranco C, Berson EL. Lack of scientific rationale for use of valproic acid for retinitis pigmentosa. British Journal of Ophthalmology, 26 October 2010 (online). 2. Clemson CM, Tzekov, R, Krebs, M, Checchi, JM, Bigelow, C, Kaushal, S. Therapeutic potential of valproic acid for retinitis pigmentosa. British Journal of Ophthalmology. July 20, 2010 [epub ahead of print]. 3. Rosner B, Glynn RJ, Lee ML. The Wilcoxon signed rank test for paired comparisons of clustered data. Biometrics 2006;62(1):185-92. 4. Berson EL, Rosner B, Weigel-DiFranco C, Dryja TP, Sandberg MA. Disease progression in patients with dominant retinitis pigmentosa and rhodopsin mutations. Invest Ophthalmol Vis Sci 2002;43:3027-36. 5. Massof R, Dagnelie G, Benzschawel T, Palmer RW, Finkelstein D. First order dynamics of visual field loss in retinitis pigmentosa. Clin Vision Sci 1990;5:1-26. 6. Berson EL, Rosner B, Sandberg MA, Hayes KC, Nicholson BW, Weigel- DiFrano C, Willett W. Vitamin A supplementation for retinitis pigmentosa. Arch Ophthalmol 1993;111(11):1456-9. 7. Schmidt, D. Adverse effects of valproate. Epilepsia ZS (Supp1.1) 1984:S44-S49. 8. Herranz, JL, Arrnijo, JA, Arteaga, R. Effectiveness and toxicity of phenobarbital, primidone, and sodium valproate in the prevention of febrile convulsions, controlled by plasma levels. Epilepsia 1984;25(1):89- 95. 9. Bourgeois, B, Beaumanoir, A, Blajev, B, de la Cruz N, Despland PA, Egli M, Geudelin B, Kaspar U, Ketz E, Kronauer C, et al. Monotherapy with valproate in primary generalized epilepsies. Epilepsia (Suppl. 2) 1987:28:S8-SI I. 10. Kaushal, S, Clemson, C, Tzekov, R, Krebs, M, Checchi, J. Re: conclusions of Clemson et al. concerning valproic acid are premature. 20 September 2010 [epub ahead of print]. 11. Peterson, GM, Naunton, M. Valproate: a simple chemical with so much to offer. Journal of Clinical Pharmacy and Therapeutics 2005;30:417-421. 12. ClinicalTrials web site. Trial entry: NCT01233609. http://clinicaltrials.gov/ct2/results?term=NCT01233609

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Competing Interest: None to declare.

Conflict of Interest:

None declared

Ryan and Margrain's letter highlights some key findings from a report they conducted on behalf of the Thomas Pocklington Trust. 1 They found that there are many people in Wales requiring visual rehabilitation who do not meet the current criteria for certification as visually impaired. They found also that there had been poor uptake in Wales of systems which were designed to support those who need aid who do not meet such guidelines (the LVL and the RVI). These are important findings that need airing and discussion, but are they really findings that should call into question the value of a system that has facilitated support to visually impaired individuals in need since 1920? This is implied by the title which is perhaps misleading and does not reflect the content of the letter. It should be noted that this study also reported that just under 14 % of those with registrable visual acuities were not registered and were not known to social services. These data are in line with those reported by Tate et al in a report commissioned by the RNIB which estimated that 89 % of people over 75 years of age who were eligible for registration were indeed registered.

1. Ryan B Margrain TH, Reidy A et al. All Wales Visual Impairment Database (AWVID). Occasional paper number 24. London: Thomas Pocklington Trust. 2009 2. Tate R, Smeeth L, Evans J, Fletcher A, Owen C, Rudnicka A The prevalence of visual impairment in the UK. A review of the literature. Report commissioned by the RNIB.

Conflict of Interest:

Currently hold a grant to collect and analyse certification data for England & Wales

Conflict of Interest:

None declared