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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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exclusive for government employees) on a worldwide basis to the BMJ
Publishing Group Ltd and its Licensees to permit this article (if
accepted) to be published in BJO editions and any other BMJPGL products to
exploit all subsidiary rights, as set out in our
licence(http://group.bmj.com/products/journals/instructions-for-
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Lack of Scientific Rationale for Use of Valproic Acid for Retinitis
Pigmentosa
Michael A. Sandberg, Ph.D., Bernard Rosner, Ph.D., Carol Weigel-
DiFranco, Eliot L. Berson, M.D.
Corresponding author:
Michael A. Sandberg, Ph.D.
Berman-Gund Laboratory, Harvard Medical School
243 Charles Street
Boston, Massachusetts 02114
USA
Email: Michael_sandberg@meei.harvard.edu
Telephone: 617-573-3605
FAX: 617-573-3216...
Lack of Scientific Rationale for Use of Valproic Acid for Retinitis
Pigmentosa
Michael A. Sandberg, Ph.D., Bernard Rosner, Ph.D., Carol Weigel-
DiFranco, Eliot L. Berson, M.D.
Corresponding author:
Michael A. Sandberg, Ph.D.
Berman-Gund Laboratory, Harvard Medical School
243 Charles Street
Boston, Massachusetts 02114
USA
Email: Michael_sandberg@meei.harvard.edu
Telephone: 617-573-3605
FAX: 617-573-3216
Author affiliations: Berman-Gund Laboratory for the Study of Retinal
Degenerations, Harvard Medical School, Massachusetts Eye and Ear
Infirmary, Boston, Massachusetts, USA
The Corresponding Author has the right to grant on behalf of all
authors and does grant on behalf of all authors, an exclusive licence on a
worldwide basis to the BMJ Publishing Group Ltd and its Licensees to
permit this article (if accepted) to be published in BJO editions and any
other BMJPGL products to exploit all subsidiary rights, as set out in our
licence.
Competing Interest: None to declare
Key words: retinitis pigmentosa, valproic acid
Word count for text: 273
"Therapeutic potential of valproic acid for retinitis pigmentosa," by
CM Clemson, R Tzekov, M Krebs, JM Checchi, C Bigelow, and S Kaushal has
significant flaws that mitigate against their conclusion that short-term
valproic acid improved the vision of patients with retinitis pigmentosa
(RP).
The investigators should have performed a case-control study,
comparing patients taking valproic acid to control patients matched for
baseline field and acuity. This would have allowed for possible floor
effects due to the low baseline function of some of the treated patients
(i.e., who might be more likely to improve rather than decline over follow
-up by chance variability) and avoided their use of historical rates of
change drawn from different populations tested by others with different
methods.
Statistical analyses should have been performed on patients, instead
of eyes, unless controlling for the intraclass correlation between fellow
eyes of the same patient. A reanalysis of their results by the signed-rank
test for cluster-correlated data1 reveals weaker effects for visual field
improvement (e.g., p = 0.14 versus no change) and visual acuity
improvement (e.g., p = 0.06 versus no change) in their cohort. In fact,
none of the presented comparisons was statistically significant with this
test.
The authors did not cite published side effects of valproic acid
(e.g., constipation, diarrhea, and hearing loss). Among patients given
valproic acid elsewhere, one reported to us a further impairment of
hearing and no visual improvement after taking this drug for several
weeks. Another showed decline in retinal function while on this drug for
one year.
We believe that the above-named report does not provide a scientific
rationale for the clinical trial that the authors recommend.
Michael A. Sandberg, Ph.D.
Bernard Rosner, Ph.D.
Carol Weigel-DiFranco, M.A.
Eliot L. Berson, M.D.
Reference
1Rosner B, Glynn RJ, Lee ML. The Wilcoxon signed rank test for paired
comparisons of clustered data. Biometrics 2006;62:185-192.
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...
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
As a research group with no commercial interest in any macular
pigment optical density (MPOD) measurement devices, or nutritional
supplements, we feel that we were well-placed to carry out this
independent clinical assessment of the reliability of MPS 9000. Our study
was prompted by the fact that we could find no reported coefficient of
repeatability value within the literature, and none was provided by the
manufacturer...
As a research group with no commercial interest in any macular
pigment optical density (MPOD) measurement devices, or nutritional
supplements, we feel that we were well-placed to carry out this
independent clinical assessment of the reliability of MPS 9000. Our study
was prompted by the fact that we could find no reported coefficient of
repeatability value within the literature, and none was provided by the
manufacturer. We had planned to use this instrument in our own research
studies investigating the impact of nutritional supplementation on MPOD.
For this purpose, we needed to know the level of MPOD change that could be
considered clinically significant. We felt that this information would
also be useful to other clinicians who had already purchased the
instrument, or were thinking of doing so.
In our study MPOD measurements were obtained as per the manufacturer
guidelines (MPOD Reference Guide and Technician Training). We were careful
to follow these instructions in the same way as a clinician would in
practice, as our aim was to assess the reliability of the MPS 9000 in a
clinical environment. Dr Murray and colleagues have provided a coefficient
of repeatability value in their letter. However, we would suggest that
this low value has been achieved by using data screening methods that are
not discussed in the operation manual that we were provided with. As such,
this may not be a true reflection of the level of repeatability that would
be achieved in ophthalmological or optometric practice, but may be more
applicable to researchers working in this area.
We do not consider the reference that Dr Murray and colleagues make
to the correlation between the MPS 9000 and other methods of MPOD
measurement to be relevant. This is not what we set out to assess; we
wanted to analyse the level of noise within MPOD measurements using the
MPS 9000. To illustrate this point, we carried out correlation analysis on
our repeat readings and found that for all four comparisons the
relationship between the two data sets was highly significant
(p<0.001). The variability between the two data sets ranges from 3-
15%. The important point here is that there may be little variability
between two data sets, and the two data sets may also be significantly
correlated, but this does not mean that there is no instrument noise. The
clinically significant change in MPOD over time could only be determined
by calculating the coefficient of repeatability.
The reference that Dr Murray and colleagues make to the measurement
of repeatability reported by van der Veen in 2009 is also irrelevant, as
this group reported a correlation coefficient, mean test-retest
variability, and a percentage value calculated by dividing the mean of the
differences by the mean value of the two estimates. None of these values
can be directly compared with our coefficient of repeatability.
Dear editor,
I read with interest Catederal et alÃâââìâââs study on the use of polymerase chain reaction (PCR) for detection of Mycobacterium tuberculosis in donor corneal tissues.1 The authors report the presence of M. tuberculosis DNA in donor corneas of patients with no documented history of tuberculosis. However there are several methodological erro...
Dear editor,
I read with interest Catederal et alâ€â„¢s study on the use of polymerase chain reaction (PCR) for detection of Mycobacterium tuberculosis in donor corneal tissues.1 The authors report the presence of M. tuberculosis DNA in donor corneas of patients with no documented history of tuberculosis. However there are several methodological errors in the study which need to be discussed. The most significant flaw is the lack of biological plausibility for the presence of M. tuberculosis in the corneal tissue, which is not known to contain any phagocytic cells, except probably at the limbus. The authors have not mentioned the size of the donor corneal button or the degree of corneal vascularization at the limbus. A large corneal button or presence of significant corneal vascularization could account for the detection of mycobacterial DNA in corneal tissue. Besides, the possibility of â€ËÅ“contaminationâ€â„¢ of the corneal surface by the aqueous cannot be ruled out.
Even then, the high incidence of M. tuberculosis DNA in â€ËÅ“TB-negativeâ€â„¢ eyes remains unexplained. The authors make a passing reference to the use of positive and negative controls during each amplification reaction, but the nature of these controls or the outcomes after amplification are not mentioned. Did the authors get accurate results with each of the controls? The basis for selection of non-TB donors is also vague as the authors have pointed out themselves. Finally, the authors refer to the low incidence of ocular tuberculosis (1-2%) in patients with pulmonary tuberculosis. However, it is well known that ocular tuberculosis is very rarely seen in patients with systemic tuberculosis.2 Hence the overall incidence of ocular tuberculosis â€â₁“ isolated, as well as in association with systemic tuberculosis, needs to be mentioned. To summarize, the issues highlighted by this study need to reviewed in light of the methodological errors and lack of biological plausibility.
Soumyava Basu
References:
1. Catedral EJ, Santos RE, Padilla MD, Fajardo-Ang C. Detection of Mycobacterium tuberculosis in corneas from donors with active tuberculosis disease through polymerase chain reaction and culture. Br J Ophthalmol. 2010;94:894-7
2. Donahue HC. Ophthalmologic experience in a tuberculosis sanatorium. Am J Ophthalmol. 1967;64:742-8
We appreciate the interest of Van Schooneveld et al.1 in our recent
BJO article.2 Our small, retrospective chart review of RP patients treated
off-label with valproic acid is only the first step in the process of
understanding the potential utility of the drug for patients with this
sight-threatening condition, for which there are no current therapeutic
options.
We appreciate the interest of Van Schooneveld et al.1 in our recent
BJO article.2 Our small, retrospective chart review of RP patients treated
off-label with valproic acid is only the first step in the process of
understanding the potential utility of the drug for patients with this
sight-threatening condition, for which there are no current therapeutic
options.
The size and the scope of our article was limited by the nature of a
retrospective chart review, which only allows analysis of follow-up that
occurred within the defined time frame. Additional factors limiting the
scope and length of the study included (1) the logistical and financial
complexity involved in following up patients in two geographically
separated states; (2) the differences in available equipment in the two
institutions; and (3) the importance of sharing a potential new treatment
with the ophthalmic community sooner rather than later.
The retrospective chart review process was begun while the senior
author was at the University of Florida, and because he moved from Florida
to Massachusetts, the analysis was carried out in Massachusetts and
appropriate Institutional Review Board approval from the Massachusetts
site was published in the article.
The valproic acid treatment regimen analyzed retrospectively in the
charts of the seven patients is detailed in the article. Prospective
follow-up was not done, nor is it allowed under the mandate of a
retrospective chart review. To clarify, the treatment of patients with
valproic acid has not been stopped for any of the patients who tolerated
it well (most of the patients). Our retrospective chart review reported on
in the BJO article captured a relatively short period for a slowly
progressive condition like RP, and we recognize that the most rigorous
validation of a therapy will be a well-designed clinical trial. A
prospective, multicenter, randomized, placebo-controlled clinical trial is
in the final stages of preparation3 in the U.S., and we will be
registering this clinical trial very soon at the U.S. clinical trials
website, www.clinicaltrials.gov.
On a separate note, as part of our current clinical practice in
Massachusetts, several RP patients new to our practice have been treated
with valproic acid; our clinical impressions of these new patients are
similar to what was reported in our article.
There is mounting evidence that valproic acid may have potent
neuroprotective properties and have other beneficial effects,4-6 and we
have intensive in vitro and in vivo experiments (including mice models of
RP) underway. The results of our experiments in the context of retinal
degenerative conditions have been reported at recent meetings.7-11 We are
planning to submit these data as articles to peer-reviewed journals.
Our work has been motivated by the spirit of translational research,
with the goal of more quickly identifying a promising therapeutic approach
and stimulating scientific interest and further research, based on
preclinical data and unexpectedly positive vision function observed in a
clinical setting. Repurposing drugs such as valproic acid, which have been
shown to be safe, is an economical and time-efficient way to bring new
treatments to patients.
Sincerely
C. Clemson
R. Tzekov
M. Krebs
J. Checchi
S. Kaushal
References:
1. Van Schooneveld MJ, Van den Born LI, Van Genderen M, Bollemeijer J
-G. Conclusions of Clemson et al. concerning Valproic Acid are premature
(letter). British Journal of Ophthalmology 25 August 2010.
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 -
doi: 10.1136/bjo.2009.175356]
3. See web page at:
http://www.umassmed.edu/VALPROIC_ACID_SHOWN_TO_HALT_VISION_LOSS_IN_PATIENTS.aspx
4. Monti B, Polazzi E, Contestabile A. Biochemical, molecular and
epigenetic mechanisms of valproic acid neuroprotection. Curr Mol
Pharmacol. 2009 Jan;2(1):95-109.
5. Suuronen T, Nuutinen T, Ryhanen T, et al. Epigenetic regulation of
clusterin/apolipoprotein J expression in retinal pigment epithelial cells.
Biochem Biophys ResCommun 2007;357:397-401.
6. Yasuda S, Liang MH, Marinova Z, et al. The mood stabilizers
lithium and valproateselectively activate the promoter IV of brain-derived
neurotrophic factor in neurons. Mol Psychiatry 2009;14:51-59.
7. S Kaushal, SM Noorwez, R Tzekov, D Huang, Y Li, RWen. The Effect of
Valproic Acid in Mouse Models of RP. Invest. Ophthalmol. Vis. Sci. 2010
51: E-Abstract 3735.
8. SM Noorwez, S Kaushal. Dose-Dependent Differential Effect of HDAC
Inhibitors on Yields of Folded P23H and WT Rhodopsin. Invest. Ophthalmol.
Vis. Sci. 2010 51: E-Abstract 5979.
9. SJ Upadhyay, JA Hossain, MP Krebs, P Baciu, S Kaushal. Effect of
HDAC Inhibitors on Oxidative Apoptosis of RPE Cells. Invest. Ophthalmol.
Vis. Sci. 2010 51: E-Abstract 496.
10. GB Peters, III, T Banzon, A Maminishkis, SS Miller, and S
Kaushal. Valproic Acid Decreases Retinal Thickness in AMD Patients and
Increases Fluid Absorption Across Human Retinal Pigment Epithelium in
vitro. Invest. Ophthalmol. Vis. Sci. 2010 51: E-Abstract 4957.
11. S Noorwez, S Kaushal. Dose-Dependent Differential Effect of HDAC
Inhibitors on Yields of Folded Rhodopsin. XIX Biennial meeting of the
International Society of Eye Research (ISER), Montreal, Canada. Abstract
797.
Dear Sir,
With great interest we read the article of Clemson et al. about a new
treatment for retinitis pigmentosa (RP). However, the authors' claim that
their data suggest that valproic acid (VPA) may be an effective treatment
for RP is unfounded and also regrettably misleading for the many desperate
RP-patients. In fact, we are surprised that the editors of the BJO have
published this study in its present form.
Firstly,...
Dear Sir,
With great interest we read the article of Clemson et al. about a new
treatment for retinitis pigmentosa (RP). However, the authors' claim that
their data suggest that valproic acid (VPA) may be an effective treatment
for RP is unfounded and also regrettably misleading for the many desperate
RP-patients. In fact, we are surprised that the editors of the BJO have
published this study in its present form.
Firstly, the design of the study as well as the medical ethical approval
(approved in Massachusetts, but conducted in Florida) is obscure: why were
the patients treated only for a very short time (2 to 6 months), while RP
is a slowly progressive chronic condition? Why were only 7 patients
treated and described as the results were as promising as the authors
claimed? Why was the treatment stopped, as there were no or few side
effects and what happened after the treatment was stopped?
Secondly, the theoretical action of VPA on the dysfunctional
photoreceptors is unsatisfactorily explained and no experimental data on
retinal tissue are provided. Why was the treatment not tested on rats or
mice with RP? In view of the limited life span of these animals,
unequivocal data on the efficacy of VPA could have been provided.
Thirdly, the authors announce their intention to start a controlled
clinical trial with VPA, but no such trial has been registered yet at the
Current Controlled Trials Register. For the RP-patients longing for
treatment, this is very disappointing, to say the least.
Dear Editor,
we have read with great interest the article of Skoloudik and coworkers on
the use of optic nerve ultrasonography in patients with intracranial
hemorrhage (ICH). The primary goal of this study was to investigate the
variations of the optic nerve sheath diameter (ONSD) early after the onset
of ICH. The authors should be commended for pointing out our interest
towards a new parameter (the relative difference be...
Dear Editor,
we have read with great interest the article of Skoloudik and coworkers on
the use of optic nerve ultrasonography in patients with intracranial
hemorrhage (ICH). The primary goal of this study was to investigate the
variations of the optic nerve sheath diameter (ONSD) early after the onset
of ICH. The authors should be commended for pointing out our interest
towards a new parameter (the relative difference between the ONSD measured
3 mm and 12 mm behind the optic disc), which proved to be more sensitive
than the absolute ONSD measurement as a predictor of elevated intracranial
pressure (EICP). However, we would like to outline two important
limitations of the study.
1. The use of CT scan imaging as the standard criterion to assess EICP is
relatively non-specific as patients with similar pictures may have
significantly different levels of ICP depending on several concurrent
factors (e.g. Sedation, hyperosmolar therapy, ventilation, intracranial
compliance). Moreover, although the resistance index in the MCA, as
measured with TCDS, is often related to ICP, it cannot discriminate
between EICP and cerebral vasospasm (1,2).
2. When considering the ONSD relative enlargement, which is a
submillimetric value, one should take the error of measurement into
account. Specifically, the current study finds a 95th percentile of ONSD
relative enlargement of 0.22 mm in healty volunteers, which is below the
median interobserver ONSD difference of other studies (3). Furthermore, to
the best of our knowledge, no previous study has systematically
investigated the ONSD interobserver variability 12 mm behind the globe.
Finally, previous studies have found that, unlike the oedema of the optic
disc, the retrobulbar ONSD is a dynamic parameter which varies almost
concurrently with changes in cerebrospinal fluid pressure (4,5).
Therefore, it is not surprising that the retrobulbar ONSD and its derived
parameters are changed in the hyperacute phase of ICH.
1. Stocchetti N. Could intracranial pressure in traumatic brain
injury be measured or predicted noninvasively? Almost. Intensive Care Med
2007;33:1682-3
2. Rasulo FA, De Peri E, Lavinio A. Transcranial Doppler ultrasonography
in intensive care. Eur J Anaesthesiol Suppl. 2008;42:167-73
3. Shah S, Kimberly H, Marill K, Noble VE. Ultrasound techniques to
measure the optic nerve sheath: is a specialized probe necessary? Med Sci
Monit 2009;15/5):MT63-8
4. Hansen HC, Helmke K. Validation of the optic nerve sheath response to
changing cerebrospinal fluid pressure: ultrasound findings during
intrathecal infusion tests. J Neurosurg 1997;87:34-40
5. Moretti R, Pizzi B, Cassini F, Vivaldi N. Reliability of optic nerve
ultrasound for the evaluation of patients with spontaneous intracranial
hemorrhage. Neurocrit Care 2009;11:406-10
Editor, I read the recent publication by Awan et al. with a great
interest [1]. Awan et al. concluded that "As compliance has been
identified as a major problem methods to improve amblyopia treatment are
needed, possibly by using educational/motivational intervention [1]."
Recently, Lee et al. proposed that
"Poor compliance with occlusion therapy was less likely to achieve
successful outcome [2]." Indeed, "how complianc...
Editor, I read the recent publication by Awan et al. with a great
interest [1]. Awan et al. concluded that "As compliance has been
identified as a major problem methods to improve amblyopia treatment are
needed, possibly by using educational/motivational intervention [1]."
Recently, Lee et al. proposed that
"Poor compliance with occlusion therapy was less likely to achieve
successful outcome [2]." Indeed, "how compliance can be enhanced" is the
topic to be discussed in management of amblyopia [3]. I have a question
whether the using of educational interventional will be successful. As a
simple process without long period for educational session, the compliance
is still low. How can we expect on the additional process? Karlica et al.
recently noted that "Frequent ophthalmologic follow ups are mandatory to
be sure that therapy is performed correctly and to prevent the possible
unfavorable effects of noncompliance [4]."
References
1. Awan M, Proudlock FA, Grosvenor D, Choudhuri I, Sarvanananthan N,
Gottlob I. An audit of the outcome of amblyopia treatment: a retrospective
analysis of 322 children. Br J Ophthalmol. 2010 Aug;94(8):1007-11.
2.Lee CE, Lee YC, Lee SY. Factors influencing the prevalence of amblyopia
in children with anisometropia. Korean J Ophthalmol. 2010 Aug;24(4):225-9.
3. Holmes JM, Repka MX, Kraker RT, Clarke MP. The treatment of amblyopia.
Strabismus. 2006 Mar;14(1):37-42.
4. Karlica D, MatijeviÃÆ’ƒÃ¢Â€ÂžÃƒÃ†’‚‡ S, GaletoviÃÆ’ƒÃ¢Â€ÂžÃƒÃ†’‚‡
D, Znaor L. Parents' influence on the treatment of amblyopia in children.
Acta Clin Croat. 2009 Sep;48(4):427-31.
Dear Editor,
We thank Authors S.C. Carroll et al for their interesting paper on the
Outcomes of orbital blowout fracture surgery in children and adolescents.1
We agree that autonomic symptoms of nausea and vomiting should alert the
clinician to the high likelihood of significant orbital trauma. This
study shows that the overall outcomes for all patients under the age of 20
were good despite delays. However, this is a hete...
Dear Editor,
We thank Authors S.C. Carroll et al for their interesting paper on the
Outcomes of orbital blowout fracture surgery in children and adolescents.1
We agree that autonomic symptoms of nausea and vomiting should alert the
clinician to the high likelihood of significant orbital trauma. This
study shows that the overall outcomes for all patients under the age of 20
were good despite delays. However, this is a heterogeneous group of
patients with orbital floor fractures with and without entrapment. We are
concerned that young patients with muscle entrapment (white eye blow out
fracture) who are at risk of ischemia are not being highlighted in this
paper.
The data in this series does support early intervention for the two
subgroups of trapdoor fractures. These groups included 6 patients with
open trapdoor fractures and 6 patients with linear closed trapdoor and in
which there is a greater risk of presumed muscle ischemia and poorer
outcome. Follow up data was only available for 4 of the 6 linear closed
trapdoor fractures, all of whom received their surgical intervention
within 2 weeks (2 within 2 days); the one that fully recovered did not
have entrapment of their inferior rectus in the fracture and the other 3
were left with residual diplopia in extreme gaze. Those patients with open
trapdoor fractures all had surgery within 8 days and all but 1 regained
full ductions but not all were symptom free. As per your comments in the
discussion, the depressed plate fractures are lower risk and indeed did
have good outcomes despite delayed surgery. In fact, in this series the
significant delays were in this patient group and the trapdoor fractures
were all operated on within 2 weeks.
Previous studies have shown that intervention within 14 days results in
complete recovery of supraductions 2. More recent studies have shown
intervention within 7 days3 or within 24 hours4 also gives complete
resolution of any symptoms of diplopia.
We, therefore, feel it important to highlight that your data does support
intervention for trapdoor fractures within 2 weeks (median 4 days) and we
feel it is possible that some of these patients may have been completely
symptom free if operated on earlier. We would encourage colleagues to
operate on these patients as soon as possible to not only maximise
potential recovery but also to alleviate any vagal symptoms.
1. Carroll SC, Ng SGJ. Outcomes of orbital blowout fracture surgery
in children and adolescents. Br J Ophthalmol 2010; 94: 736-739
2. Bansagi ZC, Meyer DR. Internal orbital fractures in the pediatric
age group: characterization and management. Ophthalmology 2000; 107(5):
829-836.
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.
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/D...
Lack of Scientific Rationale for Use of Valproic Acid for Retinitis Pigmentosa
Michael A. Sandberg, Ph.D., Bernard Rosner, Ph.D., Carol Weigel- DiFranco, Eliot L. Berson, M.D.
Corresponding author: Michael A. Sandberg, Ph.D. Berman-Gund Laboratory, Harvard Medical School 243 Charles Street Boston, Massachusetts 02114 USA Email: Michael_sandberg@meei.harvard.edu Telephone: 617-573-3605 FAX: 617-573-3216...
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...
As a research group with no commercial interest in any macular pigment optical density (MPOD) measurement devices, or nutritional supplements, we feel that we were well-placed to carry out this independent clinical assessment of the reliability of MPS 9000. Our study was prompted by the fact that we could find no reported coefficient of repeatability value within the literature, and none was provided by the manufacturer...
Dear Editor,
We appreciate the interest of Van Schooneveld et al.1 in our recent BJO article.2 Our small, retrospective chart review of RP patients treated off-label with valproic acid is only the first step in the process of understanding the potential utility of the drug for patients with this sight-threatening condition, for which there are no current therapeutic options.
The size and the scope of...
Dear Sir, With great interest we read the article of Clemson et al. about a new treatment for retinitis pigmentosa (RP). However, the authors' claim that their data suggest that valproic acid (VPA) may be an effective treatment for RP is unfounded and also regrettably misleading for the many desperate RP-patients. In fact, we are surprised that the editors of the BJO have published this study in its present form. Firstly,...
Dear Editor, we have read with great interest the article of Skoloudik and coworkers on the use of optic nerve ultrasonography in patients with intracranial hemorrhage (ICH). The primary goal of this study was to investigate the variations of the optic nerve sheath diameter (ONSD) early after the onset of ICH. The authors should be commended for pointing out our interest towards a new parameter (the relative difference be...
Editor, I read the recent publication by Awan et al. with a great interest [1]. Awan et al. concluded that "As compliance has been identified as a major problem methods to improve amblyopia treatment are needed, possibly by using educational/motivational intervention [1]." Recently, Lee et al. proposed that "Poor compliance with occlusion therapy was less likely to achieve successful outcome [2]." Indeed, "how complianc...
Dear Editor, We thank Authors S.C. Carroll et al for their interesting paper on the Outcomes of orbital blowout fracture surgery in children and adolescents.1 We agree that autonomic symptoms of nausea and vomiting should alert the clinician to the high likelihood of significant orbital trauma. This study shows that the overall outcomes for all patients under the age of 20 were good despite delays. However, this is a hete...
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