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Clinical science
Long-term follow-up for efficacy and safety of treatment of retinitis pigmentosa with valproic acid
  1. Sheena Bhalla1,
  2. Deval Joshi2,
  3. Shaminder Bhullar2,
  4. Daniel Kasuga2,
  5. Yeonhee Park3,
  6. Christine N Kay2
  1. 1University of Florida, College of Medicine, Gainesville, Florida, USA
  2. 2Department of Ophthalmology, University of Florida, Gainesville, Florida, USA
  3. 3Department of Statistics, University of Florida, Gainesville, Florida, USA
  1. Correspondence to Dr Christine N Kay, Department of Ophthalmology, University of Florida, PO Box 100284, Gainesville, FL 32610-0284, USA; ckay{at}ufl.edu

Abstract

Aims The purpose of this study was to determine the long-term efficacy and safety of valproic acid (VPA) treatment in patients with pigmentary retinal dystrophies.

Methods A retrospective chart review was conducted on 31 patients with a diagnosis of pigmentary retinal dystrophy prescribed VPA at a single centre. Visual field (VF), visual acuity (VA), length of treatment, liver enzymes and side effects were analysed. VF areas were defined using Goldmann VF (GVF) tracings recorded before, during and after VPA treatment using the V4e isopter for each eye. Using custom software, planimetric areas of VF were calculated.

Results Five of the patients (10 eyes) had two Goldmann VF tracings, allowing comparison between baseline and follow-up VF. After 9.8 months of VPA, VF decreased by 0.145 cm2 (26.478%) (p=0.432). For 22 of the patients (41 eyes), VA data was available, and logarithm of the minimum angle of resolution (logMAR) score changed by 0.056 log units (representing a decline in VA) after 14.9 months on VPA (p=0.002). Twelve patients (38.7%) reported negative side effects related to VPA use.

Conclusions VPA plays a complex role in patients with pigmentary retinal dystrophies and may be associated with VA and field decline as well as adverse side effects. Physicians should use caution with using VPA for pigmentary retinal dystrophies.

  • Retina

https://doi.org/10.1136/bjophthalmol-2013-303084

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    Introduction

    Retinitis pigmentosa (RP) is an inherited retinal dystrophy that is classically associated with nyctalopia and loss of peripheral vision. Ultimately, RP can lead to central vision loss due to progressive degeneration of rod and cone photoreceptor cells.1 RP is usually non-syndromic but more than 30 syndromic forms exist.2 The worldwide prevalence of RP is approximately 1 in 4000. Most cases of RP are familial, with approximately 50–60% cases inherited in an autosomal recessive pattern, 30–40% autosomal dominant and 5–15% X linked recessive.1 The disease is heterogeneous genetically, and over 45 genes for RP have been identified.1

    The diverse range of genes responsible for RP has made targeted therapy difficult. Research indicates that nutritional interventions, such as vitamin A palmitate3 ,4 and docosahexaenoic acid, an omega-3 fatty acid,5 may slow progression of the disease in some forms of RP, yet benefits from these supplements are modest. The role of vitamin A therapy in treatment of RP has been controversial. Some authors have expressed concern that minimal treatment effects noted in electroretinography tracings in Vitamin A treated patients may not represent meaningful visual gain.6 Neuroprotection is another mode of treatment, with several ongoing trials evaluating ciliary neurotrophic growth factor for treatment of RP.7 Proof of concept studies in animal models suggest potential meaningful gene therapy treatment for X linked RP8 and autosomal dominant RP,9 but the multiple genetic defects reported in autosomal recessive RP make this a challenging target for gene therapy efforts.

    Recently, valproic acid (VPA) has been discussed as a potential treatment for RP. VPA is typically used as an anticonvulsant and mood stabiliser, and it is known to cause GABA inhibitory effects in the central nervous system.10 ,11 In 2011, Clemson et al12 published a retrospective study to examine the efficacy and safety of off-label short-term treatment with VPA in patients seen at the University of Florida with RP. Their rationale for a possible role for VPA in treatment of RP was based on a heterologous cell culture screen of retinoids and small molecules that could increase the yield of properly folded mutant rhodopsins.12 ,13 This improvement in proper folding suggested a potential treatment for autosomal dominant RP, which is associated with improperly folded mutant rhodopsin. In addition, prior studies suggested that VPA may provide neuroprotection and downregulate the photoreceptor-specific inflammatory response pathway via apoptosis of microglial cells.14 ,15 Based on this in vitro data, it was hypothesised that VPA may be an appropriate therapy for patients with retinal dystrophies.

    Clemson et al12 found that five out of seven patients with RP had an improvement in visual fields (VFs) after an average of 4 months of oral VPA treatment. The dosage of VPA varied from 500 mg/day to 750 mg/day, which is lower than the usual dosage for anticonvulsant therapy. Two patients experienced worsening of their VF. The researchers also observed an overall increase in visual acuity (VA) upon VPA treatment. Though VPA is known for side effects such as vomiting, constipation and rash,11 the researchers stated that liver function and blood chemistries were normal and most common side effects included fatigue (10%) and stomach irritation (13%).12

    While the results of this study seem promising, the follow-up was short and the duration of treatment with VPA was brief (average 4 months), and it has been suggested that these findings may have been premature or misleading.16–18 Recently, Sisk et al17 noted that VPA treatment in RP not associated with a dominant pedigree was associated with a decline in VA and intolerable side effects, and this author suggests that treatment with VPA may not be appropriate for all genotypes. The seminal work by Clemson has been a motivating force behind a multicentre, randomised controlled phase II clinical trial to evaluate the safety and efficacy of oral VPA in patients with dominant forms of RP (NLM Identifier NCT01233609).

    The purpose of our study was to further examine the safety and efficacy of long-term VPA use in patients with RP and other retinal degenerative disorders that had been offered off-label use of this drug by a previous investigator at the University of Florida. More recently, after a transition in faculty and change in practice patterns at this institution, any patients currently seen at the University of Florida who had not already self-terminated use of VPA were asked to stop this drug until the release of prospective data on safety and efficacy. In response to criticisms that the findings reported by the previous investigator were premature,18 we wanted to further investigate and provide long-term follow-up on all of the patients at our institution who had been offered off-label use of VPA for various retinal dystrophies, including patients whose findings after short duration treatment had been previously reported.12 After obtaining institutional review board approval, we conducted a retrospective chart review of all patients with retinal dystrophies who had been prescribed VPA at the University of Florida Ophthalmology Department clinic between January 2009 and April 2012.

    Methods

    This study was a retrospective, non-randomised chart review of patients with the diagnosis of pigmentary retinal dystrophy (ICD code 362.74), who were offered off-label use of VPA. Our study was approved by the institutional review board for human subjects’ research at the University of Florida and adhered to the tenets set forth in the Declaration of Helsinki. Between January 2009 and April 2012, 31 patients were prescribed VPA by a previous investigator at the University of Florida Ophthalmology Department for a range of retinal dystrophies, including RP (n=21), rod-cone dystrophy (RCD) (n=3), cone dystrophy (n=3), Stargardt disease (n=3) and Leber congenital amaurosis (n=1) (none of the patients were genotyped). The length of treatment varied from 1 month to 57 months, and the dosage varied from 500 mg/day to 1000 mg/day. Data including patient diagnosis, dosage of VPA, best corrected VA, VF, length of treatment, liver enzymes and side effects were collected when available.

    VF areas were defined using Goldmann VF (GVF) tracings that had been performed before, during and after VPA treatment using isopter V4e for each eye. Custom software was used to enable manual measurements of isopter areas on GVF, using Matlab software (R2009A, Mathworks, Natick, Massachusetts, USA). VFs were initially digitised and saved as TIFF image files. The custom software was then used to manually trace over the VF isopter and automatically compute the enclosed isopter planimetric area (in cm2). As this was a retrospective study, GVF tracings were not available for all patients. Of the 31 patients, 5 patients had GVF data before (baseline) and during VPA treatment, while 2 patients had data during and after VPA treatment. The absolute change in VF and the per cent change from baseline were calculated.

    VA measurements were also gathered before, during and after VPA treatment. VA was measured using a Snellen chart at a distance of 20 feet, and values were converted to logarithm of the minimum angle of resolution (logMAR) score. Of the 31 patients, 21 had VA data before and during VPA treatment, and 11 also had VA recorded after treatment. The absolute change in logMAR acuity was calculated.

    The Wilcoxon signed rank test was used to calculate significance values for VA and VF measurements.

    Results

    Changes in visual field

    Of the 31 patients identified, 5 had at least two Goldmann perimetry tracings, allowing comparison between baseline and follow-up VF. Table 1 summarises the average characteristics of these patients. Four of the patients had RP (presumably autosomal recessive, as no family history to suggest an autosomal dominant or X linked recessive pattern of inheritance was noted in the chart), while one was diagnosed with RCD. The patients ranged from 14 years to 62 years (mean 38.6 years), and the total length of treatment varied between 3 months to 42 months (mean 18.8 months).

    View this table:
    Table 1

    Summary of patients included in Goldmann visual field analysis at baseline and during VPA treatment

    GVF were compared at baseline and during one time point during VPA treatment (mean 9.8 months). Areas determined by isopter V4e were converted into areas of functioning retina, as shown in figure 1. Four out of five patients had a decrease in VF in both eyes after treatment with VPA; one patient had an increase in VF in both eyes after VPA treatment. When analysed by eye, average VF for all right eyes decreased from 29.229 cm2 at baseline to 29.135 cm2 at follow-up, while average VF values for all left eyes decreased from 28.033 cm2 to 27.836 cm2. On average, the VF of both eyes decreased by 0.145 cm2 (26.478%) while on VPA (p=0.432) (table 2). The per cent change in VF per patient for each eye is depicted in figure 2.

    View this table:
    Table 2

    Absolute and per cent change in visual field after a mean of 9.8 months on valproic acid treatment

    Figure 1
    Figure 1

    Goldmann visual field (GVF) tracings from patient 2. Areas were calculated from GVF tracings (isopter V4e) as described in the methods. The top row shows baseline visual field (VF) in the left and right eyes, respectively, and the bottom row shows VF after 19 months of valproic acid treatment (VPA Tx). Both eyes displayed a decrease in VF during treatment. OD, right eye; OS, left eye.

    Figure 2
    Figure 2

    Per cent change in visual field (VF). Goldmann visual field tracings (isopter V4e) were used to calculate areas of functioning retina before and during valproic acid treatment. After a mean of 9.8 months on VPA, 8 out of 10 eyes decreased in VF.

    Two patients had GVF tracings during and after VPA treatment. One patient showed an increase in VF 8 months after discontinuing treatment (18.147% increase in the right eye and 28.835% increase in the left eye), while the other patient showed a decrease in VF 6 months off treatment (11.052% decrease in the right eye and 4.620% decrease in the left eye).

    Change in visual acuity

    Most patients experienced no change or a slight decline in VA while on VPA. Twenty-one of the 31 patients had VA data at baseline and during treatment, giving 41 right and left eyes total (one left eye was excluded due to no light perception VA). The change in logMAR acuity was +0.056 log units representing a decline in VA after a mean of 14.9 months of treatment (p=0.002). Overall, 21 eyes had no change in VA, 16 eyes had a decline in VA and 4 eyes had an improvement in VA.

    In 11 of these patients (22 eyes), we had an additional data point of post-treatment VA. Ten eyes had an improvement in VA, six eyes stayed the same and six eyes declined in VA. LogMAR acuity difference comparing during treatment to after treatment was −0.041 log units (p=0.623), representing an improvement in VA after discontinuation of VPA. LogMAR acuity difference comparing pretreatment to post-treatment in the 22 eyes was 0.022 (p=0.480) representing a decline in VA. Thus, there was a trend towards an increase in VA upon discontinuing VPA, and an overall decrease in VA comparing post-treatment acuity to baseline, but neither of these findings were statistically significant.

    Side effects

    Of the 31 patients, 12 (38.7%) reported negative side effects related to VPA use. Two (6.5%) of the patients had high serum alanine aminotransferase (ALT) and aspartate aminotransferase (AST) levels, and one (3.2%) of the patients had high ammonia levels. Other recorded side effects included lethargy (9.7%), stomach irritation (6.5%), weight gain (6.5%), rash (6.5%), hyperacuity (6.5%), malaise (3.2%) and bruising (3.2%). Nine of the 31 (29%) patients discontinued VPA due to these side effects.

    Discussion

    Currently, there is a multicentre, prospective, phase II clinical trial to evaluate the safety and efficacy of VPA in patients with autosomal dominant forms of RP. One of the motivating factors behind this clinical study was work done by Clemson et al,12 which found that patients with RP had an improvement in GVF performance and VA measurements after 4 months of treatment, but long-term data was not presented. We were unable to confirm if all of the patients represented in the Clemson 2011 publication were included in our long-term review as we did not have access to the list of patients from this first study, however both studies were retrospective reviews of patients treated with VPA at the University of Florida. We were careful in our long-term follow-up study to include all patients with a diagnosis of pigmentary retinal dystrophy treated with VPA. The patients studied in the original trial were likely included in the long-term review represented in this paper due to the overlap of the time periods studied.

    In our study, we provide long term follow-up data which, in contrast to the Clemson 2011 publication,12 does not show any benefit of off-label VPA treatment to patients with various retinal dystrophies. VPA was also associated with adverse side effects in many patients. After an average of 9.8 months on VPA, VF areas showed a declining trend in four out of five patients with RP or RCD (p=0.432). In addition, average VA significantly worsened during treatment with VPA (p=0.002). In summary, we found that VPA may not be an appropriate treatment for all retinal dystrophies.

    Though GVF and VA are subjective tests, relying on the accuracy of the patient and the examiner, they are still valuable tools in assessing changes in vision, and are often used as outcome measures in clinical trials involving patients with retinal degeneration. A thorough understanding of the effect of VPA on retinal dystrophies will require prospective data, but our results suggest that in our subset of patients with various retinal dystrophies, no positive treatment effects of VPA could be noted.

    In addition, almost 30% of the patients in this study experienced side effects that led to cessation of therapy. Though VPA is used as an anticonvulsant and a mood stabiliser, it can lead to idiosyncratic liver toxicity and teratogenicity.10 Weight gain, lethargy and stomach irritation are common consequences of the drug and were also observed among the patient cohort in this study.

    Though this study provides longer follow-up than presented in previous publications, there are still several limitations that should be mentioned. The study was retrospective and thus only a subset of patients had sufficient VA and GVF data for analysis. Snellen visual acuities were not standardised. Possible variability in GVF testing is a limitation in a retrospective study, however GVFs were always performed by trained ophthalmic technicians with standard calibration of isopters. Standard GVF protocol at our institution includes using kinetic threshold testing to plot isopters and static suprathreshold testing to subsequently map scotomas within the isopters.19 Due to the retrospective nature of the study, our analysis was limited to those patients who had GVF tracings before and after VPA treatment, and therefore the possibility of selection bias must be mentioned as a limitation to this study. Chart notes were carefully reviewed and there was no evidence to suggest that the patients who underwent subsequent GVF testing were complaining of symptoms to prompt repeat testing. Finally, specific genotypical classifications were not available for most patients as the majority of these patients had not undergone genetic testing, and it is likely that responses to VPA could vary widely depending on genetic diagnosis. The limitations noted in our retrospective study point to the need for a randomised prospective trial to thoroughly assess the safety and efficacy of VPA treatment for RP or other retinal disorders.

    The patients used in this study were prescribed VPA, despite their range of retinal dystrophies. However, the genetic basis of RP and retinal degenerative disorders are heterogeneous, and it is unlikely that one drug will uniformly be safe and effective in this broad spectrum of disorders. Rather, effective treatment options likely depend on first identifying the disease-causing mutation and then optimising treatment targeting genotype-specific pathology. Ultimately, comprehensive databases integrating genetic and clinical data will provide physicians and patients with more information regarding pathophysiology-directed options for therapy. From our study, VPA appears to play a complex role in patients with pigmentary retinal dystrophies and may be associated with VA and field decline as well as adverse side effects. Physicians should avoid prescribing VPA for RP or other pigmentary retinal dystrophies until safety and efficacy of this treatment can be appropriately evaluated in a prospective trial.

    Acknowledgments

    Correction notice This article has been corrected since it was published Online First. In Table 2, the Average in the ‘ΔVF (cm2)’ column has been amended from ‘0.145±3.937’ to ‘–0.145±3.937’.

    Acknowledgments

    Acknowledgements We would like to acknowledge Dr Byron Lam (Bascom Palmer Eye Institute; Miami, Florida) and Dr Sudarshan Ranganathan (Bascom Palmer Eye Institute; Miami, Florida) for their expertise in quantitative analysis of visual fields and development of custom software to compute isopter area on Goldmann visual fields using Matlab software (R2009A, Mathworks, Natick, Massachusetts, USA).

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    Footnotes

    • Contributors All authors contributed to the work.

    • Funding Supported in part by Foundation Fighting Blindness Career Development Award (PI: CNK, CD-CL-0711-0520-UFL) and by an unrestricted grant to the Department of Ophthalmology from Research to Prevent Blindness.

    • Competing interests None.

    • Ethics approval University of Florida Institutional Review Board.

    • Provenance and peer review Not commissioned; externally peer reviewed.