Statistics from Altmetric.com
If you wish to reuse any or all of this article please use the link below which will take you to the Copyright Clearance Center’s RightsLink service. You will be able to get a quick price and instant permission to reuse the content in many different ways.
I read with great excitement the article ‘Therapeutic Potential of Valproic Acid for Retinitis Pigmentosa’, by Clemson et al.1 Patients who received oral valproic acid (VPA) were reported to have improvement in Goldmann visual field performance and best-corrected visual acuity (BCVA) measurements after a mean 4 months of treatment. The current standard of care, vitamin A palmitate, has not been associated with any regression of disease or improvement in visual function in patients with retinitis pigmentosa (RP).2 Rather, a subgroup of patients may experience a decreased rate of cone amplitude degradation, which has been used as a surrogate marker for visual function. Therefore, this seminal work has sparked off a multicentre, prospective, randomised, controlled phase II clinical trial with the aim to evaluate the safety and efficacy of oral VPA in patients with dominant forms of RP.3 The study is currently enrolling patients, and the results will not be known until one year after the final patient is recruited.
Shortly after its publication, the study by Clemson et al was criticised for its study design, short mean follow-up (4 months) and methodology of statistical analysis, which when corrected for comparison among patients rather than eyes, resulted in a failure to demonstrate statistical significance.4 ,5 No side effects were observed in the seven patients with RP who received VPA, although VPA is notorious for its side effects and drug interactions. To the best of our knowledge, no further reports of success or failure with VPA have subsequently been published.
After the publication of Clemson et al, I offered VPA (10 mg/kg/day orally divided three times a day) on a compassionate basis to patients with RP after discussing about the potential risks, benefits and alternatives. Patients taking vitamin A palmitate were asked to discontinue treatment for one month prior to initiating VPA therapy to prevent hepatic dysfunction. Serum liver enzymes were assessed before starting treatment at 2 weeks, 6 weeks and 3 months. Complete ophthalmic examination was performed to assess anatomical and functional outcomes. Spectral domain optical coherence tomography and fundus autofluorescence testing were employed to evaluate photoreceptor structure and function, respectively.
All three patients who underwent VPA treatment experienced complications or side effects that required cessation of therapy. All of them experienced a reduction in BCVA in both eyes compared with the baseline that was not reversible with discontinuation of the drug (table 1). In the case of one patient, new-onset torsional nystagmus resolved 4 weeks after discontinuation of VPA. In another patient, intolerable photophobia developed that was relieved by discontinuing VPA. Photophobia and torsional nystagmus are known complications of VPA. In all patients, ophthalmic examination findings, refraction and fundus autofluorescence and spectral domain optical coherence tomography images remained unchanged compared with baseline during a mean 11.5 months of follow-up (range 11–12 months).
In contrast with the cohort of patients studied by Clemson et al, these patients were younger (mean age 11.7 years vs 36 years) and more severely affected at baseline. Patients were treated with VPA for a longer mean duration (150 days vs 4 months) before they all discontinued the treatment due to the intolerable side effects or reduced BCVA. All patients had sustained losses in BCVA compared with the baseline, and these were not improved by discontinuation of VPA treatment. Although none of the patients in Clemson's cohort experienced any side effects from VPA or reduction in BCVA, 7 of 13 eyes in 5 patients had no improvement in BCVA when treated with VPA.
Treatment with VPA may not be appropriate for all genotypes. Clemson et al hypothesised a benefit in patients with autosomal-dominant RP, where VPA may serve as a chaperone for rhodopsin. In this cohort, one patient had a dominant pedigree, another had an indeterminate pedigree and one patient had sporadic RP. One eye of the patient without a dominant pedigree in Clemson's cohort experienced BCVA improvement, and this was the rationale behind the use of VPA for the patients in this cohort who did not have an established dominant pedigree or genotyping. Although VPA has been described to have anti-inflammatory and neuroprotective properties, it may instead be toxic to eyes with RP that is not caused by mutations affecting rhodopsin. VPA blocks voltage-gated sodium channels and T-type calcium channels.6 Valproate has been shown to diminish high-frequency repetitive firing of action potentials of central neurons in culture, and may have a role in diminishing hyperpolarisation of photoreceptors, which fire continuously except when stimulated, by decreasing the standing potential. This theoretically may compromise photoreceptor function in eyes with recessive or sporadic RP to account for the observed visual decline and failure to recover after discontinuation of the drug.
This report should serve to discourage use of VPA in patients without dominant pedigrees for RP. Preferably, VPA would not be offered prior to genetic confirmation of mutations affecting rhodopsin. The small sample size from our study limits useful statistical analysis and generalisability, and a control group was not used. However, BCVA would not be expected to decline at the observed rate in untreated patients with RP, nor would it occur with discontinuing treatment with vitamin A palmitate alone. In contrast with the report by Clemson et al, VPA treatment was associated with significant toxicity and intolerable side effects in this small cohort. Further prospective data is needed, and will be forthcoming, regarding the safety, efficacy and applicability of VPA treatment for RP.
Competing interests None.
Provenance and peer review Not commissioned; internally peer reviewed.