The Role of Spironolactone and Rifampicin in the Management of Chronic Central Serous Chorioretinopathy - A Prospective Study

  

    
 
    
Placebo
      
 
    
Rifampicin
      
 
    
Spironolactone
  
  

    
Complete Resolution of SRF
    
1    month
      
 
    
4/19
      
(21.05%)
      
(CI-0.86%-41.24%)
    
3/22
      
(13.64%)
      
(CI-1.94%-29.21%)
      
 
    
3/21
      
(14.28%)
      
(CI-2.04%-30.61%)
      
 
  
  

    
2    months
    
6/19
      
(31.58%)
      
(CI-    8.56%-54.60%)
    
5/22
      
(22.73%)
      
(CI-3.71%-41.75%)
    
5/21
      
(23.81%)
      
(CI-3.94%-43.68%)
  
  

    
3    months
    
8/19
      
(42.10%)
      
(CI-17.66%-66.55%)
    
8/22
      
(36.36%)
      
(CI-14.53%-58.19%)
    
13/21
      
(61.90%)
      
(CI-39.25%-84.56%)
  
  

    
Number of eyes with recurrence of SRF
    
6    months
      
 
    
2/8
      
(25%)
      
(CI-13.70%-63.70%)
    
5/8
      
(62.5%)
      
(CI-19.23%-100.00%)
    
9/13
      
(69.23%)
      
(CI-40.20%-98.26%)
  
  

    
CI- 95% Confidence Interval. 
  

Table 5: Number of eyes with complete resolution and recurrence of SRF.

Discussion

CSCR patients complain of blurring of vision and seeing a central scotoma secondary to a neurosensory detachment at the macula [1]. It is often self-limiting but in 10-20 % it may become chronic with persistence of SRF leading to photoreceptor loss and extensive RPE damage and choroidal neovascularization. This may cause permanent damage to BCVA, color vision and contrast sensitivity [23]. Currently, no consensus exists regarding the treatment of chronic CSCR and novel treatments are being explored. The exact pathogenesis of the disease is unknown. A forme fruste of CSCR forms a part of the pachychoroid spectrum known as pachychoroid pigment epitheliopathy. The possible mechanisms include increased capillary fragility leading to choroidal circulation decompensation with leakage of the fluid in the sub-retinal space [24]. Glucocorticoids are implicated in the pathogenesis of CSCR and effect vascular autoregulation [25]. Rifampicin is an anti-bacterial drug and form a part of the Anti-Tubercular Treatment (ATT). It is a cytochrome P450 3A4 enzyme inducer, which increases the metabolism of endogenous corticosteroids and thereby reduces their levels in the serum, thereby helping in faster SRF resolution. It is said to have an anti-oxidative, anti-apoptotic and anti-angiogenic effects [13]. On review of literature, the first report on the effect of rifampicin in chronic CSCR was described by Ravage and Packo in 2010 [26]. They reported one patient having concomitant chronic CSCR and tuberculosis receiving rifampicin 600 mg/day as part of the ATT. There was significant improvement in symptoms, which recurred on stopping the drug and improved on reinstitution of the drug establishing a causal relationship. The largest case series of 22 patients by Sabouri et al., [27] have reported the use of rifampicin-600 mg/ day for 4-6 weeks in acute CSCR of less than 2 weeks. The mean age was 38.5±6.7 years and there was a statistically significant reduction in the macular thickness (p<0.003). In 45.5%, there was complete resolution of the SRF in comparison to 29.4% in the control group however, this was not statistically significant. There was no relapse on 9 months follow up.1 patient had severe headache 2 weeks after starting the drug.

Choudhury and co-workers [28] treated 13 CSCR patients with a duration less than 6 weeks. 10 patients showed improvement in vision with a decrease in CMT after rifampicin 600 mg/day for 4 weeks. However, the duration of the follow up was not defined with no mention of recurrence. Shulman et al., [13] in their series of 14 eyes (12 patients) with a mean duration of 28. 4 months and not treatment naive were treated for 3 months with rifampicin 300mg twice daily. There was a statistically significant reduction (p<0.05) in the retinal thickness by 25.3%, 21.2% and 21% at 1, 2 and 3 months respectively. SRF had reduced in 9 eyes (64%) and completely resolved in 6 eyes (42.8%) at month 3, of which 4 eyes remained fluid free at 6 months. There was a statistical significant improvement in BCVA (p>0.05). Two patients stopped the treatment after 2 months due to increase in blood pressure as rifampicin increases the metabolism of calcium channel blockers and the second patient developed acute cholecystitis as rifampicin is thought to increase bile acid production. Study by Venkatesh R et al., [4] 9 eyes (8 patients) with an average duration of 16 months (3-60 months). 4 eyes had sub-foveal leaks and 5 eyes had diffuse retinal pigment epitheliopathy. Treated with rifampicin- 600 mg/day for maximum period of 3 months. Complete resolution of SRF was achieved in 4/9 eyes with 2 patients at 1month and 1patient each at 2 and 3months. BCVA improvement was noted in 4/9 eyes. Mahar PS et al., [14] reported the use of Rifampin-450 mg/day in 10 patients of chronic CSCR (>6 months) with an average duration of SRF as 9.4+2.9 months. An improvement in the macular thickness was noted at 3 months from 350+82.3 to 232+54.3 μm.

The optimal dosage and duration of rifampicin in treating chronic CSCR is still unknown. In our study all the patients of chronic CSCR with a mean duration of SRF as 9.39+9.27 months. Our patients received 600mg once daily for a maximum of 2 months. 5/22 eyes showed a complete resolution of the SRF at 2 months which became 8 eyes at 3 months. However the reduction in the SRF height (p=0.085) and horizontal length of SRF (p=0.151) was not statistically significant. The BCVA improvement at 2 months in comparison to baseline was found to be statistically significant (p=0.027). Recurrence was seen in 5/8 (62.5%) eyes at 6 months. No side effect of the drug was noted. We need to keep in mind that rifampicin being hepatotoxic and having several drug interactions, a detailed medical history and LFTs at baseline are mandatory before starting the drug. The glucocorticoidinduced effects may result in choroid vessel dilatation and leakage, effects which are reversible with MR antagonists. The molecular target for MR activation in the choroid is namely K_Ca2.3 which is an endothelial hyperpolarizing calcium dependent potassium channel involved in vasorelaxation and inducing dilation of choroidal vessels [25]. Any mineralocorticoid receptor antagonist including spironolactone or eplerenone reverses the upregulation of K_Ca2.3 in the choroid demonstrating their local molecular action.

Spironolactone is the oldest MR antagonist which may exert hormonal effects at a high dose and prolonged use (>3 months) including reduced libido, gynecomastia and menstrual disturbance [29]. Eplerenone is more specific with minimal hormonal effects but has a 50 fold reduced efficacy on MR blockage and is more expensive [30]. We used spironolactone as it is more economical, more efficacious and the duration of use was short therefore the possibility of hormonal side effects was minimal. Bousquet et al., [9] in their prospective, randomized, placebo controlled crossover study of 16 eyes of 16 patients with a mean duration of SRF as 10+16.9 months. Patients were randomized to receive spironolactone 50mg or placebo once a day for 30 days. A crossover was done with a washout period of 1 week. Crossover data analysis showed a statistically significant reduction in SRF in the spironolactone group as compared to the placebo group with a significant reduction in the sub-foveal choroidal thickness in the treated eyes (p=0.02).No significant changes were noted in the visual acuity and no complications. Kapoor et al., [3] reported the role of spironolactone in the management of CSCR secondary to 3 recent steroid injections given in the back of a Caucasian female. There was evidence of pachychoroid in both the eyes. SRF showed regression on using spironolactone 50mg twice daily, increased to 50mg thrice daily for another month resulting in complete resolution of the SRF. There are several isolated case reports describing the use of spironolactone [3] and epilerenone [17,18]. In our study in the spironolactone group, the mean duration of SRF was 9.38+12.87 months. Our patients received spironolactone 50mg once daily for a maximum of 2months. 5/21 eyes showed a complete resolution of the SRF at 2months which increased to 13 eyes at 3 months. However the reduction in the height of SRF (p=0.016, p=0.008) and horizontal length of the SRF (p=0.00, p=0.00) was found to be statistically significant both at 2 and 3months respectively. The BCVA improvement at 2months in comparison to the baseline was found to be statistically significant (p=0.03). Recurrence was seen in 9/13 (69.23%) eyes at 6 months. No side effect of the drug was noted. In our placebo group an antioxidant containing lutein and zeaxanthin was given for 2 months, the mean duration of SRF was 9.38±9.86 months. 6 eyes out of 19 eyes (31.58%) showed a complete resolution of the SRF at 2 months. A statistically significant reduction of SRF height was seen at 1 and 2 months (p-value 0.005 and 0.043 respectively) and reduction of the horizontal SRF length at 2 and 3 months (p-value 0.035 and 0.025 respectively) compared to the baseline values. This may have resulted in a statistically significant visual acuity improvement at 2 months (p-value 0.028) as compared to the baseline, which showed further improved at 3 months (p-value 0.005). Out of the 6 eyes with complete resolution of SRF at 3 months, 2 eyes (33.33%) showed a recurrence at 6months. The choroidal thickness showed a statistically significant reduction (p-value 0.034 and 0.024) at 1 and 2months of follow up. Our study is the first prospective placebo controlled randomized study. On comparing, the various groups with each other we found that the rifampicin group showed a statistically significant reduction in choroidal thickness at all follow up visits. Spironolactone showed maximum reduction in the height and horizontal length of SRF as compared to the other two groups and this possibly resulted in a good visual recovery. It also showed the maximum number of the eyes with complete resolution of SRF as compared to the other two groups however the number of recurrences at 6months was the highest in this group. Placebo group showed the least number of recurrences of SRF at 6months follow up. This study has shown surprising results in the form of a significantly increased proportion of patients who recovered on treatment with spironolactone within two months. This difference was statistically and clinically significant. The limitation in our study is the sample size. Based on the absolute risk reduction, spironolactone has a NNT (Number Needed to Treat) of 5 only at the 6 months. The confounding factor here is the crossover that occurred after 2 months. This is also seen more dramatically when the recurrence rate is examined closely. The lowest recurrence with placebo and the highest with Spironolactone. The NNH (Number Needed to Harm) at 6 month time point is 2.2. The current data makes the use of spironolactone as a therapy in chronic CSCR untenable. Similarly, rifampicin too has a NNH close to 2.2 with resolution rates worse than placebo at alltime points. An intriguing possibility in our study is that the placebo chosen may have actually exerted a therapeutic effect. Although it is premature to state this with any degree of certainty, the data does suggest this. There is little evidence in literature to suggest the same. Shinojima et al., [20] in their randomized placebo controlled study treated 79 patients of chronic CSCR (>6 months) with 37 patients in the supplementation group (antioxidant with lutein) and 42 patients in the placebo group. SRF resolution was seen in 32.4% eyes in the supplementation group and 28.6% in the placebo group. There was no statistically significant difference between the 2 groups. The supplementation group showed significant improvement in BCVA. The SRF reduction rate was higher in the supplementation than in the placebo group at 6 months. Tachi N et al., [31] showed that the cessation of smoking and anti-oxidants help in resolving SRF. The major limitations of our study are small sample size, treatment with each drug for 2 months only, which may not be adequate to assess their role in the resolution of SRF in chronic CSCR and short follow up of 6 months after starting the drug. Further larger and controlled studies are indicated in order to validate these findings.

Conclusion

The patients of chronic CSCR have limited options of treatment and the resolution of SRF may not always translate into visual improvement due to an underlying unhealthy RPE at the macula. Spironolactone and placebo were comparable in the resolution of the SRF at 2 months. However, by the end of three months there was a statistically significant difference between spironolcatone and placebo, where spironolactone was found to be more efficacious in resolving SRF. The lesser efficacy of placebo was outweighed by the least number of recurrences at 6months thereby making placebo (antioxidants in our study) an attractive choice for the treatment of chronic CSCR. An interesting follow up study to do would be to compare antioxidant therapy with natural history in the prevention of recurrences. However, studies with a larger sample size maybe required in future to establish the role of these drugs in the management of chronic CSCR.

Acknowledgement

Institutional Ethical approval and consent for participation and publication was taken. The datasets used and/or analysed during the current study are available from the corresponding author. We have received no funding for this work from any organization. We have no financial interest to disclose. We have no conflict of interest with each other. The manuscript has been read and approved by all the authors. The requirements for authorship have been met, and each author believes that the manuscript represents honest work. All authors have contributed substantially.

The authors thank Dr Rupesh Agarwal, Consultant Ophthalmologist, Department of Ophthalmology and Tan Tock Seng Hospital, Singapore for reviewing and editing the manuscript. Written permission from person acknowledged has been obtained.

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