ABSTRACT

Aim:

To assess the effect of duration of the symptoms on outcome after botulinum toxin injection in anal fissure treatment.

Method:

Data of the patients who underwent botulinum toxin injection for chronic anal fissur were reviewed. Patients with a minimum follow-up of 18 months were included. One-hundred IU botulinum toxine was injected in the internal anal sphincter through 4 quadrants. Follow-up was carried out by clinic visits on post-procedure days 7, 15 and 30 and by telephone survey in 3, 6, 12 and 18th months. Refractory symptoms or recurrence were recorded as failure. The relationship between duration of the symptoms and failure was investigated and a cut-off value was determined. Patients were divided into two groups according to duration of the symtoms and outcome was compared with the patients who underwent lateral internal sphincterotomy within the same period.

Results:

There were 56 patients fulfilling inclusion criteria. Mean age was 33.1±9.4 and 39 (69.6%) patients were female. Presence of the symptoms longer than 8.5 months was predicting treatment failure (Area under curve: 0.721, confidence interval: 0.500-0.942, p=0.037). There were 38 patients in shorter symptoms group, 18 patients in longer sypmtoms group and 32 patients in lateral internal sphincterotomy group. The compelte healing rates after 21 (18-28) months of median survival were 61.1% in longer symptom botulinum toxin group, 94.7% in shorter symptom botulinum toxin group and 96.2% in lateral internal sphincterotomy group (p=0.003). One patient in botulinum toxin groups had local hematoma and one (3.1%) had minor incontinence in lateral internal sphincterotomy group.

Conclusion:

Botulinum toxin has similar outcome with lateral internal sphincterotomy in patients with shorter suration of sypmtoms. Proper patient selection may contribute to the success of the treatment in chronic anal fissur.

Introduction

Anal fissure (AF) is a painful tear extending from the anal canal to the dentate line. Although the exact pathophysiology is not known, an increase in anal tonus, decreased anodermal blood flow and local ischemia are possible mechanism.¹ Most patients have various degrees of constipation and defecation problems. These patients are in a vicious circle where pain, increased anal tonus and demanding excretion trigger each other. This cycle results in chronic inflammation and ischemic ulcers that do not heal. Symptoms lasting longer than 8 weeks are defined as chronic AF.² In chronic AF, usually internal sphincter fibers appear in the anal canal. Hypertrophic anal papillae and skin tag may accompany.

Topical nitrates and calcium channel blockers relieve the symptoms in more than half of the patients, but up to 50% recurrence rates and side effects limit the use of topical treatments in chronic AF.^3,4 The most effective treatment modality in chronic AF is lateral internal sfinkterotomy (LIS) and it is recommended to use it as the first step without waiting for failure with topical treatments in selected patients.² In many randomized controlled trials, recovery rates after LIS have been shown to be higher and recurrence is lower than topical nitrate, calcium channel blockers and botulinum toxin (BT) treatments.^5,6,7 However, post-LIS incontinence rates are still reported as high as 8-30%.^8,9

BT is a reliable and effective method for treating AF with similar healing rates and a lower side effect profile compared to topical treatments.^10,11,12 Lack of persistent side effects, easy applicability and reproducibility have brought BT as an alternative to LIS. The American Society for Colorectal Surgeons (ASCRS) 2017 reported that BT and topical treatments were equally effective at the first step in the treatment of chronic AF.²  In a new meta-analysis, the effectiveness of LIS was emphasized, but it was proposed to take into account the risk-benefit analysis in the choice of treatment because of the high rates of postoperative complications.¹³

In chronic AF treatment, there are still no guidelines on which treatment is most effective and reliable, and there are no widely accepted guidelines in the treatment of chronic AF. In clinical practice, there is a tendency to prefer LIS instead of conservative treatments. Failure and costs can be reduced after treatment if it is determined which patients can benefit from less invasive methods such as BT; complications of surgical treatment can be avoided. In our study, we aimed to investigate the effect of symptom duration on outcome with hypothesis that patients with shorter symptom duration may have more benefit with BT treatment.

Results

Between March 2016 and July 2018, 117 patients underwent a BT due to AF by a single surgeon. 38 patients with a follow-up of less than 18 months were excluded from the study. 13 patients due to other accompanying perianal disease, 4 patients due to previous anorectal surgery, 2 patients due to inflammatory bowel disease and 1 patient due to malignancy were excluded from the study. Three patients could not be reached after 3-month controls. A total of 56 patients were included in the study. The mean age was 33.1±9.4 (range, 18-57), 39 (69.6%) were female and 17 (30.4%) were male. Mean duration of symptoms was 8.5±7.4 months (range, 2 to 36 months), and duration of constipaion was 18.9±34 months (range, 2 to 200). Of the patients, 35 (62.5%) had chronic constipation. In 11 (28.2%) female patients, onset of symptoms was associated with pregnancy or delivery. Detailed demographic and clinical features are given in Table 1. After the first 30 days, 53 (94.6%) patients had complete recovery. Three (5.4%) patients had no-response to treatment. One of them was reintroduced to BT, two of them underwent LIS and all had complete recovery. Recurrence was observed at the 5^th month in a patient who underwent BT for the second time. These three patients were evaluated in the tratment failure group. In the follow-up, 6 patients relapse AF in a mean of 7.3±1.9 months. All patients underwent complete recovery after LIS. No incontinence was observed in any patient. In one (1.7%) patient, local hematoma developed in the anal region and spontaneously regressed within 1 week.

After median 21 (18-28) months, 47 (83.9%) patients had complete recovery. Three patients with no-response and 6 with recurrence, 16.1% of the patients were recorded as treatment failure. The mean symptom duration was 7.5±6.68 months in patients with successful treatment, and 13.8±8.9 months in patients who failed treatment (p=0.017). The symptom duration longer than 8.5 months predicted treatment failure with 78% sensitivity and 77% specificity. The data of 51 patients who underwent LIS due to chronic AF during the same period with BT patients were analyzed. Thirteen patients did not complete 18-month follow-up period, 5 patients with concomitant perianal disease, and 1 had previous hemorrhoidectomy were excluded from the study. Patients treated with BT were grouped according to the 8.5 month cut-off value and compared to 32 patients who underwent LIS and met the inclusion criteria. The complete healing rate in BT patients was 61.1% in ≥8.5 months group and 94.7% in <8.5 months group (p=0.003). In LIS group, complete healing was observed in 96.2% of the patients. There was no difference in complete healing rate between <8.5 months BT group and LIS group (p>0.005) (Table 2). One (3.1%) of patients in the LIS group developed minor incontinence (Cleveland Clinic Incontinence Score: 4).

Discussion

The most effective method in AF treatment is LIS. Although LIS is a day-case procedure, it’s performed under general or spinal anesthesia. Although less important complications such as pain, hemorrhage, perianalsepsis, and hematoma other than incontinence have not been well studied in the literature, they can be quite painful in clinical practice. Therefore, less interventional therapies have always been the focus of attention in the treatment of AF. Medical treatment options of topical calcium channel blockers and nitrates do not provide satisfactory long-term results.^3,4 Low adherence to these treatments and headache caused by nitrates were also associated with failure.¹⁶ Today, medical treatment is the first choice only in the treatment of acute AF.²

Botulinum toxin, which causes temporary paralysis in the internal anal sphincter, is a less invasive and safe alternative to LIS. There is no widely accepted dose and injection points in the clinical practice. In two meta-analyzes published in 2016, it was concluded that BT did not have a dose-dependent effect in terms of recovery, incontinence, and recurrence, but the studies were very heterogeneous and the follow-up period was short.^17,18 There was no difference between the injection points in both meta-analyzes. In a recent study with a median follow-up of 25 months, high-dose (80-100 IU) and low dose (20-40 IU) BT were compared and high dose BT was found to be superior to low dose in terms of patient satisfaction (90% vs 78%, p=0.05) and recurrence (23% vs 53%, p=0.0001). Long-term incontinence was not reported in either group. In our study, 100 IU BT was applied to all patients and incontinence was not observed.

In a meta-analysis of 6 studies including 393 patients, treatment response was reported as 28.6% for BT and 42.1% for nitrates (p=0.24).¹² In our study, the rate of non-response to treatment was 5.4% and increased to 16.6% in patients with complaints longer than 8.5 months. In the same meta-analysis, recurrence after BT and nitrate was 18.5% and 25.1% (p=0.22). While transient incontinence was higher with BT (10.4%) compared to nitrates (4.4%) (p=0.06), BT was found to be superior to nitrates regarding overall side-effects (33% vs 6.4%, p=0.01). Topical treatment duration, BT doses and follow-up periods were very heterogeneous, and the definitons of chronic AF and complete healing were conflicting in this meta-analysis. These result indicate the clinical conflictions in AF treatment.

In another meta-analysis, 44 randomized controlled trials involving 3268 patients with anal dilatation, LIS, anoplasty and/or fissurectomy, BT, and topical therapies were reviewed.¹³ The median follow-up was 2 years, and complete healing rates were 25-96% and 38-100% for BT and LIS. Incontinence rates were 0-10% for BT and 0-44% for LIS. In our study, incontinence did not develop after BT and minor incontinence occurred in 1 (3.1%) patient who underwent LIS. In this meta-analysis, failure rates after BT were 0-78%. In our patients, the failure rate after BT was 16%. This rate decreases to 5.3%, which is comparable with LIS (3.1%) in patients with shorter duration of symptoms.

There is no widely accepted patient selection criteria and algorithms for BT which has been increasingly preferred  as the first-line therapy for chronic AF. Clinicians usually determine the treatment options individually by considering benefit-risk analysis. Although there is no evidence to support this view in the literature, we think that surgical treatment will result in better long-term satisfaction in patients with long symptom duration and chronic constipation. Theoretically, if the factors associated with sphincter spasm and anal trauma persist after the BT effect has vanished, the relapse of the disease will be easier. We believe that this possibility is higher in patients with long-term symptoms.

Determination of risk factors for no-response or recurrence after  BT may provide better selection of the patients who are going to have more benefit from BT. In the literature, there are a few studies investigating factors related with recurrence after BT application.^19,20 These studies revealed that persisting pain after 30 days and the lack of high anal tone were associated with recurrence. In a randomized controlled trial of 99 patients in Iran in 2015, the results of LIS and topical diltiazem + BT were compared.²¹ At the end of one-year follow-up, healing rates were 65% in BT + diltiazem group and 94% in LIS group. Complete healing rates for both BT and LIS were reported to be 100% in patients with a symptom duration of less than 12 months. The complete recovery rate of LIS and BT + diltiazem was 86% and 23% in patients with symptom duration longer than 12 months (p<0.001). Differently from this study, we fund a cut-off value associated with treatment failure and  showed that patients with <8.5 months of symptoms had more benefit from BT. In our study, no topical treatment was performed with BT or LIS.

Study Limitations

The major limitations of our study are the retrospective design and small number of patients. Subgroup analysis  according to the duration of symptoms in LIS group was not performed because of small number and lack of data. Our follow-up period is sufficient considering that most of the previous studies has reported 12 months or shorter terms results.

Anal BT is a minimally invasive, safe and effective treatment. Complete healing rates  are high, however no-response and recurrence rates are still unsatisfactory when compared to LIS. In patients with shorter symptoms, outcome of BT can be better. Randomized trials should be performed to determine the criteria for BT treatment in AF.

Çalışmanın Kısıtlılıkları

Çalışmamızın en önemli kısıtlılıkları geriye yönelik tasarım ve hasta sayısının az olmasıdır. Geriye yönelik tasarım nedeniyle tedavi seçenekleri randomize edilmemiştir. Ayrıca gerek hasta sayısının azlığı gerekse verilerdeki eksiklikler nedeniyle LİS uygulanan hastalarda semptom süresine göre bir alt gruplandırma yapılmamıştır. Takip süremiz literatürdeki diğer çalışmalar ve nükslerin çoğunun ilk 12 ay içinde bildirildiği düşünülürse yeterlidir.

Anal BT uygulaması az girişimsel, güvenli ve etkin bir tedavidir. İyileşme oranları yüksek ancak yanıtsızlık ve nüks oranları LİS’le kıyaslandığında halen tatmin edici değildir. Semptom süresi kısa olan kronik AF hastalarında anal BT uygulaması daha başarılı sonuçlar verebilir. Daha geniş randomize kontrollü çalışmalarla BT’den daha fazla yarar görecek hasta grubu belirlenebilir.