epidermolysis bullosa ( eb ) consists of a heterogeneous group of rare autosomal dominant or recessive disorders , characterized by epithelial fragility .
patients with recessive dystrophic epidermolysis bullosa ( rdeb ) often develop chronic constipation caused by painful defecation from blistering and tearing due to skin fragility , as well as by poor motility from opioid analgesia , which is frequently used in those with severe eb . as a result of straining
, anal fissuring may further develop . due to these painful fissures and ongoing constipation , chronic anal fissures and anal sphincter spasm may result .
an anal fissure is a tear in the anoderm ( squamous epithelium ) distal to the dentate line . by definition ,
an acute anal fissure heals within 6 weeks with conservative local management , whereas a chronic anal fissure fails conservative management , requiring more aggressive measures .
this case demonstrates the successful use of botulinum toxin type a ( btx - a ) to relieve anal sphincter spasms and improve chronic anal fissures from eb .
a 20-year - old female with generalized , severe rdeb gradually developed chronic anal fissures , resulting in severe anal sphincter spasms and severe , disabling pain .
her quality of life ( qol ) was greatly diminished by this symptom ( qoleb pilot score of 42/75 ; frew et al . , 2009 ) .
she had inherited two heterozygous deletion mutations in the col7a1 gene , c[4918del ] in exon 52 and [ 7634del ] in exon 102 , predicting two frameshift mutations , p. [ gly1640fs ] and [ gly2545fs ] , leading to presumed downstream premature termination codons ( venugopal et al . , 2013 ) .
blistering was extensive from early infancy , causing cutaneous scarring and mitten deformities of hands and feet .
she developed known complications of eb , including squamous cell carcinoma , hepatic amyloidosis ( chaptini et al .
, 2015 ) , premature and extensive dental caries , esophageal strictures , osteoporosis , hypogonadotrophic hypogonadism , and bilateral inferior exposure keratopathy .
previous procedures included surgeries to correct hand contractures , right lower - lid ectropion repair , and regular iron and blood transfusions for anemia .
medications included long - standing phenytoin 50 mg three times daily to aid wound healing , pantoprazole , cholecalciferol , estradiol / norethisterone , pregabalin , tramadol , oxycodone , and lactulose .
g / l ) , hyponatremia ( 132 mmol / l ) , hypoalbuminemia ( 21
g / l ) , creatinine 48 mol / l , and liver function tests ( lfts ) demonstrating a cholestatic picture .
anal manometry showed resting pressure 64 cmh2o ( range : 54 - 104 ) , reduced squeeze pressure 147 cmh2o ( range : 179 - 317 ) , and sphincter length 3.5 cm ( range : 2.5 - 5 ) .
conservative measures for her anal fissures were trialed without success , including laxatives and a high - fiber diet .
glyceryl trinitrate 0.2% ointment and zinc barrier were also unsuccessful . when she was referred in november 2008 for participation in a cell therapy clinical trial in sydney in 2009 ( venugopal et al . , 2013 ) , we were asked about how to manage the fissuring .
after topical tacrolimus failed to relieve any inflammation , the suggestion was made to consider intramuscular btx - a as a therapeutic intervention . over a period of 2 years starting from age 19 years , she underwent five btx - a injections into the internal anal sphincter ( one injection approximately every 5 months ) , performed by a colorectal surgeon . in each case , a general anesthetic was used , and 50 units of btx - a in 2.5 ml of normal saline were injected into the internal anal sphincter in all four quadrants .
the patient experienced a 50% subjective improvement in her pain and spasms for at least 1 month after each injection , followed by residual improvement for many months .
four years after the cessation of injections , the patient s symptoms were still improved from baseline .
chronic anal fissures often complicate rdeb , as these patients develop constipation early on in life because of anal discomfort and medications .
once the tear in the anus mucosa occurs , it begins a cycle leading to repeated injury . the exposed internal sphincter muscle underneath the tear goes into spasm . as well as causing severe pain , the spasm pulls the edges of the fissure apart , impairing wound healing .
the spasm also causes further tearing of the mucosa with each following bowel motion . in this case ,
btx - a injections successfully relieved the anal sphincter spasm and pain secondary to recurrent anal fissures by interrupting the cycle of repeated injury .
botulinum toxin , produced by clostridium botulinum , blocks cholinergic nerve terminals and inhibits release of acetylcholine from nerve endings .
it has been used to successfully treat certain spastic disorders of skeletal muscle , such as blepharospasm and torticollis , as well as wrinkles and spastic contractures in cerebral palsy .
although there have been no documented cases of its use in eb for anal sphincter spasm or fissuring , it is commonly used to treat idiopathic anal sphincter spasm , typically given as injections around the anal canal ( 10 to 100 units total ) .
it has also been reported to improve healing in patients with chronic anal fissures ( maria et al . , 1998b ) . despite variable doses and locations of the injection ,
, 2004 , brisinda et al . , 2007 , jost and schrank , 1999 , maria et al . , 1998a , mnguez et al . , 1999 )
the healing rate appears to be related to the dose and probably to the number of puncture sites ( maria et al . , 1998a , mnguez et al . , 1999 ) .
in a randomized controlled trial , where 100 patients were treated with either btx into the internal anal sphincter or 0.2% nitroglycerin ointment for 8 weeks , after 2 months the fissures were healed in 46 ( 92% ) of 50 patients in the btx group and in 35 ( 70% ) of 50 in the nitroglycerin group ( p = 0.009 ) .
three patients in the btx group reported adverse effects ( p < 0.001 ) from mild incontinence to flatus that lasted 3 weeks after treatment but disappeared spontaneously ( brisinda et al . , 2007 ) .
in another randomized controlled trial , 50 patients with chronic anal fissures received injections of 50 units of botox formulation ( group i ) , and 50 patients received injections of 150 units of dysport toxin ( group ii ; brisinda et al . , 2004 ) .
after 2 months , 46 patients in group i and 47 patients in group ii had a healed scar .
in group i patients , the mean resting anal pressure was 41.8% lower and the maximum voluntary squeeze pressure was 20.2% lower than the baseline value . in group
ii patients , the resting anal pressure and maximum voluntary squeeze pressure were 60.0  12.0 mmhg and 71.0  30.0 mmhg , respectively .
there were no relapses in the 21 months of follow - up ( brisinda et al . , 2004 ) .
similarly , in a study where 30 patients with chronic anal fissures were randomized to intra - sphincteric btx - a or saline injection , after 2 months significantly more patients who had received btx - a had healed ( 73% versus 13% ; maria et al . , 1998a ) .
this was supported by another study where repeated btx - a therapy was used in 50 patients who failed initial ( insufficient ) btx - a treatment .
nineteen of 20 patients ( 95% ) treated with five units of btx - a were pain - free within 1 week , and healing was observed in 70% by 3 months .
twenty - two of 30 patients ( 73% ) treated with 10 units of btx - a were pain - free within 1 week , and 19 ( 63% ) demonstrated healing after 3 months ( jost and schrank , 1999 ) .
botulinum toxin injections have been used twice before in patients with eb in the literature for reasons other than anal sphincter spasm .
btx - a has been used to treat palmar and plantar hyperhidrosis , which was found to be effective and safe ( schnider et al . , 1997 , vadoud - seyedi , 2004 ) .
as hyperhidrosis contributes to frictional trauma and the development of blisters in eb simplex ( ebs ) , it was thought that btx - a may have a therapeutic role in this condition .
hence , btx - a was used in a double - blinded - study of a 43-year - old woman with ebs , localized type , to treat blisters and erosions on the plantar aspect of her feet ( abitbol and zhou , 2009 ) . the foot treated with btx - a
had decreased pain and perspiration and a 64% decrease in blister formation after 3 months compared to the control foot , which received normal saline injections ( abitbol and zhou , 2009 ) .
furthermore , a retrospective study of 14 patients ( 6 with ebs ) with foot blisters who had received botulinum toxin therapy showed that 13 ( 93% ) patients reported reduced blistering and pain , with a mean effect of 3 months ( swartling et al . , 2010 ) .
the mechanism of action of btx - a in the above cases is via blocking the autonomic cholinergic junctions of the post - ganglionic sympathetic fibers to the sweat glands , thus preventing hyperhidrosis .
the mechanism of action in improving chronic anal fissures and spasm , as depicted in this case , is likely mainly due to cholinergic nerve terminal blockade , preventing spasm , as well as blockade of the post - ganglionic sympathetic fibers , preventing sweating , and subsequent fissuring .
the main adverse effects after local injection of btx - a are weakness in the muscles adjacent to the treatment sites and , in the perianal area , fecal incontinence .
beneficial effects have been shown to last from 4 months to 1 year ( swartling et al . , 2010 ) .
the long - term outcome of btx - a treatment has not been well described in the literature ; recurrence may be common .
the report with the longest follow - up ( 42 months ) showed that in 57 patients who had healed anal fissures from btx 6 months after injection , a recurrent fissure was observed in 22 patients ( 42% ; minguez et al . , 2002 ) .
however , in the case described , long - term benefits remained after 4 years , indicating that this is a useful adjunctive treatment for rare patients with these disabling symptoms .
this case demonstrates the successful treatment of chronic anal fissures and anal sphincter spasm with botulinum toxin a injections , with nil adverse effects .
botulinum toxin a injections should be considered as a treatment for anal sphincter spasm secondary to recurrent anal fissures in eb when conservative measures fail .
 we report a 20-year - old female with generalized , severe , recessive dystrophic epidermolysis bullosa who developed secondary chronic anal fissures . this resulted in anal sphincter spasm and severe 
 , disabling pain . 
 she was treated with five botulinum toxin a injections into the internal anal sphincter over a period of 2 years and gained marked improvement in her symptoms . 
 this case demonstrates the successful use of botulinum toxin a injections to relieve anal sphincter spasm and fissuring , with long - term improvement . 
Introduction
Case report
Discussion
Conclusion