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Internal Anal Sphincter

977

P E D I A T R I C S C hildren With Nonrelaxing Internal Anal Sphincter (absence of the rectoanal inhibitory re ex). A nonrelaxing IAS

is present in those with surgically repaired HD (10) , and IAS achalasia (4,5) . T raditionally, treatment for symptomatic children with a nonrelaxing IAS, regardless of the etiology, involves surgical procedures directed at the anal sphincter, such as myectomy (11,12) . However, these procedures are irreversible, and have the potential to cause fecal incontinence, which in some long-term follow-up studies has been reported in 20 – 40 % cases (13,14) . Long-term studies demonstrate lower median anal resting pressures and lower maximal anal squeeze pressures in adult HD patients compared with controls (15) . ese ndings suggest there may be an increased baseline long-term risk for fecal incontinence in patients a er HD surgery. Many children with surgically repaired HD who go on to develop obstructive symptoms improve over time, particularly when late adoles-cence is reached (9) . erefore, given the risks associated with surgical myectomy, and potential of improvement over time, new nonsurgical options for the treatment of symptomatic chil-dren with a nonrelaxing IAS are being sought. R ecent years have seen the advent of “ c hemical ” sphincter-otomies which lower overall anal sphincter pressure through pharmacologic means. C lostridium botulinum toxin (BoTox) injection into the anal sphincter has been successfully used for the treatment of chronic anal ssures in both adults and chil-dren (16 – 21) . BoTox has also been used successfully in limited short-term studies of children with surgically repaired HD (22) , IAS achalasia (5,23) , and IAS dysfunction (24) . However, the long-term clinical outcomes of children with nonrelaxing IAS who receive anal sphincter BoTox therapy as a primary modal-ity to address gastrointestinal obstructive symptoms and / o r enterocolitis are unknown. e primary aim of this study was to determine the long-term clinical outcomes a er the application of BoTox therapy in children with nonrelaxing IAS. e secondary aim was to elucidate factors which may be involved in in uencing long-term clinical outcomes.

ETHODS A retrospective chart review of all children with nonrelaxing IAS who received BoTox injections for obstructive symptoms and / o r enterocolitis at Children ’ s Hospital Boston from 1998 to 2007 was conducted. e Committee on Clinical Investiga-tion of the Children ’ s Hospital Boston, approved this study. All children with documented follow-up a er a BoTox injec-tion were included. Obstructive symptoms were de ned by the primary gastroenterologist, and con rmed by one of the investigators (SN) and included constipation, abdominal dis-tention, straining with defecation, and retentive fecal incon-tinence. Enterocolitis episodes were identi ed by hospital discharge records, in-patient visits, and outpatient clinical visit diagnoses. B aseline symptoms were obtained by review of the history and physical examination during the initial visit to the primary

gastroenterologist, and by documentation at the time of the

rst BoTox injection by one of the investigators (SN). Symp-toms were followed by documentation at subsequent clinical visits or procedures. Rectal therapies were de ned as any ene-mas, anal dilatations, irrigations, or suppositories. All ndings were recorded using a standardized form. A ll children with HD included in the study had previously undergone corrective surgery. All included HD patients had a nonrelaxing IAS, and the presence of ganglion cells on repeat rectal biopsies at the time of the BoTox injection. I AS achalasia (IASA) was diagnosed when nonrelaxation of the IAS occurred during manometry testing (as de ned below) and ganglion cells were found to be present on rectal biopsy (5) .

A norectal manometry O n the night before the anorectal manometry, all children received a phosphate enema. e manometric studies were performed with a continuously perfused catheter using a low-compliance pneumo-hydraulic system (Model ARM2; Arndorfer Medical Specialties, Greendale, WI) as previously described (5) . e manometric catheter was made from poly-vinyl tubing and contained four recording ports separated by 1 c m at the distal end and staggered at a 90 ° angle. A latex balloon was attached to the end of the anorectal catheter and its port is connected to the recording system to register the exact time of balloon distention. Pressure readings were trans-mitted to the Medtronics Polygraphic System (Medtronics, Minneapolis, MN). All baseline measurements were set at atmospheric pressure. Initially a slow pull-through was per-formed until the area of high-pressure zone was identi ed. e balloon was then rapidly in ated with serial volumes that

started from 10 m l and increased by 10 m l up to at least 60 c m

3 . In those children in whom there was no IAS relaxation even with a balloon of 60 m l, the balloon volume was increased until we found resistance to in ation, and evidence of discom-fort was elicited in the patient. is was performed to ensure that the lack of relaxation of the IAS sphincter was real, and not a false positive result occurring because of a lack of rectal wall stimulation. Children who were not initially cooperative received oral midazolam (0.5 m g / k g) in order to aide in com-pletion of the evaluation. e intra-anal pressure was measured in all individuals a er giving appropriate time for accommodation using the slow pull-through technique. In our laboratory normal values range from 60 to 120 m m H g. e presence of IAS relaxation (rectoanal inhibitory re ex) during manometry testing was then measured for each balloon distention. Relaxation of the sphincter was de ned as present when there was a consist-ent reproducible decrease in sphincter pressure of at least 5 % from the individual ’ s baseline pressure within 15 s of the rectal balloon distention with a subsequent return to the previous baseline pressure. Children in whom the rectoanal inhibi-tory re ex could not be elicited even with maximum balloon in ation were considered as having a nonrelaxing IAS.

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B oTox administration B oTox (

C . botulinum toxin A; Allergan, Irvine, CA) injec-tions were performed under general anesthesia a er cleaning the rectum with an age-appropriate enema the night prior, as described previously (5) . Rectal cleanouts were completed both manually and with irrigations in the operating room if neces-sary in order to visualize the eld. BoTox was diluted in saline to a concentration of 100 U / m l. Using a small nasal speculum, the dentate line was identi ed by inspection and palpation. e area was then cleaned with providone – i odine. With a 1 m l syringe and a 25 – 30 gauge needle, 6 U / k g (up to 100 U total) was divided and injected equally into four quadrants.

I n those children with HD that had undergone corrective sur-gery and had persistent symptoms, the BoT ox o en was given at the time of repeated rectal biopsies to exclude persistent agan-glionosis (25) . If persistent aganglionosis was found, the patients were excluded from the present study. All children with surgically repaired HD had a barium enema performed before BoT ox injec-tion to evaluate for a transition zone or other anatomic abnormal-ity, and if present underwent rectal biopsy directly without BoT ox injection. Further BoT ox injections were given if obstructive symptoms and / o r enterocolitis continued or returned to baseline a er the initial injection. An anorectal manometry was always performed before repeat BoT ox injections to ensure a nonrelax-ing IAS was still present, and to evaluate the individual ’ s baseline sphincter pressure. Colonic manometry was performed in selected patients that continued to be intractable a er BoT ox i njection.

igure 1 shows the algorithm that we have followed in the treatment of children with nonrelaxing IAS. e decision to pursue medical therapy (BoT ox) or perform a surgical procedure was made by the family of the patient a er receiving recommendations from the child ’ s gastroenterologist and surgeon. Given a concern of the child having irreversible inconti-nence a er a myectomy, some families chose to pursue multiple BoT ox injections rather than pursue a surgical option. In general, if there was a positive response following BoT ox, but the relapses between BoT ox injections occurred at intervals longer than 3 months, repeated BoT ox injections were performed. If the response was shorter than 3 months, a myectomy was suggested ( F igure 1 ).

O utcome measures S hort-term improvement a er the initial BoTox injection was de ned as an increase in bowel movement frequency, or a decrease in the frequency of other obstructive symptoms occurring within 2 weeks a er the injection. erefore this measure re ects only symptomatic improvement, independ-ently of the use of laxatives.

L ong-term clinical outcome was determined by documented symptom characterization, and laxative use at the time of the last documented follow-up visit and was categorized into four groups. P oor . N o improvement in the number of bowel movements or other obstructive symptoms as compared to baseline, or underwent a subsequent therapeutic surgery, or hospitaliza-

Normal or high IAS pressure

BoTox

Response

Surgery

Redo pull through in HD ACE

Segmental resection

Colostomy

Ileostomy

Relapse

Repeat anorectal manometry Response

Colonic manometry and other motility studies. Expand differential

diagnosis

Repeat BoTox

Normal or high IAS pressure

Yes

Nonrelaxing IAS

Yes In postoperative HD,

exclude anatomic problems and/or

persistent aganglionosis

Close follow-up

Yes

Consider myectomy

Yes

Dysmotility

F igure 1 .

A lgorithm for the evaluation and treatment of children with nonrelaxing internal anal sphincter (IAS). ACE, antegrade colonic enemas; HD, Hirschsprung’s disease.

979

P E D I A T R I C S C hildren With Nonrelaxing Internal Anal Sphincter tion for obstructive symptoms and / o r an enterocolitis episode

within 3 months of the last documented follow-up. F air .

I mprovement in the number of bowel movements or other obstructive symptoms as compared to baseline but with retentive fecal incontinence episodes greater than once a week, or consist-ent rectal therapy (e.g. enema, suppository, irrigation) usage. G ood . I mprovement in the number of bowel movements or other obstructive symptoms as compared to baseline with continued usage of laxatives. E xcellent .

I mprovement in the number of bowel movements or other obstructive symptoms as compared to baseline with-out the need for laxatives.

F or analysis purposes excellent and good long-term outcomes were classi ed as being favorable.

H ospitalization rates per year for enterocolitis or to manage obstructive symptoms (e.g. constipation cleanout) were obtained before and a er the initial BoT ox injection. Duration of BoT ox e cacy was determined based on the time interval between initial injection of BoT ox and one of the following: return to baseline symptoms, hospitalization for obstructive symptoms and / o r enterocolitis, surgical procedure for obstructive symptoms, documented clinical decision to proceed with another BoT ox injection, or time interval from injection to last documented follow-up visit. Fecal incontinence was determined to be a complication of the BoT ox injection if new fecal soiling developed during the rst week a er injection, or if there was an increase by at least one in the number of fecal accidents per day as compared to baseline.

S tatistics D ata are reported as mean ± s tandard error of the mean. Com-parisons between children with surgically repaired HD and those

with IAS achalasia were performed with 2 -analysis when com-paring proportions or independent Student ’ s t -tests. Comparisons between baseline and short and long-term results were performed

with 2

-analysis when comparing proportions or paired t -test analysis. Binary multivariate stepwise logistic regression was completed with favorable and unfavorable long-term outcomes being the dependent variable. 2 -Analysis was used to compare proportions in all other testing performed. Maximum resting sphincter pressure, age at the time of the rst BoTox, and age at the time of the last follow-up were categorized into three evenly distributed groups for regression analysis. A P value of < 0.05 was considered as statistically signi cant. Survival analysis was used to determine time to failure within each group. Log-rank test was used to compare the time to failure between groups. All statistical analyses were performed using SPSS (version 15.0).

R ESULTS

B aseline characteristics A

total of 73 children (30 with HD, and 43 with IAS achalasia) were included. eir main characteristics are shown in T able 1 .

nitial corrective operations in children with HD included 16 (53.3 % ) Soave, 9 (30 % ) Duhamel, 4 (13.3 % ) Swenson, and 1 (3.3 % ) unknown pull-through performed at an outside institu-tion. e extent of the original aganglionosis included 19 (63.3 % ) with short segment (rectum to sigmoid colon) involvement, 7 (23.3 % ) with long segment involvement (rectum to descending, transverse or ascending colon), and 4 (13.3 % ) with total colonic involvement with or without small bowel involvement.

A lthough similarities such as age at time of initial pres-entation were found in children with HD and IAS achalasia, the two groups di ered with respect to gender distribution, anal sphincter resting pressure at the time of initial BoTox injection, enterocolitis episodes, and baseline usage of rectal therapies ( T able 1 ). A total of 4 children in the entire group had Down ’ s syndrome, with 3 of these children having HD.

S hort-term results A

n initial clinical improvement in bowel movement frequency and a decrease in obstructive symptoms within 2 weeks a er the rst injection was seen in 65 of 73 (89 % ) of all patients. is included 27 of 30 (90 % ) of those with surgically repaired HD and 38 of 43 (88.3 % ) of those with IAS achalasia. Of 30 children who required rectal therapies (e.g. enemas, irrigations, suppositories) before an initial BoT ox injection, only 13 (7 with HD, and 6 with IAS achala-sia) children continued to use rectal therapies within 2 weeks a er the initial BoT ox injection ( P < 0.01) ( F igure 2 ). In those who clini-cally responded to the initial BoT ox injection, the mean duration of improvement was 7.8 ± 1.5 months (9.9 ± 3.1 months with HD, and 6.3 ± 1.3 months with IAS achalasia, NS). e original extent of the aganglionosis in those with sur-gically repaired HD did not determine initial

improvement

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P E D I A T R I C S C humpitazi e t al .

ge, sex, type of surgical correction, or length of the initial aganglionosis did not predict long-term outcome.

H ospitalizations A total of 40 (54.8 % ) children with nonrelaxing IAS had been hospi-talized for obstructive symptoms and / o r entero c olitis before BoT ox therapy. e hospitalization rate decreased from 1.9 ± 0.4 hospi-talizations per year to 0.5 ± 0.8 hospitalizations per year ( P < 0.01). is decrease occurred in those previously hospitalized with pri-marily obstructive symptoms (e.g. constipation) with a decrease from 1.6 ± 0.6 hospitalizations per year to 0.2 ± 0.1 hospitalizations

( P = 0.38) with 16 of 19 short segment, 7 of 7 long segment, and

4 of 4 total colonic having an initial improvement.

L ong-term results e mean follow-up period a er the initial BoTox injec-tion was 32.1 ± 2.9 months in all patients. Children with HD (41.2 ± 4.9 months) were followed for longer than those with IAS achalasia (25.9 ± 3.1 months), P < 0.05. A mean of 2.7 ± 0.2 injections was given per child, with 56 (76.7 % ) children receiv-ing multiple injections (range 1 – 8 injections). A total of 39 (53.4 % ) children had a favorable (excellent or good) clinical long-term outcome ( F igures 3 and 4 ) at the time of their last follow-up. ese favorable outcomes were main-tained for 17.1 ± 3.1 months a er the last injection. Of 43, 28 (65.1 % ) children with IAS achalasia had an excellent or good long-term clinical outcome as compared with 11 of 30 (36.7) to those with HD ( P < 0.05). In the group of IASA the mean time to failure was 45.7 ± 6.1 weeks, and in the Hirschsprung ’ s group it was.33.8 ± 5.3 weeks ( P < 0.08) ( F igure 5 ).

P redictors of long-term response O

nly improvement to the initial BoTox injection predicted a suc-cessful long-term outcome. Overall, 38 of 65 (58.5 % ) children that improved a er the initial injection had a favorable long-term outcome even if they required more than one injection ( F igure 4 ). Only 13 (7 IASA and 6 HD) children had a favorable long-term outcome following a single successful BoTox injection ( F igure 4 ) (mean follow-up 23.2 ± 6.4 months). Having a short-term improvement predicted a favorable long-term outcome only in those with IAS achalasia in which 28 of 38 (73.6 % ) with initial improvement, improved ( P < 0.01) as compared with 10 of 27 (37.0 % ) of those with HD that had initial improvement. E ight children did not have a short-term clinical improvement a er the initial BoTox injection ( F igure 4 ). Only 1 (7.1 % ) of these 14 children had a favorable long-term clinical outcome.

510152025

N u m b e r o f p a t i e n t s

IASA

All

F igure 2 .

R ectal therapies (enemas, irrigations, or suppositories) before initial BoTox therapy and after initial BoTox therapy categorized in all patients, those with Hirschsprung ’ s disease (HD), and those with internal anal sphincter achalasia (IASA).

Good Fair Poor

P e r c e n

F igure 3 .

D istribution of long-term clinical outcomes by percentage into excellent, good, fair, and poor clinical long-term outcome categories in all 73 patients, and by Hirschsprung ’ s disease (HD) or internal anal sphincter achalasia (IASA). Ex, excellent.

Initial BoTox

injection (n =73)

Did not improve (n =8)

Improved

(n =65)

Multiple injections (n =6)

Multiple injections (n =50)

Single injection only (n =15)

Single injection only (n =2)

Excellent /good

(n =25)

Fair/poor (n =25)Excellent/good

(n =13)

Fair (n =2)

Fair/poor (n =6)Fair/poor (n =1)

Good (n =1)

F igure 4 .

F low diagram delineating initial short-term outcome and subsequent long-term clinical outcome based on having received only an initial BoTox injection or multiple injections.

981

P E D I A T R I C S C hildren With Nonrelaxing Internal Anal Sphincter per year ( P < 0.05). ose who had previously been hospitalized for

enterocolitis ( n = 13) had a decrease from 2.3 ± 0.6 hospitalizations per year to 1.0 ± 0.3 hospitalizations per year ( P = 0.06).

C omplications F ecal incontinence occurred in 7 of 73 (9.5 % ) following BoTox therapy. e average baseline anal sphincter baseline

pressure in these seven was 100.5 ± 21.6 m m H g, and was not

signi cantly di erent than the 86.4 ± 2.0 m m H g observed in those without incontinence. e duration of incontinence lasted for less than 3 days in 6 of the 7 children with this com-plication. One child (baseline maximal anal resting pressure of 40 m m H g) had fecal incontinence lasting 4 weeks. Incon-tinence was evenly distributed between both groups occurring in 3 with HD, and 4 with IAS achalasia. Of the 3 with HD, none had short-segment original aganglionosis (1 long segment and 2 total colonic). Transient rectal pain a er waking from gen-eral anesthesia occurred in one patient with IASA. S ubsequent evaluations and surgical procedures

N ine children that did not respond to BoTox underwent colonic manometry evaluations (two with HD and seven with

IASA). All 9 were abnormal, with 5 demonstrating a complete lack of high amplitude propagating contractions and general-ized neuropathy, and 4 having only high amplitude propagat-ing contractions in the proximal colon, with absent activity in the le side of the colon.

A total of 21 children (12 HD, 9 IASA) underwent 28 thera-peutic surgical procedures during the follow-up period. Some children underwent multiple surgical procedures ( T able 2 ). Children with HD (12 of 30) trended toward being more likely than those with IAS achalasia (9 of 43) to undergo a subsequent surgical procedure ( P = 0.11). A total of 10 children underwent a subsequent myectomy. In seven, the myectomy was performed when symptoms recurred following a successful initial response to BoTox. ree of these seven remained asymptomatic without any further procedures. Four became symptomatic again: one responded to a sub-sequent BoTox injection, and three went on to have a surgical appendicostomy for the administration of antegrade colonic enemas (ACE procedure).

None of the three children undergoing myectomy following a lack of initial improvement with BoTox showed improvement a er the myectomy. ey all had abnormal colonic motility. All three underwent further surgical procedures. ese included one repeat myectomy, one ileostomy, and one ACE procedure. P redicting long-term clinical outcome

W ith the use of multivariate regression, having IAS achalasia ( P = 0.01), and demonstrating short-term improvement a er an initial BoTox injection (P ≤ 0.05) predicted a favorable long-term outcome. Factors which did not predict long-term outcome included gender, baseline maximal anal sphincter pressure, age of rst BoTox injection, previous hospitalization, rectal therapy usage, developmental delay, having enterocolitis as a symptom, and age at last follow-up. In children with HD, the extent of the

original aganglionosis, and the type of original surgical proce-dure did not signi cantly predict favorable vs. unfavorable long-term clinical outcome in the regression model. Colonic motility was performed in selected intractable patients, and there was a trend for colonic dysmotility ( P = 0.064) to predict an unfavo-rable long-term result. However, we do not have information regarding colonic motility in patients with a favorable outcome. D ISCUSSION is study is the rst to evaluate both the short and long-term outcome of anal sphincter BoTox therapy in a large number of children with nonrelaxing IAS. We found that BoTox was e ec-tive, as it was associated with an improvement in short and long-term gastrointestinal obstructive symptoms and / o r enterocolitis episodes, a short-term decrease in the need for rectal therapies, and a signi cant decrease in hospitalization rates for those

C u m u l a t i v e p r o b a b l i t y o f s u c c e s s

1.0

0.8

0.6

0.4

0.2

0.0

P <0.08

IAS achalasia

Hirschsprung’s

Time to failure (months)

F igure 5 .

T ime to failure in children with internal anal sphincter achalasia (IASA) and children with Hirschsprung ’ s disease. In the group with IASA the mean time to failure was 45.7 ± 6.1 weeks, and in the Hirschsprung ’ s group it was 33.8 ± 5.3 weeks ( P <

0.08).

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P E D I A T R I C S C humpitazi e t al .

disease. Explanations for this di erence may include having more children with surgically repaired HD in our analysis, and di erences in regard to the types of corrective surgery and extent of the original aganglionosis in our population. Nonetheless, these results imply that BoTox may have equal e cacy in chil-dren who originally had short or long-segment aganglionosis.

F inding that the initial short-term response to the anal sphincter BoTox injection, particularly in those with IAS acha-lasia, predicts long-term clinical outcome is not surprising as one would not expect those who did not initially respond to do well in long term. is nding is supported by the lack of a favo-rable long-term outcome seen in those children who received multiple BoTox injections despite not improving a er the rst injection. is may be due in part to the obstructive symptoms and / o r enterocolitis episodes not being solely related to the nonrelaxing IAS. Other factors that cannot be addressed with anal sphincter BoTox alone such as generalized colonic dysmo-tility (as was seen in intractable patients) may have played a role, leading to a need for further interventions. e need to consider more di use dysmotility is supported by the abnormal colonic manometry evaluations found in all 9 children tested with intractable symptoms following BoTox therapy. e application of BoTox was safe, and there were no major complications. Overall 10.8 % had minor complications, with the most common one being fecal incontinence, which was of short duration and easy to manage in most patients. All fecal incontinence events resolved within 4 weeks, comparing favo-rably to the long-term incontinence, which may result from anal sphincter myectomy (13,14) . We found that transient inconti-nence was more common in children with HD who originally had long segment involvement. One child with long segment HD experienced more prolonged fecal incontinence, and in that case the anal sphincter pressure was low. No other patient reviewed had an anal sphincter pressure less than 50 m m H g.

I t has been suggested that anal sphincter BoTox therapy may be used as a diagnostic tool to predict which patients will respond to a successful subsequent anal sphincter myectomy (3) . is is only partially supported by the results of this study. All children who did not improve a er an initial BoTox and subsequently under-went a myectomy continued to require further surgical interven-tions, suggesting that a lack of response to BoTox predicts failure of myectomy. However, of those who improved with BoTox and subsequently underwent myectomy, the majority 4 of 7 (57 % ) also continued to require further interventions, indicating that an initial response to BoTox does not ensure long-term response a er a myectomy. Prospective studies to address the relationship between BoTox response and myectomy outcome are needed. e primary weakness of this study is that it is retrospective. As such, follow-up intervals and the number of BoTox injec-tions given were not standardized. Factors such as concomi-tant laxative usage, dietary modi cations, behavioral changes or interventions, or other medical therapies such as outpatient antibiotic regimens were not accounted for. e threshold for seeking evaluation a er BoTox therapy may have varied in the studied population. Symptom improvement was subjective and

who had been previously hospitalized. We also found that it was safe, with ~ 11 % having transient, minor complications. A total of 89 % of the patients had an initial clinical improve-ment. is short-term success following BoTox injection was comparable between those with IAS achalasia and those with HD. e relatively high initial success corroborates the ndings seen in previous smaller studies with an initial improvement in 18 of 29 (90 % ) (5) of those with IAS achalasia, 14 of 18 (77.7 % ) (22) with HD a er corrective surgery, and 22 of 24 (91.7 % ) (24) of those with IAS dysfunction. I n comparison, only 53 % had a favorable long-term clinical outcome. is decrease in long-term as compared to short-term e cacy has been described in other gastrointestinal conditions such as esophageal achalasia (26) in which BoTox therapy has been used. Recognizing that BoTox provides a transient direct e ect estimated to last only for 3 – 4 months (19) , the sustained long-term response found in some children suggests that mech-anisms beyond a transient decrease in anal sphincter pressure are likely playing a role. It has been suggested (5) that second-ary anatomic changes such as decreased rectosigmoid dilation may improve function. Other mechanisms may involve perma-nent or more long-lasting unknown alterations in IAS function with BoTox usage, interval development and maturity of def-ecation dynamics that may be facilitated by easier evacuation a er therapy, development of better behavioral coping methods or strategies to address functional contributions, or intermittent waxing and waning of symptoms. Given the chronic nature of the symptoms in children with a nonrelaxing IAS, and that the improvements occurred only a er BoTox injection in otherwise intractable patients suggests BoTox therapy played a strong role in the improvements that occurred. Future studies following functional and physiologic parameters in a prospective manner may be able to provide further insight into the mechanisms of success in those with favorable long-term clinical outcomes. e long-term response to the BoT ox varied according to the underlying diagnosis as children with IAS responded better than those with Hirschsprung ’ s . e di erences in baseline character-istics (e.g. gender distribution, sphincter pressure) and long-term clinical outcomes between those with HD and IAS achalasia sug-gests di erent underlying pathophysiologic processes between the two groups despite sharing a nonrelaxing IAS. Factors potentially in uencing unfavorable outcome in those with HD may include a less functional post-surgical neorectum (or other surgical ana-tomic changes), a higher prevalence of colonic dysmotility (27) , or persistent enteric nervous system abnormalities. Higher symptom severity before BoT ox as re ected by factors such as increased rec-tal therapy usage may also have a function. e varied long-term response may also be related to the natural history of IAS achalasia as compared to HD, as the natural history of IAS achalasia is cur-rently uncharacterized.

W e also found that in the group with HD, the initial extent of the aganglionosis was not a signi cant factor in the short-term or long-term response to BoTox. is is in contrast to the study by Minkes and Langer (22) , in which a short-term improvement was more likely in those with short-segment

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P E D I A T R I C S C hildren With Nonrelaxing Internal Anal Sphincter based on history. However, some of the nonstandardized factors

may have been ameliorated by the fact that one of the investiga-tors (SN) was involved in the care of all the patients. erefore, medical management and the interventions used tended to be uniform throughout the population studied. e results suggest that BoT ox therapy has long-term e cacy in certain children with nonrelaxing IAS. Given a high initial suc-cess rate with the possibility of long-term therapeutic bene t, a low number of transient adverse e ects, and a signi cant decrease in hospitalization rates, BoT ox may provide a safe short-term and long-term therapeutic option for children with a nonrelaxing IAS.

A CKNOWLEDGMENTS

e thank Dr William Klish, Dr Rachel Rosen, and Dr Robert Shulman for their helpful criticism and thoughtful comments. We also thank Jessica Lewis for her technical assistance.

C ONFLICT OF INTEREST

G uarantor of the article: Samuel Nurko, MD, MPH. S peci c author contributions : Conception, design, and performance of the study: Bruno P . Chumpitazi, Steven J. Fishman, and Samuel Nurko; monitoring of data

acquisition, creation of database, and data cleaning: Bruno P . Chumpitazi and Samuel Nurko; analysis and interpretation: Bruno P . Chumpitazi, Steven J. Fishman, and Samuel Nurko; critical revision of paper: Bruno P . Chumpitazi, Steven J. Fishman, and Samuel Nurko; all listed authors have seen and have approved the submitted paper. All authors take full responsibility for the content of the paper. F inancial support : None. P otential competing interests : None.

S tudy Highlights W HAT IS CURRENT KNOWLEDGE

C hildren with a nonrelaxing internal anal sphincter (IAS) may develop obstructive symptoms and / o r enterocolitis. 3

U sual treatment includes surgical myectomy which may have long-term side effects. 3

A nal sphincter C lostridium botulinum toxin (BoTox) injection is a nonsurgical approach to decrease anal sphincter pressure.

P reliminary studies show it provides short-term improvement in these children.

H owever, the long-term results of BoTox therapy in children with nonrelaxing IAS is unknown. W HAT IS NEW HERE

B oTox decreased hospitalization rates in previously hospitalized children with nonrelaxing IAS. 3

C omplications of BoTox therapy in children with nonrelaxing IAS are low.

H aving an initial improvement after BoTox and having IAS achalasia predicted a favorable long-term outcome. 3

B oTox may provide a safe, long-term therapy for children with nonrelaxing IAS.

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